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<SPAN STYLE="color:#000000;position:absolute;left:115.30pt;top:74.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 48.00pt">Guidance for FDA</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:156.00pt;top:129.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 48.00pt">Reviewers and</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:212.65pt;top:184.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 48.00pt">Sponsors</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.20pt;top:294.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 28.02pt">Content and Review of Chemistry,</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:88.60pt;top:326.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 28.02pt">Manufacturing, and Control (CMC)</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:73.05pt;top:358.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 28.02pt">Information for Human Gene Therapy</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:73.35pt;top:390.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 28.02pt">Investigational New Drug Applications</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:265.50pt;top:422.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 28.02pt">(INDs)</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:500.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Additional copies of this guidance are available from the Office of Communication, Training,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:514.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">and Manufacturers Assistance (HFM-40), 1401 Rockville Pike, Suite 200N, Rockville, MD</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:528.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">20852-1448, or by calling 1-800-835-4709 or 301-827-1800, or from the Internet at</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:542.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt"><a href="http://www.fda.gov/cber/guidelines.htm.">http://www.fda.gov/cber/guidelines.htm</a></FONT><FONT STYLE="font-size: 12.00pt">.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:570.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">For questions on the content of this guidance, contact the Office of Cellular, Tissue, and Gene</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:584.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Therapies at 301-827-5102.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:293.80pt;top:654.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">U.S. Department of Health and Human Services</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:380.30pt;top:668.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Food and Drug Administration</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:305.50pt;top:682.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Center for Biologics Evaluation and Research</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:485.65pt;top:696.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">April 2008</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:792.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:828.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:260.30pt;top:864.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Table of Contents</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:898.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">I.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:898.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">INTRODUCTION............................................................................................................. 1</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:918.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">A.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:918.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">How will FDA Reviewers and Sponsors Use this Guidance?............................ 2</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:932.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">B.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:932.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">How is this Guidance Organized? ....................................................................... 2</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:952.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">II.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:952.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">ADMINISTRATIVE INFORMATION TO BE DOCUMENTED BY FDA</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:967.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">REVIEWERS .................................................................................................................... 3</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:993.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">III.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:993.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">PRODUCT MANUFACTURING AND CHARACTERIZATION INFORMATION</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1007.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">TO BE SUBMITTED BY SPONSORS AND DOCUMENTED BY FDA</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1021.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">REVIEWERS .................................................................................................................... 4</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1041.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">A.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1041.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Product Manufacturing – Components and Materials ..................................... 4</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1055.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">1.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:1055.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Vector.......................................................................................................... 4</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1069.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">2.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:1069.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Cells ............................................................................................................ 5</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1083.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">3.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:1083.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Reagents...................................................................................................... 9</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1096.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">4.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:1096.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Excipients.................................................................................................. 12</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1110.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">5.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:1110.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Additional Considerations ........................................................................ 12</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1125.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">B.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1125.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Product Manufacturing – Procedures .............................................................. 14</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1138.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">1.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:1138.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Vector Production/Purification .................................................................. 14</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1152.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">2.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:1152.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Preparation of ex Vivo Gene-Modified Autologous or Allogeneic Cells ... 15</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1166.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">3.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:1166.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Process Timing and Intermediate Storage ................................................ 16</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1180.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">4.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:1180.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Final Formulation ..................................................................................... 16</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1201.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">IV.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1201.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">PRODUCT TESTING.................................................................................................... 16</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1221.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">A.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1221.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Microbiological Testing...................................................................................... 17</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1234.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">1.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:1234.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Sterility Testing (Bacterial and Fungal Testing) ...................................... 17</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1248.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">2.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:1248.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Mycoplasma.............................................................................................. 19</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1262.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">3.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:1262.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Adventitious Agent Testing...................................................................... 19</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1277.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">B.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1277.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Identity................................................................................................................. 22</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1291.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">C.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1291.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Purity.................................................................................................................... 22</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1305.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">1.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:1305.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Residual Contaminants ............................................................................. 22</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1318.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">2.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:1318.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Pyrogenicity/Endotoxin ............................................................................ 23</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1333.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">D.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1333.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Potency................................................................................................................. 23</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1347.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">E.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1347.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Other .................................................................................................................... 24</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1361.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">1.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:1361.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">General Safety Testing.............................................................................. 24</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1375.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">2.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:1375.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Viability .................................................................................................... 24</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1389.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">3.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:1389.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Cell Number/Dose .................................................................................... 24</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1409.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">V.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1409.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">FINAL PRODUCT RELEASE CRITERIA TESTING.............................................. 24</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1435.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">VI.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1435.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">PRODUCT STABILITY................................................................................................ 25</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1461.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">VII.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1461.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">OTHER ISSUES ............................................................................................................. 26</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1481.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">A.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1481.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Product Tracking................................................................................................ 26</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1495.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">B.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1495.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Labeling ............................................................................................................... 26</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:304.30pt;top:1534.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">i</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:1584.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:1620.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1656.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">C.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1656.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Container/Closure............................................................................................... 27</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1670.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">D.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1670.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Environmental Impact ....................................................................................... 27</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1684.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">E.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1684.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Qualification of the Manufacturing Process .................................................... 27</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1698.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">F.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1698.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Biostatistics.......................................................................................................... 28</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1718.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">VIII.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1718.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">PRECLINICAL STUDIES TO BE DOCUMENTED BY FDA REVIEWERS........ 29</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1738.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">A.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1738.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Summary of Concept Studies............................................................................. 29</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1753.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">B.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1753.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Gonadal Distribution.......................................................................................... 29</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1773.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">IX.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1773.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">CLINICAL STUDIES TO BE DOCUMENTED BY FDA REVIEWERS................ 29</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1793.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">A.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1793.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Protocol Title....................................................................................................... 29</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1807.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">B.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1807.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Subject Population.............................................................................................. 29</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1821.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">C.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1821.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Route of Administration..................................................................................... 30</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1835.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">D.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1835.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Dose ...................................................................................................................... 30</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1849.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">E.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1849.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Frequency ............................................................................................................ 30</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1863.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">F.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1863.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Genetic, Biochemical, and Immunological Testing.......................................... 30</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1877.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">G.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1877.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Informed Consent ............................................................................................... 30</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1891.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">H.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1891.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Recombinant DNA Advisory Committee (RAC) Review................................ 30</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1911.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">X.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1911.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">RECOMMENDATION TO BE DETERMINDED BY FDA REVIEWERS ............ 30</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1937.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">XI.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1937.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">COMMENTS TO SPONSOR GENERATED BY FDA REVIEWERS .................... 31</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1957.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">A.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1957.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Clinical Hold........................................................................................................ 31</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1971.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">B.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1971.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Non-Clinical Hold ............................................................................................... 31</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1991.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">XII.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1991.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">REFERENCES................................................................................................................ 32</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2017.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">APPENDIX A – PRODUCT REVIEW TEMPLATE (GENE THERAPY).......................... 35</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2043.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">APPENDIX B – CONSIDERATIONS FOR DEVELOPMENT OF FINAL PRODUCT</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2057.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">RELEASE CRITERIA SPECIFICATIONS AND STABILITY PROTOCOLS ..... 40</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2077.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">A.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:2077.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Development of Release Acceptance Criteria .................................................. 40</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2091.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">B.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:2091.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Development of Acceptance Criteria Analytical Procedures ......................... 40</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2105.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">C.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:2105.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Development of Stability Protocols ................................................................... 41</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:302.65pt;top:2326.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">ii</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:2376.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:2412.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:156.95pt;top:2448.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 16.02pt">Guidance for FDA Reviewers and Sponsors</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:87.95pt;top:2485.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 16.02pt">Content and Review of Chemistry, Manufacturing, and Control</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.40pt;top:2503.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 16.02pt">(CMC) Information for Human Gene Therapy Investigational New</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:217.80pt;top:2522.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 16.02pt">Drug Applications (INDs)</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2560.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this</FONT></FONT></i></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:2557pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:2557pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:67pt;top:2557pt;width:478pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:2557pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:2557pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:2558pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:2558pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2573.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">topic.  It does not create or confer any rights for or on any person and does not operate to bind</FONT></FONT></i></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:2573pt;width: 1pt;height:13pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:2573pt;width: 1pt;height:13pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2587.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">FDA or the public.  You can use an alternative approach if the approach satisfies the</FONT></FONT></i></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:2587pt;width: 1pt;height:13pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:2587pt;width: 1pt;height:13pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2601.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">requirements of the applicable statutes and regulations.  If you want to discuss an alternative</FONT></FONT></i></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:2601pt;width: 1pt;height:13pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:2601pt;width: 1pt;height:13pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2615.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">approach, contact the appropriate FDA staff.  If you cannot identify the appropriate FDA staff,</FONT></FONT></i></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:2615pt;width: 1pt;height:13pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:2615pt;width: 1pt;height:13pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2629.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">call the appropriate number listed on the title page of this guidance.</FONT></FONT></i></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:2643pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:2643pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:67pt;top:2643pt;width:478pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:2643pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:2643pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:2628pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:2628pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2662.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">I.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2662.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">INTRODUCTION</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2690.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">This guidance document provides to you, sponsors of a human gene therapy investigational new</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2704.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">drug application (IND), recommendations on the chemistry, manufacturing, and control (CMC)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2718.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">information to include in an original IND.  This guidance also applies to combination products</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2732.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">that contain a human gene therapy biological product in combination with a drug or device as</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2746.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">part of the final product.  Also, this guidance instructs FDA CMC reviewers about the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2760.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">information to record and assess as part of an IND review, taking into consideration the various</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2774.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">manufacturing challenges for these products.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2802.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">In order to deliver a safe and effective product, human gene therapies present many</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2816.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">manufacturing challenges.  Some of these challenges include the variability and complexity</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2830.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">inherent in the components used to generate the final product, such as the source of cells (i.e.,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2844.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">autologous or allogeneic), the potential for adventitious agent contamination, the need for aseptic</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2858.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">processing, and in the case of ex vivo genetically modified cell therapies the inability to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2872.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">“sterilize” the final product because it contains living cells.  Distribution of these products can</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2886.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">also be a challenge due to stability issues and the frequently short dating period of many ex vivo</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2900.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">genetically modified cell products, which may necessitate release of the final product for</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2914.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">administration to a patient before certain test results are available.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2942.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">This guidance finalizes the draft guidance entitled, “Guidance for FDA Review Staff and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2956.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Sponsors:  Content and Review of Chemistry, Manufacturing, and Control (CMC) Information</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2970.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">for Human Gene Therapy Investigational New Drug Applications (INDs)” dated November 2004</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2984.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(69 FR 64958; November 9, 2004).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:3012.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">FDA’s guidance documents, including this guidance, do not establish legally enforceable</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:3026.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">responsibilities.  Instead, guidances describe the FDA’s current thinking on a topic and should be</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:3040.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">viewed only as recommendations, unless specific regulatory or statutory requirements are cited.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:3054.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">The use of the word should in FDA’s guidances means that something is suggested or</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:3068.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">recommended, but not required.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:303.00pt;top:3118.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">1</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:2376.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile1414621255.htm_files\outputfile1414621255_background3.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:3168.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:3204.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3240.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">A.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3240.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">How will FDA Reviewers and Sponsors Use this Guidance?</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3268.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">FDA’s primary objectives in the review of INDs are to help ensure the safety and rights</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3282.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">of human subjects in all phases of an investigation and, in Phases 2 and 3, to help ensure</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3296.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">that the quality of the scientific evaluation of the investigational product is adequate to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3310.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">permit an evaluation of its safety and effectiveness (21 CFR 312.22(a)).  This guidance</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3324.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">will help sponsors and FDA reviewers to assess, given the phase of the investigation,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3338.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">whether sufficient information is provided to assure the proper identification (identity</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3352.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">testing), quality, purity, and strength (one aspect of potency) of the investigational</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3366.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">product (21 CFR 312.23(a)(7)(i)).  These principles apply to investigational biological</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3380.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">products and drugs; however, specific terms, such as safety, identity, purity, and potency,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3394.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">are generally understood to be applicable to biological products and are used throughout</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3408.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">this document.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3436.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">If you are a FDA reviewer, you will use this guidance as you assess the safety, identity,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3450.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">purity, and potency of an investigational product and you will use the format of the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3464.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">human gene therapy CMC review template (Appendix A) in preparing your reviews.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3478.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Because of the wide variability of the contents of IND amendments, you are only</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3492.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">expected to use the attached template during review of original IND submissions.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3506.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">However, you should consult this document for guidance throughout the investigational</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3520.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">new drug development process.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3548.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">The human gene therapies CMC review instructions and template described in this</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3562.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">guidance are tools to assist FDA in the review of human gene therapy INDs.  They are</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3576.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">designed to serve as a guide to help ensure that all applicable regulatory requirements are</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3590.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">reviewed at the appropriate stage of product development.  In addition to the CMC</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3604.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">review instructions and template, some general considerations are discussed in Appendix</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3618.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">B that should be helpful in assessing proposed release criteria testing and specifications.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3632.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Section 10.70 (21 CFR 10.70) provides further instruction to FDA reviewers regarding</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3646.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">documentation of review decisions.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3674.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">If you are a sponsor of a human gene therapy IND, you may use this guidance in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3688.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">developing an IND submission that will be adequate to permit FDA reviewers to make an</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3702.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">assessment of the safety, identity, purity, and potency of your investigational product.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3716.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Other regulatory documents that may be relevant are listed in the references (see Section</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3730.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">XII below).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3758.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">B.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3758.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">How is this Guidance Organized?</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3786.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">This guidance is organized in a format that generally corresponds to the sections in the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3799.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">CMC review template provided in Appendix A.  In each section, where necessary, we</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3813.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(FDA) provide recommendations as to the information you may submit in your original</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3827.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">IND submission.  As necessary throughout this document, we give specific instructions</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3841.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">to FDA reviewers concerning their documentation and assessment of an IND submission</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3855.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">during the CMC review.  Many of the instructions for FDA reviewers provided in this</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3869.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">guidance are distinguished by the designation “Note to FDA Reviewers.”</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:303.00pt;top:3910.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">2</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:3960.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:3996.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4060.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">II.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4060.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">ADMINISTRATIVE INFORMATION TO BE DOCUMENTED BY FDA</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4074.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">REVIEWERS</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4102.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Note to FDA Reviewers</FONT></u><FONT STYLE="font-size: 12.00pt">:  Document in your review all of the IND information listed below.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4116.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Most of this information should be available on Form FDA 1571, the sponsor’s cover letter, or</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4130.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the reviewer assignment notice from the Regulatory Project Manager (RPM) of the application</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4144.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">division.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:90.00pt;top:4171.95pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4173.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">BB-IND Number (assigned by Center for Biologics Evaluation and Research (CBER)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4187.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">after receipt);</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:90.00pt;top:4200.65pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4202.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Date of submission;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:90.00pt;top:4215.45pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4216.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">30-day review due date;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:90.00pt;top:4230.20pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4231.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Sponsor – name, address, title, phone, fax;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:90.00pt;top:4244.95pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4246.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Sponsor point of contact (sponsor’s authorized representative) – name, address, title,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4260.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">phone, fax;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:90.00pt;top:4273.70pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4275.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Title of IND;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:90.00pt;top:4288.45pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4289.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Proposed use;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:90.00pt;top:4303.20pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4304.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Product description;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:90.00pt;top:4317.95pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4319.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Phase of study;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:90.00pt;top:4332.75pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4334.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Cross-referenced INDs, investigational device exemptions (IDEs), and master files</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4348.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(MFs):  List all regulatory files (IND, IDE, MF) that the sponsor has obtained permission</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4362.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">to cross-reference in support of this file.  The file under review must contain a letter</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4376.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">signed by the person who submitted the cross-referenced file (21 CFR 312.23(b)), giving</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4390.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">FDA permission to cross-reference the file.  This letter should identify the nature of the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4404.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">information being cross-referenced (e.g., pre-clinical, product manufacturing, and/or</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4417.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">clinical) and where it is located within the file being cross-referenced.  You should verify</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4431.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">that the cross-referenced information satisfies the IND requirement for which the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4445.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">information is cited.  If the letter of cross-reference is absent or inadequate, or the cross-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4459.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">referenced information is inadequate for the purpose cited, the RPM or the reviewer</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4473.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">should notify the sponsor to obtain additional information;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:90.00pt;top:4487.30pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4488.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Key words:  Include three to four words that can be used to identify the product,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4502.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">indication, and any materials, components, or devices that may be part of the final</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4516.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">product or used in the manufacturing process.  These key words should be general</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4530.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">enough to be used in a database search;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:90.00pt;top:4544.00pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4545.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Introduction/rationale:  Summarize relevant information on the development of the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4559.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">product if the sponsor provides this information.  In addition, document and assess, as</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4573.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">appropriate, the sponsor’s scientific rationale and justification for using the product for</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4587.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the indication under review; and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:90.00pt;top:4600.70pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4602.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Study objectives.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:303.00pt;top:4702.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">3</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:4752.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:4788.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4824.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">III.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4824.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">PRODUCT MANUFACTURING AND CHARACTERIZATION INFORMATION</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4838.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">TO BE SUBMITTED BY SPONSORS AND DOCUMENTED BY FDA</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4852.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">REVIEWERS</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4880.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">As described in the following sections, you should provide a detailed description of where and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4894.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">how the gene therapy product is manufactured.  You should include all of the components and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4908.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">materials used during the manufacture of the gene therapy product, such as the vector, cells, cell</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4922.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">bank systems, and any reagents or excipients.  In addition, you should describe all procedures</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4936.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">used during the manufacturing process.  Examples of these procedures may include vector</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4950.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">derivation, purification, preparation of cell banks systems and testing, including final</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4964.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">formulation of the product.  This information will allow us to assess the identity, quality, purity,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4978.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">and potency of your product.  For further information, refer to the guidance on “Content and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4992.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5006.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Including Well-Characterized, Therapeutic, Biotechnology-Derived Products” (Ref. 1).  In</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5020.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">addition, you may refer to the other documents listed in the references (see Section XII below).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5048.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">We also encourage sponsors to use the format and headings described in Appendix A to facilitate</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5062.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">an efficient review by FDA.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5090.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Note to FDA Reviewers</FONT></u><FONT STYLE="font-size: 12.00pt">:  Document and assess product manufacturing and characterization</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5104.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">information in your IND reviews.  Organize the CMC review using the format and headings</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5118.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">described in Appendix A and below, as appropriate.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:5146.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">A.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:5146.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Product Manufacturing – Components and Materials</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:5174.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Note to FDA Reviewers</FONT></u><FONT STYLE="font-size: 12.00pt">:  Document the source of all materials and components and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:5188.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">summarize the testing performed on those materials and components, and review the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:5202.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">specific instructions and recommendations set out below.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:5230.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Your IND must include a list of all components used in manufacturing of your product</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:5244.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(21 CFR 312.23(a)(7)(iv)(b)).  The sections below detail the information on</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:5258.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">manufacturing components that we recommend you submit in an IND, and that FDA</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:5272.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">reviewers will document and assess.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:5300.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">1. Vector</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:5328.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">You should provide the following information about your vector</FONT></u><FONT STYLE="font-size: 12.00pt">:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:5356.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">a.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:5356.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Gene Therapy Vector Construct</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:5384.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">A description of the history and detailed derivation of the gene therapy vector</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:5398.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">including:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:5425.55pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5426.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">The gene map, with relevant restriction sites, and any vector constructs</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5440.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">used during generation of the final vector and their sources;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:5454.30pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5455.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">The gene insert;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:303.00pt;top:5494.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">4</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:5544.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:5580.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:5616.00pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5617.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Regulatory elements, such as promoter, enhancer, and poly-adenylation</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5631.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">signal; and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:5644.75pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5646.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Selection markers.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:5674.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">b.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:5674.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Vector  Diagram</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:5702.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">A diagram of the vector identifying the gene insert and regulatory regions, and any</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:5716.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">other relevant elements, such as pertinent restriction endonuclease sites:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:5743.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Note to FDA Reviewers</FONT></u><FONT STYLE="font-size: 12.00pt">:  Document the vector diagram by scanning it into the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:5757.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">review document.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:5785.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">c.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:5785.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Sequence  Analysis</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:5813.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Vectors 40 kilobases (kb) or less:  We recommend that you fully sequence all</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:5827.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">vectors under 40 kb, perform sequence analysis, and submit an annotated sequence</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:5841.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">of the entire vector.  You should provide a summary of the sequence analysis,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:5855.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">indicating the origin and function of each component of the vector that accounts for</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:5869.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">all nucleotides such as promoters, known coding sequences, polyadenylation</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:5883.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">signals, origins of replication and restriction sites used during construction of the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:5897.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">vector or for diagnostic tests.  You should provide an evaluation of the significance</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:5911.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">of all discrepancies between the expected sequence and the experimentally</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:5925.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">determined sequence and an evaluation of the significance of any unexpected</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:5939.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">sequence elements, including open reading frames.  We recommend viral vectors be</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:5953.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">sequenced from the master viral bank (MVB) when appropriate.  Plasmid sequence</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:5967.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">should be obtained from the master cell bank (MCB), and retroviral vector sequence</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:5981.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">should be obtained from the MVB/packaging cell line or from DNA obtained after</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:5995.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">transduction of a stable cell line.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:6023.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Vectors greater than 40 kb:  You should summarize the extent and results of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:6037.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">sequence analysis that you have performed including any testing performed by</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:6051.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">restriction endonuclease analysis.  We recommend that you perform sequence</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:6065.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">analysis of the gene insert, flanking regions, and any regions of the vector that are</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:6079.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">modified.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:6107.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">2. Cells</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:6135.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">a.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:6135.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Allogeneic and/or Autologous Cell Components</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:6163.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">You should describe the following information in your IND:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:6190.80pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6192.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Cell source:  tissue and cell type (e.g., colon, hematopoietic, neuronal, T-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6206.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">cells);</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:6219.55pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6220.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Mobilization protocol:  document whether or not donor cells are mobilized</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6234.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">or activated in vivo in the donor;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:303.00pt;top:6286.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">5</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:5544.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile1414621255.htm_files\outputfile1414621255_background7.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:6336.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:6372.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:6408.00pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6409.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Collection or recovery method:  state the procedure used to obtain cells</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6423.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(e.g., surgery or leukapheresis indicating the device used if possible), the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6437.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">name and location of the collection facility, and transport conditions if</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6451.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">shipped to a processing facility for further manufacturing; and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:6464.70pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6466.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Donor screening and testing:  the donor screening and testing that is</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6480.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">performed to determine donor eligibility.  Requirements for screening and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6494.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">testing donors of human cells and tissues are described in 21 CFR Part</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6508.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">1271 (see final rule, “Eligibility Determination for Donors of Human</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6522.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Cells, Tissues and Cellular and Tissue-Based Products (HCT/Ps)”) (Ref.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6535.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">2).  When appropriate, you should document the donor safety testing that</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6549.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">is performed.  In addition, FDA has published a final “Guidance for</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6563.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Industry:  Eligibility Determination for Donors of Human Cells, Tissues,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6577.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">and Cellular and Tissue-Based Products (HCT/Ps)” (Ref. 3).  We</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6591.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">recommend that you review this guidance to ensure that the donor</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6605.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">qualification criteria described in your IND are consistent with current</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6619.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">recommendations.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:6647.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">1) Autologous</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.30pt;top:6675.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">You are not required to make a donor eligibility determination or to perform</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.30pt;top:6689.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">donor screening for cells and tissues for autologous use (21 CFR</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.30pt;top:6703.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">1271.90(a)(1)).  However, you should determine whether your manufacturing</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.30pt;top:6717.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">procedures increase the risk of propagation of pathogenic agents that may be</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.30pt;top:6731.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">present in the donor.  If so, you should document whether the donor is</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.30pt;top:6745.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">reactive for specific pathogens.  Also, you should describe precautions to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.30pt;top:6759.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">prevent the spread of viruses or other adventitious agents to persons other</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.30pt;top:6773.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">than the autologous recipient (see Ref. 2).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:6801.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">2) Allogeneic</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.30pt;top:6829.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">You must perform donor screening and testing as required in 21 CFR Part</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.30pt;top:6843.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">1271 for all allogeneic cells or tissues except those that meet the exceptions</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.30pt;top:6857.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">in 21 CFR 1271.90(a).  Donors of all types of cells and tissues must be</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.30pt;top:6871.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">screened and tested for HIV-1, HIV-2, hepatitis B virus (HBV, surface and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.30pt;top:6885.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">core antigen), hepatitis C virus (HCV), Treponema pallidum (syphilis), and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.30pt;top:6899.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">CJD (screening only).  Donors of viable leukocyte-rich cells or tissues should</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.30pt;top:6913.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">be screened and tested for human T-lymphotropic virus types 1 and 2</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.30pt;top:6927.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(HTLV-1, HTLV-2) and CMV.  In addition, you should document whether</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.30pt;top:6941.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">FDA-licensed, cleared, or approved test kits are used in these detection</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.30pt;top:6955.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">assays and document which tests are used.  Include a description of the type</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.30pt;top:6969.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">of serological, diagnostic, and clinical history data obtained from the donor.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.30pt;top:6983.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">You should consider other issues such as typing for polymorphisms and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:303.00pt;top:7078.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">6</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:7128.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:7164.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.30pt;top:7200.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">human leukocyte antigen (HLA) matching, where appropriate.  If cord blood</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.30pt;top:7214.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">or other maternally derived tissue is used, you should describe testing and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.30pt;top:7228.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">screening performed on birth mothers.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7256.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Note to FDA Reviewers</FONT></u><FONT STYLE="font-size: 12.00pt">:  Communicate with the clinical reviewer regarding any</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7270.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">issues or concerns relating to the screening or testing of the donor cells.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7298.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">b.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:7298.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Cell Bank System</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7326.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">You should describe pertinent information, as described in Sections 1) through 3)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7340.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">below, relating to the cell bank system (i.e., master cell bank (MCB), and working</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7354.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">cell bank (WCB)) used in product manufacture.  In addition, you should describe</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7368.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the history, source, derivation, characterization of each cell bank (both MCB and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7382.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">WCB), and the frequency at which testing is performed.  For further information,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7396.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">refer to the document on “Points to Consider in the Characterization of Cell Lines</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7410.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Used to Produce Biologicals” (Ref. 4).  See also ICH document Q5D, “Derivation</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7424.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">and Characterization of Cell Substrates Used for Production of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7438.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Biotechnological/Biological Products” (Ref. 5), and, where applicable, “Guidance</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7452.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">for Industry:  Source Animal, Product, Preclinical, and Clinical Issues Concerning</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7466.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the Use of Xenotransplantation Products in Humans” (Ref. 6) and the “PHS</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7480.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Guideline on Infectious Disease Issues in Xenotransplantation” (Ref. 7).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:492.30pt;top:7478.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">1</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7508.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Note to FDA Reviewers</FONT></u><FONT STYLE="font-size: 12.00pt">:  Document and assess the testing that is performed on</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7522.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">each cell bank.  Determine if the most relevant and critical testing for the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7536.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">particular gene therapy product has been performed.  Appropriate tests should be</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7550.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">performed depending on the species of origin used to derive the cell bank.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:7578.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">1)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:7578.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Master Cell Bank (MCB)/Packaging Cell Line</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:404.45pt;top:7576.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">2</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.50pt;top:7606.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">You should include in the IND information regarding MCB history, source,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.50pt;top:7620.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">derivation and characterization, including testing to adequately establish the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.50pt;top:7633.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">safety, identity, purity, and stability of the cells.  This section will likely</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.50pt;top:7647.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">address:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:7675.35pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:7676.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Product microbiologic characteristics, including sterility, mycoplasma, in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:7690.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">vivo and in vitro testing for adventitious viral agents, as appropriate (see</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:7704.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Section IV below);</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:7718.05pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:7719.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Freedom from the presence of specific pathogens, including, for human</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:72pt;top:7755pt;width:144pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:7762.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 6.48pt">1</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:77.75pt;top:7764.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">If a feeder cell line of animal origin is used to propagate human cells (i.e., human and non-human animal cells are</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:7776.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">co-cultivated), the final product falls within the definition of a xenotransplantation product (see both Refs. 9 and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:7787.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">10).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:7798.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 6.48pt">2</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:77.75pt;top:7799.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">If an ecotropic cell line was used during the generation of a retroviral producer cell line, we recommend that</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:7811.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">sponsors test for ecotropic retrovirus (see “Product testing”). Reviewers would assess and document the testing that</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:7822.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">was performed.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:303.00pt;top:7870.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">7</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:7128.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile1414621255.htm_files\outputfile1414621255_background9.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:7920.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:7956.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:7992.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">cells, testing for CMV, HIV-1 & 2, HTLV-1 & 2, EBV, B19, HBV, and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8006.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">HCV, as appropriate.  For cell lines that are exposed to bovine or porcine</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8020.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">components (e.g., serum, serum components, trypsin), appropriate testing</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8034.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">would include testing for bovine and/or porcine adventitious agents.  See</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8048.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">further discussion of bovine components and reagents in Section III.A.2.a;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:8061.90pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8063.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Identity of the cells, including tests to distinguish the specified cells</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8077.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">through physical or chemical characteristics of the cell line (i.e.,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8091.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">phenotype, genotype, or other markers);</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:8104.65pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8106.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Purity of banked cells, including identification and quantification of any</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8119.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">contaminating cells;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:8133.35pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8134.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Testing for activity of cells (e.g., activated lymphocytes, dopamine</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8148.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">secretion, insulin secretion) and cell maturation (e.g., dendritic cells).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8162.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">This should be performed if activity is relevant to the therapeutic nature of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8176.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the product;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:8190.05pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8191.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">End of production cells (EOP).  This should be tested on a one time basis</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8205.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">to assess genetic stability of the MCB/packaging cell line; and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:8218.80pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8220.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Processes critical to product safety, as applicable, including:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:198.00pt;top:8234.85pt;z-index:3;"><FONT FACE ="Courier New" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">o</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:8234.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Culture conditions used, including documentation of all media, and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:8248.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">reagents/components used during production, with copies of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:8262.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">relevant certificates of analysis (COA);</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:198.00pt;top:8276.80pt;z-index:3;"><FONT FACE ="Courier New" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">o</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:8276.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Method of introduction of vector (transfection, transduction,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:8290.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">infection) into MCB/parental cells to establish vector producer</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:8304.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">cell;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:198.00pt;top:8318.70pt;z-index:3;"><FONT FACE ="Courier New" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">o</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:8318.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Analysis and selection of producer cell clone; and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:198.00pt;top:8332.70pt;z-index:3;"><FONT FACE ="Courier New" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">o</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:8332.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Cryopreservation, storage, and recovery of the MCB, including</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:8346.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">information pertaining to cell density, number of vials frozen,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:8359.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">storage temperature, and cell bank location; and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:198.00pt;top:8374.65pt;z-index:3;"><FONT FACE ="Courier New" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">o</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:8373.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Genetic and phenotypic stability of the MCB after multiple</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:8387.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">passages as well as viability of cells after cryopreservation.  We</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:8401.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">recommend that, while the IND is in effect, you perform a stability</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:8415.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">assessment EOP as a one-time test.  This testing is usually</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:8429.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">performed later in product development and would be included as</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:8443.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">part of the biologics license application (BLA).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:8471.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">2)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8471.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Master Viral Bank (MVB)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:8499.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">You should provide a description of the MVB and the testing that you have</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:8513.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">performed to ensure safety, purity, and identity.  We recommend that you</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:8527.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">address:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:8555.10pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8556.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">History and derivation of the MVB;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:8569.85pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8571.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Culture conditions used during tissue culture scale up;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:8584.65pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8586.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Testing of media and other reagents used during production, including</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8599.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">COAs;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:303.00pt;top:8662.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">8</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:8712.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:8748.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:8784.00pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8785.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Product microbiologic characterization – including sterility, mycoplasma,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8799.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">in vivo and in vitro testing for adventitious viral agents, as appropriate;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:8812.75pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8814.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Freedom from the presence of specific pathogens, such as human viruses</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8828.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">if the cell line is of human origin, or pathogens specific to the origin of the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8842.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">production cell line (e.g., murine, non-human primate,;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:8855.45pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8856.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Tests to identify presence of replication competent virus;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:8870.25pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8871.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Identity testing to establish the presence of gene therapy vector and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8885.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">therapeutic transgene (e.g., Southern blot); and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:8898.95pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8900.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Information pertaining to the cryopreservation of the MVB, including</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8914.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">condition and storage location(s).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:8942.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">3)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8942.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Working Cell Bank (WCB)/Working Viral Bank (WVB)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.30pt;top:8970.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">The WCB/WVB may have been derived from one or more vials of the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.30pt;top:8984.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">MCB/MVB.  As discussed in the guidance documents referenced in III.A2a,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.30pt;top:8998.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the amount of information needed to document characterization of the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.30pt;top:9012.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">WCB/WVB (derived from the MCB, and MVB, respectively) is usually less</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.30pt;top:9026.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">extensive than that needed to document characterization of the MCB/MVB.  If</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.30pt;top:9040.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">there is a two tiered cell bank system in place (MCB, MVB), we recommend</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:166.30pt;top:9054.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">that you test the WCB/WVB for:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:9081.55pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9082.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">In vitro adventitious viral agent testing;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:9096.30pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9097.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Replication competent virus;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:9111.05pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9112.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Bacterial and fungal sterility;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:9125.85pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9127.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Mycoplasma; and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:9140.60pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9141.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Limited identity testing (e.g., Southern blot, flow cytometry).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:9169.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">3. Reagents</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:9197.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">You must list in your IND any reagents used in manufacturing the product (21 CFR</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:9211.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">312.23(a)(7)(iv)(b)).  For the purpose of this guidance, reagents are those materials</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:9225.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">that are used for cellular growth, differentiation, selection, purification, or other</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:9239.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">critical manufacturing steps but are not intended to be part of the final product.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:9253.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Examples include fetal bovine serum, trypsin, digestion enzymes (e.g., collagenase,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:9267.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">DNAse) growth factors, cytokines, monoclonal antibodies, antibiotics, cell</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:9281.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">separation devices, and media and media components.  These reagents can affect the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:9295.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">safety, potency, and purity of the final product, especially by introducing</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:9309.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">adventitious agents.  For monoclonal antibodies, refer to the guidance on “Points to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:9323.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Consider in the Manufacture and Testing of Monoclonal Antibody Products for</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:9337.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Human Use” (Ref. 8) for further information.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:9365.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">a.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:9365.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Tabulation of Reagents Used in Manufacture</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:9393.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">We recommend that you provide the following information on all reagents used</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:9407.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">during product manufacturing:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:303.00pt;top:9454.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">9</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:8712.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile1414621255.htm_files\outputfile1414621255_background11.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:9504.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:9540.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:9590.00pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9591.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">concentration of the reagent at the manufacturing step at which it is used;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:9604.75pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9606.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">vendor/supplier;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:9619.50pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9620.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">source:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:198.00pt;top:9635.55pt;z-index:3;"><FONT FACE ="Courier New" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">o</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:9634.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">human:  If human albumin is used, you should have procedures in</FONT></FONT></i></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:9648.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">place to ensure that no recalled lots were used during manufacture</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:9662.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">or preparation of the product.  If using human AB serum, ensure</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:9676.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">serum is obtained from an approved blood bank and meets all</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:9690.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">blood donor criteria.  For all other reagents that are human derived</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:9704.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">you should identify whether it is a licensed product, or clinical or</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:9718.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">research grade, and provide a COA or information regarding</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:9732.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">testing of the donor and/or reagent.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:198.00pt;top:9747.40pt;z-index:3;"><FONT FACE ="Courier New" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">o</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:9746.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">porcine:  If porcine products are used, a COA or other</FONT></FONT></i></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:9760.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">documentation that the products are free of porcine parvovirus.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:198.00pt;top:9775.35pt;z-index:3;"><FONT FACE ="Courier New" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">o</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:9774.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">bovine:  If a reagent is derived from bovine material, you should</FONT></FONT></i></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:9788.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">identify the bovine material, the source of the material, information</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:9802.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">on the location where the herd was born, raised, and slaughtered,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:9816.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">and any other information relevant to the likelihood that the animal</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:9830.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">may have ingested animal feed prohibited under 21 CFR 589.2000.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:9844.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">It may be that bovine material is introduced at different points in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:9858.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">production of a reagent; the information described above should be</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:9872.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">provided for all bovine materials used.  For more information see,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:9886.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">“Proposed Rule: Use of Materials Derived from Cattle in Medical</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:9900.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Products Intended for Use in Humans and Drugs Intended for Use</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:9914.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">in Ruminants,” (72 FR 1581; January 12, 2007); found at</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:9928.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt"><a href="http://www.fda.gov/cber/rules/catruminant.htm.">http://www.fda.gov/cber/rules/catruminant.htm</a></FONT><FONT STYLE="font-size: 12.00pt">. In addition, you</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:9942.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">should provide a COA to document that bovine materials are</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:9956.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">compliant with the requirements for the ingredients of animal</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:9970.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">origin used for production of biologics described in 9 CFR 113.53.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:9998.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Note to FDA Reviewers: </FONT></u><FONT STYLE="font-size: 12.00pt">For all animal derived products, enter the following</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10012.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">information in the animal components database:  source organism,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10026.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">supplier/vendor, country of origin, and stage of manufacture.  Additionally, the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10040.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">information provided on bovine materials should be evaluated to determine</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10054.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">whether, for informed consent that is adequate under 21 CFR Part 50, the subject</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10068.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">should be informed of the potential risk that TSE agents have been introduced</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10082.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">into the final product.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:10109.60pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10110.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Reagent quality:  We recommend that you use FDA-approved or cleared,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10124.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">or clinical grade reagents whenever they are available.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10152.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Note to FDA Reviewers</FONT></u><FONT STYLE="font-size: 12.00pt">:  If the reagent is regulated as a biological product, drug,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10166.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">or device, consider whether a consultative review should be obtained.  See</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10180.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Section III.A.5.b below for further information about consultative review process.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:10246.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">10</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:9504.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile1414621255.htm_files\outputfile1414621255_background12.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:10296.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:10332.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:10368.00pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10369.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">COA or cross-reference letters:  If you are using a research grade (not</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10383.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">FDA-approved or cleared) reagent as part of the manufacturing process,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10397.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">we recommend that you provide information verifying the source, safety,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10411.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">and performance of the reagent.  If the vendor of the reagent has a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10425.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">regulatory file with the FDA, a cross-reference letter from the sponsor</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10439.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">may be provided in the IND.  If a COA from the reagent manufacturer is</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10453.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">used, you may assess whether the testing performed is adequate (see</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10467.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">“Qualification Program” below) and provide that information in the IND.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10495.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Note to FDA Reviewers</FONT></u><FONT STYLE="font-size: 12.00pt">:  For letters of cross-reference, include the regulatory file</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10509.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">number and consider the need for a consultative review to determine whether</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10523.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">there are any safety concerns or other outstanding issues.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10551.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">b. Qualification Program</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10579.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">If the reagent is not FDA-approved or cleared, additional testing may be needed</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10593.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">to ensure the safety and quality of the reagent.  We recommend that you establish</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10607.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">a qualification program that includes safety testing (sterility, endotoxin,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10621.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">mycoplasma, and adventitious agents), functional analysis, purity testing, and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10635.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">assays (e.g., residual solvent testing) to demonstrate absence of potentially</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10648.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">harmful substances.  The extent of testing will depend on how the specific reagent</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10662.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">is used in the manufacturing process.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10690.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">c.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:10690.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Determination of Removal of Reagents from Final Product</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10718.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">You should test the final product for residual manufacturing reagents with known</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10732.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">or potential toxicities and describe the test procedures you use to detect residual</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10746.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">levels of these reagents in the final product.  We recommend that you determine</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10760.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">whether a qualification study is sufficient to document their removal, or whether</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10774.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">lot release testing is appropriate prior to initiation of clinical trials.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10802.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">d. Other Concerns</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10830.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Because some patients may be sensitive to penicillin, we recommend that you do</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10844.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">not use beta-lactam antibiotics during the manufacturing of a therapeutic product</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10858.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">for humans.  If beta-lactam antibiotics are used, we recommend that you provide a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10872.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">rationale for their use and describe precautions to prevent hypersensitivity</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10886.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">reactions.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10914.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Note to FDA Reviewers</FONT></u><FONT STYLE="font-size: 12.00pt">:  If beta-lactam antibiotics are used during</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10928.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">manufacturing, consult with the clinical reviewer concerning appropriate</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10942.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">exclusion criteria for the study and proper informed consent to address potential</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10956.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">patient sensitivity.  Discuss with the sponsor the rationale for using beta-lactam</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10970.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">antibiotics and whether an alternative to beta-lactam antibiotics can be used as an</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10984.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">appropriate substitute.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:11038.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">11</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:10296.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile1414621255.htm_files\outputfile1414621255_background13.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:11088.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:11124.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:11160.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">4. Excipients</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:127.45pt;top:11188.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">For the purpose of this guidance, an excipient is any component that is intended to be</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:127.45pt;top:11202.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">part of the final product, such as human serum albumin or Dimethyl Sulfoxide</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:127.45pt;top:11216.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(DMSO).  You must list in your IND all excipients used during manufacture of the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:127.45pt;top:11230.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">product that are intended to be present in the final product (21 CFR</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:127.45pt;top:11244.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">312.23(a)(7)(iv)(b)).  You should include the concentration and source of the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:127.45pt;top:11258.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">excipients.  Also, you must provide information regarding the qualification of all</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:127.45pt;top:11272.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">excipients that are present in the final product (21 CFR 211.84(a)).  For further</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:127.45pt;top:11286.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">information, please see Section III.A.2 above on reagents.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:11314.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">5. Additional Considerations</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11342.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">a. Combination Products</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11370.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">This guidance also applies to combination products containing a human gene</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11384.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">therapy biological product in combination with a drug or device as part of the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11398.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">final product.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:209.30pt;top:11396.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">3</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:219.85pt;top:11398.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">When intended for a different use, the drug or device component</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11412.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">may already have FDA marketing approval or clearance (e.g., new drug</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11426.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">application (NDA), a premarket approval application (PMA), or a premarket</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11440.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">notification (510(k)), or it may be previously unstudied.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11468.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">If information describing the drug or device component has already been</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11482.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">submitted to FDA (e.g., in another IND, IDE, or Master File), you may submit a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11496.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">letter of authorization authorizing FDA to reference the previous submission for</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11510.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">CMC or other information related to the drug or device component of your</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11524.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">product.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11552.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Note to FDA Reviewers</FONT></u><FONT STYLE="font-size: 12.00pt">:  Determine the regulatory status of the drug or device</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11566.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">either by contacting the RPM from the center with jurisdiction for the drug or</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11580.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">device or the sponsor directly, if necessary.  If the drug or device has been</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11593.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">approved for any use, confirm and document this in your review.  In most cases,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11607.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">request a consultative or collaborative review from the Center for Drug</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11621.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Evaluation and Research (CDER) or the Center for Devices and Radiological</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11635.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Health (CDRH) even if the drugs or device components were previously approved</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11649.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">for another use.  Confer with your supervisor if it is unclear whether a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11663.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">consultative or collaborative review is needed.  Once an adequate letter of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11677.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">authorization is submitted, verify</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:72pt;top:11726pt;width:144pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:11734.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 6.48pt">3</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:77.75pt;top:11736.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Regulations on combination products are found in 21 CFR Part 3, which describes how we will determine which</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:11747.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">component of FDA has primary jurisdiction for the premarket review and regulation of a combination product.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:11759.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 10.02pt">Note to FDA Reviewers</FONT></u><FONT STYLE="font-size: 10.02pt">: If you have any concerns regarding the appropriateness of the jurisdictional assignment or</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:11771.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">regulatory mechanism, you should contact the Office of Cellular, Tissues, and Gene Therapies’ jurisdictional</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:11782.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">officer.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:11830.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">12</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:11088.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile1414621255.htm_files\outputfile1414621255_background14.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:11880.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:11916.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11952.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">that the referenced file contains the needed information.  Inform the consultative</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11966.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">or collaborative reviewer that the information referenced in the letter of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11980.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">authorization should be reviewed as part of the application.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12008.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">b. Consultative Reviews</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12036.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Note to FDA Reviewers</FONT></u><FONT STYLE="font-size: 12.00pt">:  Follow the standard operating procedures and policies</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12050.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(SOPP) on the “Intercenter Consultative/Collaborative Review Process” (Ref. 9).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12064.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Specify the questions the consultative reviewer should address, identify the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12078.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">specific sections of the IND applicable to those questions, and request a date for</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12092.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">completion of the consultative review.  The requested date should be determined</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12106.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">by coordinating with the consulting review center and be based on timeframes</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12120.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">mandated by statute, the priority of the consultative review request, and the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12134.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">workload of the designated reviewer.  The RPM will request the consultative or</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12148.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">collaborative review from the appropriate Center/Division using the form in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12162.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Appendix 1 of the SOPP.  Given the tight IND deadlines, work with the RPM to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12176.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">contact the appropriate Center/Division before sending the consult request to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12190.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">identify the appropriate reviewer and ensure that the review can be completed</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12204.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">within the time requirements.  Also, as described in the SOPP, the RPM should</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12218.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">send to the Office of Combination Products a copy of the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12232.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">consultative/collaborative request for monitoring/tracking purposes.  The RPM</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12246.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">should follow up with the consultative reviewer to confirm that essential</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12260.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">documents are received along with the consultative review request.  If problems</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12274.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">that affect the timeliness of the consultative review occur during the consult</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12288.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">review period, discuss with your supervisor how to share these experiences with</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12302.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the Office of Combination Products, which is responsible for monitoring the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12316.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">efficiency and effectiveness of the intercenter consultative/collaborative review</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12330.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">process.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12358.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">c.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:12358.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Review of Device Components</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12385.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Note to FDA Reviewers</FONT></u><FONT STYLE="font-size: 12.00pt">:  In the device consultative/collaborative review request,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12399.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">describe the device component, and where to find relevant information in the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12413.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">submission.  You should ask the consultative reviewer to identify concerns with</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12427.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">how the device component will be used, to determine whether appropriate types</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12441.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">of biocompatibility and other device testing were performed adequately, and to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12455.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">assess testing of any hardware and software controlling the hardware.  In addition,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12469.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">if the sponsor asserts barrier or performance claims, identify information relative</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12483.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">to these claims for the consultative reviewer to assess.  You should document in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12497.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the review basic information concerning the device, such as the device name,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12511.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">vendor or source, purpose, regulatory status, and a brief description of the device.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12525.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">When the consultative/collaborative review is completed, and signed off by the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12539.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">appropriate CDRH supervisory chain, attach it to your review and communicate</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12553.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">any outstanding issues to the sponsor.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:12622.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">13</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:11880.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile1414621255.htm_files\outputfile1414621255_background15.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:12672.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:12708.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12744.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">d.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12744.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Review of Drug Components</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12772.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Note to FDA Reviewers</FONT></u><FONT STYLE="font-size: 12.00pt">:  In the drug consultative/collaborative review request,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12786.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">describe the drug component of the combination product and state where to find</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12800.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">relevant information on the component in the submission.  Ask the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12814.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">consultative/collaborative reviewer to identify any concerns with how the drug</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12828.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">will be used and also to evaluate the methods of manufacturing and the adequacy</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12842.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">of results from testing of the drug substance and/or drug product.  You should</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12856.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">document in your review basic information concerning the drug component, such</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12870.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">as the drug name, vendor or source, purpose, regulatory status, and a brief</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12884.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">description of the use of the drug.  When the consultative/collaborative review is</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12898.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">completed and signed off by appropriate CDER supervisory chain, attach it to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12912.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">your review and communicate any outstanding issues to the sponsor.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12940.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">e.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:12940.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Summarize Any Areas of Concern to be Addressed</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12968.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Note to FDA Reviewers</FONT></u><FONT STYLE="font-size: 12.00pt">:  Summarize any areas of concern identified during the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12982.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">review of the product components.  Discuss these concerns with the sponsor</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12996.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">and/or communicate them in a letter to the sponsor, as described in Section XI,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:13010.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">“Comments to Sponsor Generated by FDA Reviewers”.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:13038.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">B.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:13038.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Product Manufacturing – Procedures</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:13066.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">You should include a detailed description (list or summary) of all procedures used during</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:13080.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the collection, production, and purification of the gene therapy product.  We believe that</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:13094.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">a schematic of the production and purification process, and in-process and final product</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:13108.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">testing, helps to provide more clearly this information.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:13136.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Note to FDA Reviewers</FONT></u><FONT STYLE="font-size: 12.00pt">:  If provided by the sponsor, append a copy of the process</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:13150.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">schematic to the IND review.  If a schematic is not included, briefly summarize the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:13164.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">processing steps used during product manufacturing.  In addition, summarize any areas of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:13178.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">concern identified during the review of any submitted product manufacturing procedures.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:13192.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Discuss these concerns with the sponsor and/or communicate to the sponsor in a letter, as</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:13206.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">described in Section XI, “Comments to Sponsor Generated by FDA Reviewers”.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:13234.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">1.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:13234.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Vector Production/Purification</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:13261.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">You should include the following in your procedures:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:159.85pt;top:13289.35pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:177.85pt;top:13290.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">all purification steps in order of processing, for example:  centrifugation,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:177.85pt;top:13304.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">column purification, and density gradients;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:159.85pt;top:13318.10pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:177.85pt;top:13319.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">reagents/components used during vector manufacture;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:159.85pt;top:13332.85pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:177.85pt;top:13334.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">describe cell lines used during production of vector product including; cell</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:177.85pt;top:13348.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">passage number and cell plating density; and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:159.85pt;top:13361.60pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:177.85pt;top:13362.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">culturing procedures, and media components used, including serum,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:177.85pt;top:13376.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">growth factors, and antibiotics used during cell propagation.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:13414.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">14</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:12672.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile1414621255.htm_files\outputfile1414621255_background16.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:13464.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:13500.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:13550.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">2.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:13550.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Preparation of ex Vivo Gene-Modified Autologous or Allogeneic Cells</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:13578.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Autologous or allogeneic cells can be modified by using viral or plasmid vectors.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:13592.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">We recommend that you describe the following procedures:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:13618.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">a.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13618.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Method of Cell Collection/Processing/Culture Conditions</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:13649.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">You should describe the cells used for ex vivo modification (i.e., cell lines,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:13663.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">tumor cells, donor derived cells).  If non-banked autologous or allogeneic cells</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:13677.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">are used, describe the volume and number of cells collected.  You should</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:13691.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">include any mechanical or enzymatic digestion steps used.  You should describe</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:13705.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the use of any cell selection device or separation device, including density</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:13719.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">gradients, magnetic beads, or fluorescence activated cell sorting (FACS).  You</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:13733.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">should include a description of culture systems (flasks, bags, etc.), and state</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:13747.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">whether the system is closed or open.  Also, you should describe any in-process</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:13761.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">testing that will be performed during these procedures.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:13787.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">b.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13787.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Ex Vivo gene modification</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:13818.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">You should describe in detail the modification procedure, such as, transfection,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:13832.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">or infection.  You should describe in detail the selection of cells (methods,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:13846.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">devices, reagents) as well as any other cell modification steps such as</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:13860.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">irradiation.  If the cells are cultured after the genetic modification occurs, you</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:13874.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">should include the culture conditions used and time in culture.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:13900.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">c.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13900.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Irradiation of ex vivo gene modified cells</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:13931.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">If the autologous or genetically modified allogeneic cell product is irradiated</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:13945.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">before injection, you should provide data to demonstrate that the genetically</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:13959.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">modified cells are rendered replication-incompetent, but still maintain their</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:13973.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">desired characteristics after irradiation.  You should describe the documentation</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:13987.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">of calibration of the cell irradiator source.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:14015.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">d. Final Harvest</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:14043.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">You should provide a detailed description of the final harvest.  You should</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:14056.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">inform FDA whether the final cell harvest is centrifuged prior to final</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:14070.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">formulation, and if so, describe the wash conditions and media used.  You</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:14084.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">should also inform FDA in your IND submission whether the cells are</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:14098.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">cryopreserved after formulation or formulated immediately and given to the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:14112.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">patient.  If the final harvest is stored, you should describe the storage</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:14126.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">conditions and the length of storage, and provide appropriate supporting data</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:14140.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(see Section VI below).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:14206.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">15</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:13464.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile1414621255.htm_files\outputfile1414621255_background17.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:14256.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:14292.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:14328.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">3.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:14328.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Process Timing and Intermediate Storage</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:14356.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Report the approximate time elapsed for each step in vector production including</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:14370.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">vector purification, intermediate holding steps (i.e., storage of bulk harvest) and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:14384.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">cryopreservation of final vector product.  In addition, if the final product is ex vivo</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:14398.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">genetically modified cells, you should report the approximate time elapsed for each</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:14412.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">step from cell collection, to transduction, to final harvest.  It is important to know the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:14426.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">time limit of each step in production to determine what, if any, in-process testing to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:14440.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">perform. If the final product is cryopreserved before injection into patients, you</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:14454.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">should include this information along with any stability studies initiated (see Section</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:14468.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">VI.A.1 below).  Also, you should describe the time and conditions of storage prior to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:14482.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">patient administration.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:14510.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Note to FDA Reviewers</FONT></u><FONT STYLE="font-size: 12.00pt">:  Describe and assess the procedures in place to ensure the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:14524.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">stability of the bulk harvest while in storage.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:14552.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">4. Final Formulation</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:14580.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">You must describe the formulation of the final product, including excipients such as</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:14594.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">growth factors or human serum albumin (21 CFR 312.23(a)(7)(iv)(a)).  You should</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:14608.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">state the source of these components (see Section II.A.3 above).  You should identify</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:14622.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the vendor and final concentration of these excipients used in the final product.  If the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:14636.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">final product is delivered to the clinical site frozen, you should include a description</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:14650.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">of how the product will be shipped and data to show that the product can be thawed</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:14664.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">with consistent results.  In addition, if the product is shipped, you should provide data</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:14678.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">on product stability during shipping (see Section VI.A.2 below).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:14720.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">IV.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:14720.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">PRODUCT TESTING</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:14748.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">We recommend that product testing for gene therapies include, but not be limited to,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:14762.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">microbiological testing (including sterility, mycoplasma, and adventitious viral agent testing) to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:14776.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">ensure safety and assessments of other product characteristics such as identity, purity (including</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:14790.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">endotoxin), viability, and potency.  We recommend that you perform this testing throughout the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:14803.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">manufacturing process, including on the manufacture of cell banks, to evaluate the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:14817.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">manufacturing process itself and to ensure the quality and consistency of the product.  You</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:14831.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">should describe the specifications used for intermediate acceptance criteria and final product</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:14845.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">release criteria.  Specifications are the quality standards (i.e., tests, analytical procedures, and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:14859.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">acceptance criteria) that confirm the quality of products and other materials used in the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:14873.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">production of a product.  Acceptance criteria mean numerical limits, ranges, or other attributes or</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:14887.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">variables for the tests described.  Specifications should be appropriate to the stage of product</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:14901.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">development, because release criteria should be refined and tightened as product development</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:14915.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">progresses toward licensure (see Appendix B).  You should submit test results related to lot</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:14929.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">release, characterization testing, MCB/MVBs, and WCB/WVBs in tabular form including the lot</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:14943.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">number or identifier, date of manufacture, test, test method, the sensitivity and specificity of test</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:14957.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">methods and, when appropriate, release criteria.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:14998.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">16</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:14256.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile1414621255.htm_files\outputfile1414621255_background18.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:15048.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:15084.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:15134.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Product testing is an integral part of ensuring control of the manufacturing process and lot-to-lot</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:15148.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">consistency.  Therefore, it is important to identify critical parameters in the manufacturing</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:15162.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">process and critical product attributes to ensure the desired clinical effect of the final product.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:15176.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Refer to the “FDA Guidance Concerning Demonstration of Comparability of Human Biological</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:15190.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Products, Including Therapeutic Biotechnology-Derived Products” (Ref. 10) for additional</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:15204.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">information.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:15232.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Note to FDA Reviewers</FONT></u><FONT STYLE="font-size: 12.00pt">:  Document the testing performed.  Assess the appropriateness of that</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:15246.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">testing and the acceptance criteria, based on any results previously obtained by the sponsor.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:15274.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">A.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15274.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Microbiological Testing</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:15302.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">We recommend that you perform microbiological testing on cell banks, in-process</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:15316.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">intermediates, and the final product, as appropriate.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:15344.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">1.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15344.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Sterility Testing (Bacterial and Fungal Testing)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:15372.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Current practices for sterility testing.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15400.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">a. Test Method</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15428.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Suitable sterility tests include the test described in 21 CFR 610.12 and the test</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15442.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">described in United States Pharmacopoeia (USP) <71> Sterility Tests (23</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:497.65pt;top:15440.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">rd</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15456.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">edition, 1995), (Ref. 11).  Later versions of the USP<71> are also suitable.  If you</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15470.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">are using another test method, you should describe its suitability.  Note that under</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15484.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">21 CFR 610.9, prior to product licensing, the alternative method must be shown</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15498.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">to provide assurances of the safety, purity, potency and effectiveness of the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15512.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">biological product equal to or greater that the assurances provided by the method</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15526.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">or process specified in the 21 CFR 610.12 method.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15554.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">If you use antibiotics in manufacturing, you should provide documentation that</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15568.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the antibiotics were removed prior to sterility testing.  If the antibiotics cannot be</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15582.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">removed from the final product, we recommend that you assess the validity of the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15595.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">sterility assay using the bacteriostasis and fungistasis testing as described in USP</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15609.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt"><71> Sterility Tests.  Use of this assay is designed to ensure that any residual</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15623.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">antibiotic present in the product does not interfere with the results of sterility</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15637.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">testing.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15665.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Note to FDA Reviewers</FONT></u><FONT STYLE="font-size: 12.00pt">:  If the Sponsor proposes to use an alternative method in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15679.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">place of the traditional sterility methods described in 21 CFR 610.12, then you</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15693.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">will need to assess the adequacy of this alternative test method and the data</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15707.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">provided to provide assurances of the safety, purity, potency and effectiveness of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15721.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the biological product equal to or greater than the assurances provided by the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15735.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">method or process specified in the general standard (21 CFR 610.9).  The</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15749.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">completeness of the validation study for the alternative method used during the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:15790.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">17</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:15048.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile1414621255.htm_files\outputfile1414621255_background19.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:15840.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:15876.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15912.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">product development should reflect an assessment of risk associated with the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15926.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">application of the method (e.g., stage of the manufacturing process).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15954.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">b. Test Timing</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15982.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Sponsors frequently perform in-process sterility testing at critical points during</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15996.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">manufacturing, such as during purification, or after ex vivo gene modification or</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16010.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">extended culture periods.  You should identify when in-process sterility testing is</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16024.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">performed during manufacturing and the test method used.  The test method that</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16038.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">you choose for in-process sterility testing should be adequate to provide assurance</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16052.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">of product sterility.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16080.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">If you freeze the final product before its use, we recommend that you perform</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16094.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">testing on the product prior to cryopreservation, so that results will be available</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16108.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">before the product is administered to a patient.  However, if the product</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16122.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">undergoes manipulation (e.g., washing, culturing) after thawing, particularly if</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16136.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">procedures are performed in an open system, you may need to repeat sterility</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16150.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">testing.  You should incorporate the results of in-process sterility testing into your</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16164.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">acceptance criteria for final product specifications.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16192.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">If your product has a short dating period and must be administered to patients</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16206.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">before sterility test results of the final product are available, then you will need to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16220.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">develop an alternate approach to provide sterility assurance.  As an alternative</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16234.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">approach, we recommend that you perform all of the following tests:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:16261.55pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:16262.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">in-process sterility testing on a sample taken 48 to 72 hours prior to final</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:16276.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">harvest or after the last re-feeding of the cultures</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:16290.30pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:16291.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">a rapid microbial detection test such as a Gram stain or other procedure on</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:16305.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the final formulated product</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:16319.05pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:16320.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">sterility testing compliant with 21 CFR 610.12 on the final formulated</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:16334.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">product</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16362.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Under this alternative approach the release criteria for sterility would be based on</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16376.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">a negative result of the Gram stain and a no-growth result from the 48 to 72 hour</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16390.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">in-process sterility test.  Although in this situation the results of the sterility</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16404.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">culture performed on the final product will not be available for product release,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16418.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">this testing will provide useful data.  A no-growth result will provide assurance</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16432.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">that an aseptic technique was maintained.  A positive result will provide</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16446.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">information for the medical management of the subject, and trigger an</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16460.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">investigation of the cause of the sterility failure.  The sterility culture on the final</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16474.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">formulated product and when possible the in-process culture should be continued</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16488.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">to obtain the full 14 day sterility test result even after the product has been given</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16502.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">to the patient.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16530.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">In all cases where product release is prior to obtaining results from a full 14 day</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16544.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">sterility test, the investigational plan should address the actions to be taken in the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:16582.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">18</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:15840.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile1414621255.htm_files\outputfile1414621255_background20.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:16632.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:16668.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16704.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">event that the 14 day sterility test is determined to be positive after the product is</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16718.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">administered to a subject.  You should report the sterility failure, results of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16732.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">investigation of cause and any corrective actions, in an information amendment</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16746.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">submitted to your IND in a timely manner, within 30 calendar days after initial</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16760.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">receipt of the positive culture test result (21 CFR 312.31).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16788.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">The investigator should evaluate the subject for any signs of infection that may be</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16802.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">attributable to the product sterility failure.  If the patient experiences any serious</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16816.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">and unexpected adverse drug experience that could be from administration of the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16830.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">sterility failure of the gene therapy product, then you must report this information</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16844.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">to FDA in an IND safety report no more than 15 calendar days after your initial</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16858.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">receipt of the information (21 CFR 312.32).  If you determine that an</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16872.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">investigational drug presents an unreasonable and significant risk to subjects, you</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16886.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">must discontinue those investigations that present the risk, notify FDA, all</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16900.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Institutional Review Boards, and all investigators (21 CFR 312.56(d)).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:16928.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">2. Mycoplasma</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:16956.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">There are several potential sources of mycoplasma contamination.  Two major</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:16970.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">sources include animal serum products used in culture and the culture facility</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:16984.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">environment, particularly with open culture systems.  We recommend that you</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:16998.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">perform mycoplasma testing on the product at the manufacturing stage when the test</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:17012.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">is most likely to detect contamination, such as after pooling of cultures for harvest but</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:17026.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">prior to cell washing.  Testing should be conducted on both cells and supernatant.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:17040.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">We recommend that you inform FDA whether there is in-process testing for</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:17054.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">mycoplasma during extended culture procedures.  Due to the limited dating period of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:17068.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">many ex vivo genetically modified cellular products, it is frequently not feasible for a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:17082.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">sponsor to perform the recommended culture-based assay (see Ref. 4) for release</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:17096.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">testing.  In those cases, we recommend the use of polymerase chain reaction (PCR)-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:17110.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">based mycoplasma assays or another rapid detection assay during product</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:17124.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">development.  As part of your BLA, you should submit appropriate data to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:17137.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">demonstrate that the PCR or alternative test has adequate sensitivity and specificity.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:17165.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">3.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:17165.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Adventitious Agent Testing</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:17193.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">As appropriate, you should perform and describe in your IND adventitious agent</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:17207.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">testing as set out below.  For more information on adventitious agent testing, refer to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:17221.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">“Points to Consider in the Characterization of Cell Lines Used to Produce</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:17235.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Biologicals” and ICH guidance Q5A:  “Guidance on Viral Safety Evaluation of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:17249.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Biotechnology Products Derived From Cell Lines of Human or Animal Origin” (Refs.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:17263.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">4 and 12).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:17291.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">a.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:17291.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">In Vitro Viral Testing</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:17319.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">When cell lines are used, you should describe the cell lines and perform in vitro</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:17333.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">viral testing.  In vitro viral testing should be performed on the MCB, WCB, MVB,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:17374.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">19</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:16632.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile1414621255.htm_files\outputfile1414621255_background21.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:17424.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:17460.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:17496.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">WVB, and final vector product, and as a one time test on the EOP.  Testing should</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:17510.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">be conducted by inoculating the test sample (MCB, WCB, MVB, WVB, final vector</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:17524.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">product) onto various susceptible indicator cell lines such as the human cell line</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:17538.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">MRC-5 or Vero cells which are primate in origin.  The choice of cells used would</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:17552.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">depend on the species of origin of the product to be tested.  An appropriate test</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:17566.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">should include monolayer cultures of the same species and tissue as that used for</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:17580.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">production of the product, as well as a human and a non-human primate cell line</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:17594.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">susceptible to human viruses.  In addition, the test would include a measure of both</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:17608.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">cytopathic and hemadsorbing viruses.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:17636.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">In the event that the product is a cytolytic virus, it will need to be neutralized using</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:17650.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">specific antibodies prior to in vitro adventitious testing of the MVB, WVB and final</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:17664.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">product.  If neutralizing antibodies are not available, then only in vivo adventitious</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:17678.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">agent testing needs to be performed on the MVB, WVB and final product until</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:17692.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">appropriate neutralizing antibodies are developed.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:17720.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">b.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:17720.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">In Vivo Viral Testing</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:17748.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">When cell lines are used, we recommend that you perform and submit data on in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:17762.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">vivo viral assays carried out by inoculating the test sample (MCB, MVB) into</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:17776.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">animals such as adult and suckling mice and embryonated hen eggs.  You should</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:17790.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">consider whether to include additional testing of guinea pigs, rabbits, or monkeys.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:17804.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Such studies would assess the test animals for any indication of illness.  If such</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:17818.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">additional testing is appropriate, you should describe and explain the suitability of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:17832.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the animals used.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:17860.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">c.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:17860.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Selected Testing for Adventitious Viruses</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:17888.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">We recommend that you test your MCB and MVB for appropriate, species-specific</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:17902.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">viruses.  You should describe the testing that is performed, the different stages of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:17916.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">manufacturing where those tests are performed (e.g., cell banks, viral banks, final</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:17930.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">product), and the test methods used.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:17958.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">1)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:184.50pt;top:17958.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Species-Specific Viruses</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:17986.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">You should describe all species-specific virus testing performed on the MCB</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18000.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">and MVB.  We believe that all rodent cell lines used during product</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18013.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">manufacturing should be tested for rodent specific viruses.  These viruses are</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18027.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">usually detected by antibody production tests, murine antibody production</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18041.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(MAP), rat antibody production (RAP), or hamster antibody production (HAP).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18055.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">If human cell lines are used in the therapeutic product, we recommend that you</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18069.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">perform testing for human pathogens (CMV, HIV-1 & 2, HTLV-1 & 2, EBV,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18083.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">HBV, HCV, and B19) and other human viral agents, as appropriate. We</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18097.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">recommend such testing because these cells are manipulated (cultured for</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18111.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">extended time periods) and human pathogens can be introduced or propagated</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:18166.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">20</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:17424.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile1414621255.htm_files\outputfile1414621255_background22.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:18216.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:18252.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18288.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">during the extended culture periods.  Human viral agents may be tested using a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18302.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">PCR-based test system.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18330.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">When the gene therapy product is produced in a human cell line, e.g., an</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18344.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">adenoviral vector produced in human 293 cells, you should test for the presence</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18358.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">of additional human viruses such as adenovirus and adeno-associated virus</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18372.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(AAV), and describe those tests in your IND.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18400.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">2) Testing for Retroviruses</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18428.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">When the MCB and MVB are used for production of vectors other than</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18442.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">retroviral vectors, you should test the MCB and MVB for retroviral</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18456.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">contamination using Reverse Transcriptase (RT) assays and electron</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18470.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">microscopic analysis, and include a description of those tests in your IND.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18498.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">We recommend that you perform testing for replication competent retrovirus</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18512.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(RCR) in the production of retroviral vectors at multiple points in production,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18526.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">including MVB, WVB, vector supernatants, end of production cells, and ex vivo</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18540.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">modified cells.  For further information on retroviral testing refer to the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18554.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">“Guidance for Industry:  Supplemental Guidance on Testing for Replication</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18568.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Competent Retrovirus in Retroviral Vector Based Gene Therapy Products and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18582.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">During Follow-up of Patients in Clinical Trials Using Retroviral Vectors” (Ref.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18596.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">13).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18624.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">For cells that produce vectors containing amphotropic murine leukemia virus</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18638.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">envelope, we recommend that you test for RCR using a permissive cell line such</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18652.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">as Mus dunni and describe that testing in the IND.  If an ecotropic packaging</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18666.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">cell line is utilized during retroviral vector production, you should conduct and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18680.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">describe an ecotropic retroviral assay for the detection of low-level viral</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18694.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">contamination in the MCB.  Murine ecotropic viral contamination can be</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18708.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">detected using either XC or D56 plaque assay methods.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18735.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">You should describe how vector supernatant is tested.  An appropriate test of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18749.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">vector supernatant lots would be by amplification on a permissive cell line such</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18763.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">as Mus dunni, followed by detection in an appropriate indicator cell assay such</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18777.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">as PG-4 S+L-.  An appropriate test of the pooled End of Production (EOP) cells</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18791.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">would be by co-culture with a permissive cell line such as Mus dunni for</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18805.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">amphotropic virus, and the amplified material assayed in an appropriate</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18819.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">indicator cell assay.  We have determined that detection of RCR in ex vivo</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18833.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">modified cells requires cells to be cultured for at least 4 days post transduction.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18848.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Therefore, ex vivo gene modified cells that are cultured for</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:449.20pt;top:18847.20pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">t</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:458.80pt;top:18848.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">4 days should use</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18862.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">RCR testing as a release assay.  If ex vivo gene modified cells are cultured for <</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18876.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">4 days, archiving cells would be appropriate in place of active RCR testing.  If it</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18890.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">is not possible to have results from the RCR assay prior to treatment, we</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18904.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">recommend that you initiate the culture assay and perform an alternative method</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:18918.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(such as PCR) for product release.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:18958.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">21</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:19008.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:19044.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:19094.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">3) Adenoviruses</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:19122.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">For studies using adenoviral vectors, we recommend that you conduct tests for</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:19136.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">replication competent adenovirus (RCA) on MVB as well as the final vector.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:19150.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">We believe that an appropriate maximum level of RCA contamination would be</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:19164.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">< 1 in 3 x 10</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:223.15pt;top:19162.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">10</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:234.20pt;top:19164.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">viral particles, and that the adenoviral particle to infectious unit</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:19179.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(iu) ratio would be</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:254.80pt;top:19177.95pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">d</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:264.40pt;top:19179.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">30 to 1.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:19207.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">4)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:184.50pt;top:19207.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Adeno-Associated Virus (AAV)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:19235.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">For studies using AAV, we recommend that you conduct tests to determine</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:19249.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the amount of replication competent AAV present in the final vector product</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:19263.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">and report the results in your IND.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:19291.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">B.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:19291.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Identity</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:19319.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">We recommend that you verify the identity of the MCB/MVB, WCB/WVB, and the final</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:19333.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">product by assays that will identify the product and distinguish it from other products</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:19347.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">being processed in the same facility.  For the final product, identity testing is important to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:19361.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">ensure that the contents of the vial are labeled appropriately.  For additional information</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:19375.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">on labeling, refer to Section VII.B below.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:19403.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">If the final product is an ex vivo genetically modified cell product, we recommend that you</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:19417.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">test the final cell product for identity.  Testing should include an assay to measure the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:19431.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">presence of vector (i.e., expression assay, restriction digest) and an assay specific for the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:19445.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">cellular component of the final product (i.e., cell surface markers).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:19473.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">C.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:19473.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Purity</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:19501.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Product purity is defined as relative freedom from extraneous material in the finished</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:19515.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">product, whether or not harmful to the recipient or deleterious to the product (21 CFR</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:19528.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">610.3(r)).  Purity testing includes assays for pyrogenicity/endotoxin (see below), residual</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:19542.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">proteins or reagents/components used during vector manufacture, such as cytokines, growth</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:19556.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">factors, antibodies, and serum, and in the case of ex vivo modified cells any unintended</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:19570.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">cellular populations or cell debris.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:19612.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">1.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:19612.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Residual Contaminants</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:19640.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">The appropriate purity testing should include assays for residual proteins, DNA,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:19654.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">RNA, and solvents used during production and purification, and reagents used</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:19668.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">during manufacture such as cytokines, growth factors, antibodies, and serum. If the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:19682.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">product is a genetically modified ex vivo cell therapy product, appropriate purity</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:19696.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">testing should include a measurement of contaminating cell types or cell debris.  For</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:19750.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">22</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:19008.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile1414621255.htm_files\outputfile1414621255_background24.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:19800.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:19836.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:19872.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">further information, refer to ICH Q3 on “Impurities” (Ref. 14).  You should describe</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:19886.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">in your IND the purity testing you conduct and your specifications for release.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:19914.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">2. Pyrogenicity/Endotoxin</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:19942.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">The rabbit pyrogen test method is the currently required method for testing</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:19956.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">biological products for pyrogenic substances (21 CFR 610.13).  Although the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:19970.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">pyrogenicity test is required, there may be specific cases where this test method can</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:19984.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">not be performed for release due to properties of the final product (i.e., short product</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:19998.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">shelf life, toxicity of product in rabbits).  Under these circumstances, a test method</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:20012.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">such as the Limulus Amebocyte Lysate test method (LAL) may be used as an</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:20026.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">alternative method, but prior to licensure must be shown to provide equal or greater</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:20040.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">assurances of safety, purity, and potency (see 21 CFR 610.9).  The 1987 FDA</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:20054.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Guideline on Validation of the Limulus Amebocyte Lysate (LAL) Test as End-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:20068.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Product Endotoxin Test for Human and Animal Parenteral Drugs, Biological</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:20082.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Products, and Medical Devices (Ref. 15) sets forth acceptable conditions for use of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:20096.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">LAL.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:20124.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">For any parenteral drug, except those administered intrathecally, we recommend that</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:20138.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the upper limit of acceptance criterion for endotoxin be 5 EU/kg body weight/hour.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:20152.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">For intrathecally-administered drugs, we recommend an upper limit of acceptance</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:20166.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">criterion of 0.2 EU/kg body weight/hour.  You should describe in your IND the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:20180.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">pyrogenicity/endotoxin testing you conduct, and your acceptance criterion for</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:20194.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">release.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20222.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Note to FDA Reviewers</FONT></u><FONT STYLE="font-size: 12.00pt">:  Document in your review the specification for</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20236.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">pyrogenicity/endotoxin testing and verify that testing is on the final product and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20250.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">that results are available prior to lot release.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:20278.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">D.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20278.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Potency</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:20306.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">You should describe and justify all assays you will use to measure potency.  We</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:20320.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">recommend that these assays be quantitative, but in addition, they may include a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:20334.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">qualitative biological assay.  For a Phase 1/Phase 2 study, we recommend that the assay</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:20348.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">quantify the expression of a gene therapy vector product.  For a Phase 3 study, we</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:20362.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">recommend that the potency assay consist of in vivo or in vitro tests that measure an</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:20376.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">appropriate biological activity.  If development of a quantitative biological assay is not</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:20390.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">possible, then a quantitative physical assay which correlates with and is used in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:20404.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">conjunction with a qualitative biological assay can be used.  Note that potency assays are</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:20418.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">part of lot release and should be validated prior to licensure.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:20542.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">23</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:19800.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile1414621255.htm_files\outputfile1414621255_background25.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:20592.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:20628.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:20664.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">E.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20664.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Other</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:20692.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">1.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20692.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">General Safety Testing</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:20720.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Testing for general safety is required for licensure of all gene therapy vector products,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:20734.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">unless the product is exempt under 21 CFR 610.11(g).  General safety testing is</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:20748.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">performed on biological products intended for administration to humans and specific</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:20762.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">tests are described in 21 CFR 610.11.  You should inform FDA whether general safety</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:20776.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">testing is being performed during product development.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:20804.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Note to FDA Reviewers</FONT></u><FONT STYLE="font-size: 12.00pt">:  Advise the sponsor regarding the applicability of the general</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:20818.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">safety test for the product under review.  (Revisions to the General Safety Requirements</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:20832.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">for Biological Products (68 FR 10157; March 4, 2003) (Ref. 16)).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:20860.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">2. Viability</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:20888.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">You should establish minimum release criteria for viability.  For genetically</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:20902.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">modified cellular therapies, the minimum acceptable viability specification is</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:20916.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">generally set at 70 percent.  If this level cannot be achieved, we recommend that you</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:20930.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">submit data in support of a lower viability specification, demonstrating, for example,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:20944.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">that dead cells and cell debris do not affect the safe administration of the product</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:20958.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">and/or the therapeutic effect.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:20986.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">3. Cell Number/Dose</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:21014.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">If your final product is a genetically modified cell therapy, you should develop</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:21028.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">specifications for the minimum number of viable and functional cells as part of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:21042.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">product testing and release.  We recommend that you inform FDA whether a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:21056.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">maximum number/dose of cells to be administered has been established, and the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:21070.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">basis for that level.  For administration of a gene vector, you should describe your</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:129.60pt;top:21084.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">dose as the concentration of plasmid DNA, viral particle number, or titer.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:21126.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">V.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:21126.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">FINAL PRODUCT RELEASE CRITERIA TESTING</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:21154.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">The final product is the final formulated product used for administration to human subjects.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:21168.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Final product release criteria testing should be performed on each lot of product manufactured.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:21182.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">In some situations, each dose could be considered a single lot, depending on the manufacturing</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:21196.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">process.  The results from final product release criteria testing should be available prior to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:21210.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">administration to a human subject.  If results from final product testing will not be available prior</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:21224.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">to release, we recommend that you clearly indicate this in the IND, together with your</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:21238.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">specifications, and include a description of the reporting notification process if the acceptance</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:21252.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">criteria are not met.  We recommend that you provide, in table format, all of your proposed</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:21265.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">specifications (tests for safety, purity, potency, and identity as described in Section IV, test</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:21279.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">methods, and acceptance criteria), including test sensitivity and specificity, where appropriate,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:21334.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">24</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:20592.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile1414621255.htm_files\outputfile1414621255_background26.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:21384.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:21420.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:21456.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">for the final product.  (Note that, before the product may be licensed, these parameters must be</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:21470.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">validated (21 CFR 211.165(e)).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:21512.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">VI.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:21512.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">PRODUCT STABILITY</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:21540.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Stability testing must be performed during early phases of the clinical trial to establish that the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:21554.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">product is sufficiently stable for the time period required by the study (21 CFR 312.23(a)(7)(ii)).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:21568.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Data supporting a final formulation and dating period will be necessary for licensure.  You</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:21582.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">should describe the stability measures you will use to support your studies.  For further</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:21596.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">information, refer to ICH Q5C:  “Quality of Biotechnological Products:  Stability Testing of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:21610.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Biotechnological/Biological Products,” (Ref. 17), ICH Guideline Q1A(R):  “Stability Testing of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:21624.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">New Drugs and Products” (revised guideline) (Ref. 18), ICH Guideline Q1E:  “Evaluation of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:21638.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Stability Data” (Ref. 19).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:21666.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Note to FDA Reviewers</FONT></u><FONT STYLE="font-size: 12.00pt">:  Assess the product development plan in the IND review to determine</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:21680.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">how much stability data are needed for the current phase of investigation and whether sufficient</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:21694.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">data are included in the submission.  If submitted, include preliminary data in your review.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:21708.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Assess whether proposed expiration dating is appropriate.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:21736.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Stability Testing</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:21764.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Under 21 CFR 312.23(a)(7)(ii), you must conduct stability testing in all phases of the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:21778.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">IND, to demonstrate that the product is within acceptable chemical and physical limits</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:21792.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">for the planned duration of the proposed clinical investigation.  If a very short term</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:21806.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">clinical investigation is proposed, the stability data submitted may be correspondingly</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:21820.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">limited.  You should submit a stability protocol and data for both in-process material and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:21834.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the final gene product.  A proposed stability protocol should include a measure of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:21848.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">product sterility, identity, purity, quality, and potency.  For each test conducted, you</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:21862.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">should describe the test method, sampling time points (there should be a zero-time point),</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:21876.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">testing temperature, and other appropriate information, including your justification of the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:21890.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">assays used to indicate product stability, measuring those parameters for the duration of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:21904.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">storage required by the clinical protocol.  We recommend sterility testing be performed at</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:21918.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">zero-time, end of stability study, and at an intermediate point during the study.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:21946.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Note to FDA Reviewers</FONT></u><FONT STYLE="font-size: 12.00pt">:  If the sponsor plans to use the product past the duration of the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:21960.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">clinical trial (e.g., for a separate trial being conducted after the initial trial), verify that</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:21974.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">testing establishes stability throughout the relevant time period.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:22002.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">1)  In-Process Stability Testing</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:22029.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">You should describe the stability protocol that will be used to ensure that the final</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:22043.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">product is stable during the period of cryopreservation, measuring the parameters</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:22057.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">described in Section VI.A, as appropriate.  A comparison is often made of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:22071.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">analyses carried out pre-freeze and post-thaw.  You should describe any stability</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:22126.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">25</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:21384.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile1414621255.htm_files\outputfile1414621255_background27.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:22176.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:22212.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:22248.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">testing performed on the product during the holding steps, such as</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:22262.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">cryopreservation of final product and storage of bulk product.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:22290.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">2)  Final Product Stability Testing</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:22318.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">You should include any data that demonstrate that the product is stable between</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:22332.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the time of product formulation and infusion to subjects to aid in establishing an</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:22346.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">expiration-dating period.  We recommend that you conduct the testing at the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:22360.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">appropriate temperatures and at time points consistent with predicted storage</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:22374.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">times.  If the product is shipped from the manufacturing site to the clinical site,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:22388.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">describe the time and shipping conditions (e.g., packaging, temperature).  Your</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:22402.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">stability protocol should be adequate to demonstrate that product integrity,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:22416.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">sterility, and potency are maintained under the proposed shipping conditions.  We</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:22430.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">further recommend that validation studies using conditions that stress the system</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:22444.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">be initiated by Phase 3 and completed prior to submission of a BLA.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:22486.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">VII.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:22486.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">OTHER ISSUES</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:22514.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">A.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:22514.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Product Tracking</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:22542.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">For all products, you should establish a product tracking and segregation system.  An</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:22556.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">adequate system should allow identification of the therapeutic product from collection to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:22570.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">administration of the product and should include procedures to ensure that the product is</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:22584.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">segregated from other products in incubators, hoods, and cryopreservation units.  You</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:22598.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">must establish and maintain a system of tracking that enables the tracking of all products</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:22612.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">from the donor to the consignee or final disposition, and from consignee or final</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:22626.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">disposition to donor (21 CFR 1271.290(b)).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:22654.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">B.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:22654.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Labeling</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:22682.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">You should describe the product labeling used throughout the manufacturing process and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:22696.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">on the final product container.  As described in 21 CFR 312.6(a), the label for an</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:22710.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">investigational product must contain the following statement:  “Caution:  New Drug –</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:22724.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Limited by Federal law to Investigational Use.”  To minimize the potential for mix-ups</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:22738.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">for products manufactured in multi-use facilities and for patient-specific products, we</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:22752.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">recommend that the product label contain the date of product manufacture, storage</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:22766.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">conditions, expiration date and time (if appropriate), product name, and two non-personal</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:22780.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">patient identifiers.  As HCT/Ps, labeling for ex vivo genetically modified cell therapy</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:22794.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">products must meet the requirements in 21 CFR 1271.250.  For autologous donors and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:22808.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">other situations described in 21 CFR 1271.90(a) for which a donor eligibility</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:22822.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">determination is not required, you must include the applicable required labeling in 21</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:22836.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">CFR 1271.90(b).  For example, for autologous cells intended for autologous use you</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:22849.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">must label the product “FOR AUTOLOGOUS USE ONLY” (21 CFR 1271.90(b)(1)),</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:22863.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">and “NOT EVALUATED FOR INFECTIOUS SUBSTANCES” if donor testing and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:22918.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">26</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:22176.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile1414621255.htm_files\outputfile1414621255_background28.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:22968.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:23004.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23040.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">screening is not performed (21 CFR 1271.90(b)(2)).  For more information, refer to Ref.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23054.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">3.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23082.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">C.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:23082.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Container/Closure</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23110.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">You should describe the types of container and closure used, and that you have</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23124.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">determined that the containers and closures are compatible with the product.  For more</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23138.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">information, refer to “Guidance for Industry:  Container Closure Systems for Packaging</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23152.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Human Drugs and Biologics; Chemistry, Manufacturing, and Controls Documentation”</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23166.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(Ref. 20) and “Guidance for Industry:  Container Closure Systems for Packaging Human</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23180.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Drugs and Biologics, Questions and Answers” (Ref. 21).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23208.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">D.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:23208.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Environmental Impact</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23236.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Under 21 CFR 312.23(a)(7)(iv)(e), you must submit either a claim for categorical</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23250.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">exclusion under 21 CFR 25.30 or 25.31, or an environmental assessment under 21 CFR</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23264.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">25.40.  Such categorical exclusion is ordinarily granted, absent extraordinary</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23278.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">circumstances indicating that the specific proposed action might significantly affect the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23292.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">quality of the human environment.  Extraordinary circumstances are described in 40 CFR</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23306.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">1508.27 and may include actions that create a potential for serious harm to the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23320.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">environment and actions that adversely affect a species or the critical habitat of a species</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23334.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">determined to be endangered, threatened, or entitled to special protection (21 CFR</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23348.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">25.21).  See the “Guidance for Industry:  Environmental Assessment of Human Drug and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23362.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Biologics Applications” (Ref. 22) for additional information.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23390.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Note to FDA Reviewers</FONT></u><FONT STYLE="font-size: 12.00pt">:  Document in your review whether the sponsor has claimed a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23404.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">categorical exclusion or evaluate the sponsor’s assessment of any extraordinary</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23418.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">circumstances using this product.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23446.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">E.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:23446.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Qualification of the Manufacturing Process</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23474.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">The manufacturing process for gene therapy products entails the use of reagents and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23488.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">source materials of differing complexity, variability and risk for introduction of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23502.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">adventitious agents.  Qualification of reagents and source materials, as well as ensuring</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23516.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">that appropriate controls are in place for monitoring manufacturing consistency and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23530.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">product quality, are key elements in ensuring that subjects receive a product that is</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23544.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">consistently safe, pure, and potent.  We recommend that, prior to production of clinical</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23558.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">lots and initiation of clinical studies, you establish and implement written procedures to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23572.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">ensure proper manufacturing oversight.  This includes the responsibilities and procedures</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23586.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">applicable to the quality control unit.  We recommend that you establish a quality control</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23600.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(QC) plan and document that plan in writing.  For example, a sound QC plan must</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23614.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">provide for the following functions:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:23641.45pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:23642.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Responsibility for examining the various components used in the production of a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:23656.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">product (e.g., containers, closures, in-process materials) to ensure that they are</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:23670.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">appropriate and meet defined, relevant quality standards (21 CFR 211.84(a));</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:23710.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">27</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:22968.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile1414621255.htm_files\outputfile1414621255_background29.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:23760.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:23796.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:23832.00pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:23833.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Responsibility for review and approval of production procedures, testing</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:23847.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">procedures and acceptance criteria (21 CFR 211.22(c));</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:23860.75pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:23862.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Responsibility for releasing or rejecting each clinical batch based on a cumulative</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:23876.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">review of completed production records and other relevant information (21 CFR</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:23890.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">211.22(a), 21 CFR 211.165, 21 CFR 211.192); and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:23903.45pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:23904.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Responsibility for investigating and initiating corrective actions if unexpected</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:23918.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">results or errors occur during production (21 CFR 211.22(a), 21 CFR 211.192).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23946.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">You should summarize the QC plan that is in place to prevent, detect, and correct</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23960.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">deficiencies that may compromise product integrity or function, or that may lead to the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23974.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">possible transmission of adventitious infectious agents.  We recommend that QC</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:23988.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">responsibilities be performed independently from production responsibilities by</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24002.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">dedicated QC personnel who are familiar with QC principles.  You should conduct</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24016.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">internal audits at planned intervals to evaluate effective implementation of the quality</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24030.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">plan and to determine if processes and products meet established parameters.  You should</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24044.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">develop and document audit procedures to ensure that the planned audit schedule takes</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24058.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">into account the relative risk of the various QC activities, the results of previous audits</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24072.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">and corrective actions, and the need to audit the entire operation at least annually.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24100.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Note to FDA Reviewers</FONT></u><FONT STYLE="font-size: 12.00pt">:  Document that you have reviewed the summary of the QC</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24114.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">plan.  Note each individual who has authority over the QC unit and the individual’s</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24128.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">assigned duties.  Document the date of the most recent internal audits of the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24142.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">manufacturing operations and those of contract manufacturers, vendors, or other parties.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24170.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">You should describe the changeover procedures that are followed to ensure that no cross-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24184.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">contamination occurs among ex vivo genetically modified cells intended for an individual</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24198.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">subject and other products stored or produced in the same facility.  You should describe</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24212.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the use of PCR assays for detecting area clearance, cleaning and decontamination</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24226.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">reagents and segregation of activities, and the qualification of aseptic processing steps.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24240.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Because most ex vivo genetically modified cell therapy products are not subject to final</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24254.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">sterile filtration prior to infusion, you should manufacture these products under aseptic</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24268.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">conditions.  A media fill is an appropriate method to qualify that the process produces a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24282.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">sterile product.  Refer to the “Guidance for Industry:  Sterile Drug Products Produced by</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24296.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Aseptic Processing – Current Good Manufacturing Practice” (Ref. 23) for further</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24310.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">information.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24338.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Note to FDA Reviewers</FONT></u><FONT STYLE="font-size: 12.00pt">:  Obtain consultative reviews from the Division of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24352.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Manufacturing and Product Quality, CBER, to assess any data submitted by the sponsor</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24366.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">on facilities and environmental issues such as decontamination and cleaning validation.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24394.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">F.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:24394.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Biostatistics</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24422.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Note to FDA Reviewers</FONT></u><FONT STYLE="font-size: 12.00pt">:  Obtain consultative reviews for relevant portions of the CMC</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24436.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">section from the Division of Biostatistics to ensure the adequacy of proposed</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24450.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">experimental designs and analytic plans.  There are many significant design and analysis</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24464.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">issues in the areas of assay validation, establishing specifications, evaluation of product</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:24502.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">28</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:23760.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile1414621255.htm_files\outputfile1414621255_background30.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:24552.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:24588.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24624.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">potency, and evaluation of product stability.  Proper statistical design and analysis of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24638.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">such studies are essential to ensure reliable documentation of the safety, purity, and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24652.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">potency of the product.  If applicable, document in your review recommendations from</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24666.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the Biostatistics consult.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:24708.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">VIII.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24708.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">PRECLINICAL STUDIES TO BE DOCUMENTED BY FDA REVIEWERS</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24736.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">A.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:24736.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Summary of Concept Studies</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24764.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Note to FDA Reviewers</FONT></u><FONT STYLE="font-size: 12.00pt">:  Document information provided by the sponsor to support the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24778.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">scientific rationale underlying the proposal.  Include a brief summary of preclinical data</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24792.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">that was generated using in vivo animal studies and/or in vitro studies to assess the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24806.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">product’s activity, efficacy, and any safety issues observed during the study.  Some issues</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24820.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">specific to gene therapy that should be documented include localization or trafficking of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24834.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">vectors, and level and persistence of gene expression.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24862.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">B.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:24862.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Gonadal Distribution</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24890.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Note to FDA Reviewers</FONT></u><FONT STYLE="font-size: 12.00pt">:  For gene therapy vectors used for direct in vivo administration,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24904.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">work in consultation with the pharmacology/toxicology reviewer to document data that</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24918.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">demonstrate the extent to which a vector is able to disseminate out of the administration</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24932.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">site and distribute to the gonads.  In most cases, this information is not available at the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24946.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">beginning of the Phase 1 study but would become available in the course of product</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24960.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">development.  Such data are usually obtained by using a PCR assay.  In cases where a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24974.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">novel vector, route of administration, indication, or vector delivery system is proposed,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:24988.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">preclinical studies to assess vector dissemination may be appropriate prior to initiation of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25002.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the Phase 1 study.  Document in your review the sensitivity of this assay (amount</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25017.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">vector/</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:141.40pt;top:25015.65pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">P</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:148.30pt;top:25017.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">g cellular DNA), including assay controls (positive, negative and spiked</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25030.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">controls).  We believe that the PCR assay sensitivity should be less than 50 copies of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25045.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">vector genome per</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:200.35pt;top:25044.35pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">P</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:207.25pt;top:25045.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">g cellular DNA.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:25087.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">IX.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25087.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">CLINICAL STUDIES TO BE DOCUMENTED BY FDA REVIEWERS</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:25115.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Note to FDA Reviewers</FONT></u><FONT STYLE="font-size: 12.00pt">:  Provide a brief description of the following in the CMC review:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25143.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">A.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:25143.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Protocol Title</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25171.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Name of the protocol.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25199.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">B.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:25199.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Subject Population</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25227.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Define the population; e.g., size, gender, race, age, etc.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:25294.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">29</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:25344.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:25380.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25416.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">C.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:25416.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Route of Administration</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25444.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Define; e.g., oral, intravenous, intramuscular, etc.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25472.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">D.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:25472.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Dose</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25500.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Include the dosing regimen and whether there is a dose escalation.  Document the dosing</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25514.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">range and number of subjects enrolled in each dose.  Describe the plans for dose</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25528.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">escalation and what time interval/data evaluations occur between dose increases.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25556.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">E.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:25556.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Frequency</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25584.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Include the frequency of dose injections per treatment cycle and the number of proposed</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25598.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">cycles.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25626.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">F.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:25626.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Genetic, Biochemical, and Immunological Testing</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25654.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Assess, in conjunction with the clinical reviewer, whether all genetic and/or product-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25668.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">specific biochemical and immunological testing of subjects is appropriate for the stage of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25682.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">clinical investigation.  Evaluate the sensitivity and specificity of the test methods used to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25696.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">demonstrate biological activity (e.g., immunological assay, PCR) and document this</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25710.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">information in your review.  In conjunction with the clinical reviewer, verify and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25724.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">document that serum from a patient on a retroviral gene therapy protocol is analyzed for</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25738.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the presence of RCR at 3, 6, and 12 months after treatment.  If all post-treatment assays</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25752.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">are negative during the first year, then yearly patient samples may be archived (Ref. 13).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25780.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">G.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:25780.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Informed Consent</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25808.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">If the informed consent document is submitted for your review, verify that the product is</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25822.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">described accurately and completely.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25850.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">H.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:25850.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Recombinant DNA Advisory Committee (RAC) Review</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25878.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">If the sponsor or the sponsor’s institution receives NIH funding for DNA recombinant</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25892.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">studies or if any clinical sites used in the study receive NIH funding for Recombinant DNA</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25906.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">studies, you should remind the sponsor that under the NIH Recombinant DNA Guidelines,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25920.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">NIH will not allow the protocol to be initiated until the Recombinant DNA Advisory</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25934.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Committee (RAC) review has occurred.  Confirm that the sponsor has submitted the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25948.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">protocol to RAC for review.  For additional information refer to the “NIH Guidelines for</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:25962.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Research Involving Recombinant DNA Molecules” (Ref. 24).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:26004.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">X.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:26004.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">RECOMMENDATION TO BE DETERMINDED BY FDA REVIEWERS</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:26032.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Note to FDA Reviewers</FONT></u><FONT STYLE="font-size: 12.00pt">:  Describe any information that is missing or incomplete, and issues that</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:26046.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">require additional clarification.  Provide an overall assessment from the CMC perspective of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:26086.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">30</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:25344.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile1414621255.htm_files\outputfile1414621255_background32.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:26136.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:26172.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:26208.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">whether the trial may proceed or should be placed on clinical hold.  Document all information</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:26222.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">obtained from the sponsor through telephone conversations or faxes.  Note this documentation in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:26236.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the Recommendation Section of the Product Review Template, throughout the review document,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:26250.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">or as an attachment to the review, as appropriate.  Upon completion, sign and date the review</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:26264.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">and then obtain concurrence from your supervisor.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:26306.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">XI.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:26306.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">COMMENTS TO SPONSOR GENERATED BY FDA REVIEWERS</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:26334.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Note to FDA Reviewers</FONT></u><FONT STYLE="font-size: 12.00pt">:  Draft letter comments on unresolved issues as discussed below.  Refer</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:26348.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">to SOPP 8201, “Issuance of and Response to Clinical Hold Letters for Investigational New Drug</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:26362.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Applications” (Ref. 25), for additional information.  After you have obtained supervisory</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:26376.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">concurrence on your review, forward your comments to the RPM for inclusion in a letter to the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:26390.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">sponsor.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:26418.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">A.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:26418.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Clinical Hold</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:26446.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Clinical hold comments are comments that the sponsor must satisfactorily address prior</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:26460.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">to allowing clinical studies to proceed after FDA has imposed a clinical hold.  These</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:26474.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">comments must meet the criteria listed in 21 CFR 312.42(b).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:26502.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">B.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:26502.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Non-Clinical Hold</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:26530.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Non-clinical hold comments are comments that the sponsor should address as product</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:26544.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">development progresses.  In some cases, a sponsor may need to address specific</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:26558.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">manufacturing issues by a certain point in clinical development, such as prior to initiation</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:26572.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">of Phase 3 studies.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:26878.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">31</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:26136.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile1414621255.htm_files\outputfile1414621255_background33.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:26928.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:26964.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:27000.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">XII.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:27000.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">REFERENCES</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:27028.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">1.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27028.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Guidance for Industry:  Content and Format of Investigational New Drug Applications</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27042.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27056.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Biotechnology-Derived Products, November 1995,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27070.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt"><a href="http://www.fda.gov/cder/guidance/phase1.pdf.">http://www.fda.gov/cder/guidance/phase1.pdf.</a></FONT><FONT STYLE="font-size: 12.00pt"></FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:27098.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">2.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27098.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Final Rule:  Eligibility Determination for Donors of Human Cells, Tissues, and Cellular</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27112.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">and Tissue-Based Products, (69 FR 29786, May 25, 2004),</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27126.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt"><a href="http://www.fda.gov/cber/rules/suitdonor.pdf.">http://www.fda.gov/cber/rules/suitdonor.pdf.</a></FONT><FONT STYLE="font-size: 12.00pt"></FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:27154.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">3.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27154.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Guidance for Industry:  Eligibility Determination for Donors of Human Cells, Tissues, and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27168.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Cellular and Tissue-Based Products (HCT/Ps), August 2007,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27182.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt"><a href="http://www.fda.gov/cber/gdlns/tissdonor.pdf.">http://www.fda.gov/cber/gdlns/tissdonor.pdf.</a></FONT><FONT STYLE="font-size: 12.00pt"></FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:27210.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">4.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27210.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Points to Consider in the Characterization of Cell Lines Used to Produce Biologicals, July</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27224.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">12, 1993, </FONT><FONT STYLE="font-size: 12.00pt"><a href="http://www.fda.gov/cber/gdlns/ptccell.pdf.">http://www.fda.gov/cber/gdlns/ptccell.pdf.</a></FONT><FONT STYLE="font-size: 12.00pt"></FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:27252.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">5.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27252.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">ICH Guidance on Quality of Biotechnological/Biological Products:  Derivation and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27266.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Characterization of Cell Substrates Used for Production of Biotechnological/Biological</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27280.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Products, (63 FR 50244, September 21, 1998), </FONT><FONT STYLE="font-size: 12.00pt"><a href="http://www.fda.gov/cber/gdlns/qualbiot.pdf.">http://www.fda.gov/cber/gdlns/qualbiot.pdf.</a></FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:27308.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">6.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27308.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Guidance for Industry:  Source Animal, Product, Preclinical and Clinical Issues</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27322.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Concerning the Use of Xenotransplantation Products in Humans, April 2003,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27336.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt"><a href="http://www.fda.gov/cber/gdlns/clinxeno.htm.">http://www.fda.gov/cber/gdlns/clinxeno.htm</a></FONT><FONT STYLE="font-size: 12.00pt">.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:27364.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">7.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27364.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">PHS Guideline on Infectious Disease Issues in Xenotransplantation, January 19, 2001,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27378.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt"><a href="http://www.fda.gov/cber/gdlns/xenophs0101.htm.">http://www.fda.gov/cber/gdlns/xenophs0101.htm</a></FONT><FONT STYLE="font-size: 12.00pt">.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:27406.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">8.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27406.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27420.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Human Use, February 28, 1997, </FONT><FONT STYLE="font-size: 12.00pt"><a href="http://www.fda.gov/cber/gdlns/ptc_mab.pdf.">http://www.fda.gov/cber/gdlns/ptc_mab.pdf.</a></FONT><FONT STYLE="font-size: 12.00pt"></FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:27448.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">9.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27448.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Manual of Standard Operating Procedures and Policies: Intercenter</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27462.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Consultative/Collaborative Review Process, Version 4, dated June 18, 2004,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27475.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt"><a href="http://www.fda.gov/oc/ombudsman/intercentersop.pdf.">http://www.fda.gov/oc/ombudsman/intercentersop.pdf.</a></FONT><FONT STYLE="font-size: 12.00pt"></FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:27503.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">10.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27503.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">FDA Guidance Concerning Demonstration of Comparability of Human Biological Product,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27517.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Including Therapeutic Biotechnology-derived Products, April 1996,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27531.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt"><a href="http://www.fda.gov/cber/gdlns/comptest.pdf.">http://www.fda.gov/cber/gdlns/comptest.pdf.</a></FONT><FONT STYLE="font-size: 12.00pt"></FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:27559.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">11.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27559.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">United States Pharmacopoeia (USP), Chapter <71> Sterility Tests, 23</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:434.20pt;top:27557.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">rd</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:443.90pt;top:27559.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">edition, 1995,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27573.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt"><a href="http://www.usp.org.">http://www.usp.org.</a></FONT><FONT STYLE="font-size: 12.00pt"></FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:27601.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">12.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27601.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">ICH Guidance on Viral Safety Evaluation of Biotechnology Products Derived From Cell</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27615.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Lines of Human or Animal Origin, (63 FR 51074, September 24, 1998),</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27629.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt"><a href="http://www.fda.gov/cber/gdlns/virsafe.pdf.">http://www.fda.gov/cber/gdlns/virsafe.pdf.</a></FONT><FONT STYLE="font-size: 12.00pt"></FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:27670.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">32</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:27720.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:27756.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:27806.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">13.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.05pt;top:27806.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Guidance for Industry:  Supplemental Guidance on Testing for Replication Competent</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27820.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Retrovirus in Retroviral Vector Based Gene Therapy Products and During Follow-up of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27834.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Patients in Clinical Trials Using Retroviral Vectors, dated October 2006,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27848.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt"><a href="http://www.fda.gov/cber/gdlns/retrogt1000.htm.">http://www.fda.gov/cber/gdlns/retrogt1000.htm</a></FONT><FONT STYLE="font-size: 12.00pt">.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:27876.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">14.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27876.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">ICH Topic Q3.  Impurities.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27890.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Guidance for Industry:  Q3A Impurities in New Drug Substances, February 2003,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27904.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">http://www.fda.gov/cber/gdlns/ichq3a.pdf.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27918.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Guidance for Industry:  Q3B(R2) Impurities in New Drug Products, July 2006,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27932.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">http://www.fda.gov/cber/gdlns/ichq3br.pdf.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27946.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Guidance for Industry:  Q3C Impurities: Residual Solvents, December 1997,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27960.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">http://www.fda.gov/cber/gdlns/q3cresolvent.pdf.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:27988.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">15.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:27988.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Guideline on Validation of the Limulus Amebocyte Lysate test as an End-Product</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:28002.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Endotoxin Test for Human and Animal Parenteral Drugs, Biological Products and Medical</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:28016.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Devices, 1987, http://www.fda.gov/cber/gdlns/lal.pdf.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:28044.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">16.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:28044.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Revisions to the General Safety Requirements for Biological Products, 68 FR 10157,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:28058.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">March 4, 2003.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:28086.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">17.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.05pt;top:28086.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Guideline for Industry:  Quality of Biotechnological Products: Stability Testing of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:28100.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Biotechnological/Biological Products, July 1996 (ICH Q5C),</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:28114.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">http://www.fda.gov/cder/guidance/ichq5c.pdf.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:28142.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">18.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:28142.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Guidance for Industry:  Q1A(R2): Stability Testing of New Drug Substances and Products</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:28156.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(Revision 2), November 2003, http://www.fda.gov/cber/gdlns/ichstab.pdf.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:28184.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">19.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:28184.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Guidance for Industry:  Q1E:  Evaluation of Stability Data, June, 2004,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:28198.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">http://www.fda.gov/cber/gdlns/ichstabdta.pdf.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:28226.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">20.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:28226.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Guidance for Industry:  Container Closure Systems for Packaging Human Drugs and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:28240.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Biologics; Chemistry, Manufacturing, and Controls Documentation, May 1999,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:28254.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">http://www.fda.gov/cber/gdlns/cntanr.pdf.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:28282.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">21.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:28282.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Guidance for Industry:  Container Closure Systems for Packaging Human Drugs and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:28296.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Biologics, Questions and Answers, May 2002,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:28310.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">http://www.fda.gov/cber/gdlns/cntanrq&a.pdf.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:28338.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">22.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:28338.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Guidance for Industry:  Environmental assessment of Human Drug and Biologics</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:28351.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Applications, Revision 1, July 1998, http://www.fda.gov/cber/gdlns/environ.pdf.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:28379.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">23.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:28379.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Guidance for Industry:  Sterile Drug Products Produced by Aseptic Processing – Current</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:28393.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Good Manufacturing Practice, September 2004,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:28407.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">http://www.fda.gov/cber/gdlns/steraseptic.htm.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:28462.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">33</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:28512.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:28548.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:28584.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">24.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:28584.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">NIH Guidelines for Research Involving Recombinant DNA Molecules (NIH Guidelines),</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:28598.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">April 2002, http://www4.od.nih.gov/oba/rac/guidelines/guidelines.html.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:28626.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">25.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:28626.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Manual of Standard Operating Procedures and Policies Investigational New Drug; Issuance</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:28640.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">of and Response to Clinical Hold Letters for Investigational New Drug Applications, SOPP</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:28654.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">8201, Version #3, April 27, 1999, http://www.fda.gov/cber/regsopp/8201.htm.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:29254.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">34</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:29304.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:29340.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:29376.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">APPENDIX A – PRODUCT REVIEW TEMPLATE (GENE THERAPY)</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:29404.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">PRODUCT REVIEW (GENE CELL)</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:75.00pt;top:29418.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Supervisor Concurrence/Date</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:71.95pt;top:29432.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">IND:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:141.40pt;top:29432.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">XXXX</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:239.95pt;top:29432.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Sponsor’s Submission Date:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:400.25pt;top:29432.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Month DD, YYYY</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:239.90pt;top:29446.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">30 Day Review Due Date:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:400.30pt;top:29446.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Month DD, YYYY</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:239.90pt;top:29460.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">STATUS: Pending</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:79.50pt;top:29488.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">DATE:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:262.50pt;top:29488.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Month DD, YYYY</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:79.50pt;top:29516.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">REVIEWER:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:262.50pt;top:29516.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Your Name</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:262.50pt;top:29530.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Your Title, OCTGT/DCGT/Your Branch</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:79.50pt;top:29544.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">THROUGH:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:262.50pt;top:29544.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Branch Chief Name</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:262.50pt;top:29558.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Branch Chief, OCTGT/DCGT/Branch</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:79.50pt;top:29586.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">SPONSOR:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:259.50pt;top:29586.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Name:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:259.50pt;top:29600.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Address:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:259.50pt;top:29614.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Title:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:259.50pt;top:29628.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Phone:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:259.50pt;top:29642.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Fax:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:79.50pt;top:29670.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">SPONSOR POINT OF CONTACT:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:259.50pt;top:29684.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Name:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:259.50pt;top:29698.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Address:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:259.50pt;top:29712.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Title:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:259.50pt;top:29726.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Phone:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:259.50pt;top:29740.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Fax:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:79.50pt;top:29768.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">TITLE OF IND:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:79.50pt;top:29796.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">PROPOSED USE:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:79.50pt;top:29824.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">REVIEW TEAM:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:259.50pt;top:29824.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Clinical:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:259.50pt;top:29838.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Pharm-Tox:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:259.50pt;top:29852.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">RPM:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:259.50pt;top:29866.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Consults:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:79.50pt;top:29894.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">PRODUCT DESCRIPTION:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:79.50pt;top:29922.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">PHASE OF STUDY:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:79.50pt;top:29950.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">CROSS-REFERENCED INDS, IDES, MFS:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:79.50pt;top:29978.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">KEY WORDS:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:30006.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">INTRODUCTION / RATIONALE:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:30046.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">35</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:30096.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:30132.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:30182.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">STUDY OBJECTIVES:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:30210.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">PRODUCT MANUFACTURING AND CHARACTERIZATION:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:30238.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Product Manufacturing - Components</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:30266.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Cells</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:30294.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Allogeneic or Autologous Cell Components</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:30322.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Cell Source:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:30350.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Method of Collection:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:30378.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Donor Screening:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:30392.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Description</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:30420.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Tabulation of Testing</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:30448.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Cell Bank System - If Applicable</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:30476.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Master Cell Bank (MCB)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:30490.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Description</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:30518.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Tabulation of Testing</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:30546.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Working Cell Bank (WCB)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:30560.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Description</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:126.00pt;top:30588.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Tabulation of Testing</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:30616.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Reagents</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:30644.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Tabulation of Reagents Used in Manufacture</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:57.25pt;top:30672.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Reagent/Excipient</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:165.60pt;top:30672.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Concentration at use</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:277.55pt;top:30672.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Source</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:376.55pt;top:30672.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Grade</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:458.10pt;top:30672.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Vendor</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:516.60pt;top:30672.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">COA</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:51pt;top:30671pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:51pt;top:30671pt;width:108pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:52pt;top:30672pt;width:107pt;height: 1pt;background-color:#e4e4e4;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:159pt;top:30671pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:160pt;top:30671pt;width:111pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:160pt;top:30672pt;width:111pt;height: 1pt;background-color:#e4e4e4;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:271pt;top:30671pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:272pt;top:30671pt;width:98pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:272pt;top:30672pt;width:98pt;height: 1pt;background-color:#e4e4e4;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:370pt;top:30671pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:371pt;top:30671pt;width:80pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:371pt;top:30672pt;width:80pt;height: 1pt;background-color:#e4e4e4;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:452pt;top:30671pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:453pt;top:30671pt;width:57pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:453pt;top:30672pt;width:57pt;height: 1pt;background-color:#e4e4e4;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:510pt;top:30671pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:511pt;top:30671pt;width:48pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:511pt;top:30672pt;width:48pt;height: 1pt;background-color:#e4e4e4;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:559pt;top:30671pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:559pt;top:30671pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:51pt;top:30672pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:51pt;top:30686pt;width:108pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:159pt;top:30672pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:160pt;top:30686pt;width:111pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:271pt;top:30672pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:272pt;top:30686pt;width:98pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:370pt;top:30672pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:371pt;top:30686pt;width:80pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:452pt;top:30672pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:453pt;top:30686pt;width:57pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:510pt;top:30672pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:511pt;top:30686pt;width:48pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:559pt;top:30672pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:559pt;top:30686pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:30701.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Qualification Program</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:30729.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Determination of Removal of Reagents from Final Product</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:30757.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Combination Products - If Applicable</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:30785.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Drug or Device Components - If Applicable</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:30838.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">36</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:30096.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile1414621255.htm_files\outputfile1414621255_background38.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:30888.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:30924.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:30960.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Consult Review Issues:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:30988.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Areas of Concern for Components:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:31016.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Product Manufacturing - Procedures</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:31044.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Preparation of Autologous or Allogeneic Cells</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:31072.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Method of Cell Collection/Processing/Culture Conditions</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:31100.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Irradiation - If Applicable</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:31128.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Process Timing & Intermediate Storage</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:31156.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Final Harvest</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:31184.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Timing/Methods/Wash Procedure</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:31212.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Final Formulation</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:31240.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Formulation/Infusion Buffer</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:31268.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Excipients</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:90.00pt;top:31296.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Cell Density/Concentration in the Final Product</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:31310.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Storage Method Prior to Use</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:31338.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Areas of Concern for Manufacturing</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:31366.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">PRODUCT TESTING</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:31394.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">In-Process Testing and Criteria</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:31422.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Tabulation of Tests, Manufacturing Step, Test Methods, Criteria, and Test Sensitivity &</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:31435.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Specificity</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:31630.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">37</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:31680.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:31716.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:79.15pt;top:31753.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Test</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.90pt;top:31753.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Manufacturing</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.90pt;top:31767.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Step Where</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.90pt;top:31781.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Performed</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:257.40pt;top:31753.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Method</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:320.40pt;top:31753.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Criteria</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:396.90pt;top:31753.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Sensitivity</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:468.90pt;top:31753.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Specificity</FONT></FONT></FONT></SPAN>
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<SPAN STYLE="position:absolute;font-size:0;left:73pt;top:31794pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:74pt;top:31794pt;width:83pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:157pt;top:31794pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:157pt;top:31794pt;width:93pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:251pt;top:31794pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:252pt;top:31794pt;width:62pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:314pt;top:31794pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:315pt;top:31794pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:391pt;top:31794pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:391pt;top:31794pt;width:71pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:463pt;top:31794pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:463pt;top:31794pt;width:74pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:537pt;top:31794pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:73pt;top:31795pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:157pt;top:31795pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:251pt;top:31795pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:314pt;top:31795pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:391pt;top:31795pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:463pt;top:31795pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:537pt;top:31795pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:79.15pt;top:31810.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Mycoplasma</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:73pt;top:31809pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:74pt;top:31809pt;width:83pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:157pt;top:31809pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:157pt;top:31809pt;width:93pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:251pt;top:31809pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:252pt;top:31809pt;width:62pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:314pt;top:31809pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:315pt;top:31809pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:391pt;top:31809pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:391pt;top:31809pt;width:71pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:463pt;top:31809pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:463pt;top:31809pt;width:74pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:537pt;top:31809pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:73pt;top:31810pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:157pt;top:31810pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:251pt;top:31810pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:314pt;top:31810pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:391pt;top:31810pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:463pt;top:31810pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:537pt;top:31810pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:79.15pt;top:31825.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Purity</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:79.15pt;top:31839.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(endotoxin)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:73pt;top:31824pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:74pt;top:31824pt;width:83pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:157pt;top:31824pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:157pt;top:31824pt;width:93pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:251pt;top:31824pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:252pt;top:31824pt;width:62pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:314pt;top:31824pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:315pt;top:31824pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:391pt;top:31824pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:391pt;top:31824pt;width:71pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:463pt;top:31824pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:463pt;top:31824pt;width:74pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:537pt;top:31824pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:73pt;top:31825pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:157pt;top:31825pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:251pt;top:31825pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:314pt;top:31825pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:391pt;top:31825pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:463pt;top:31825pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:537pt;top:31825pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:79.15pt;top:31854.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Purity (other</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:79.15pt;top:31868.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">contaminants)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:73pt;top:31853pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:74pt;top:31853pt;width:83pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:157pt;top:31853pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:157pt;top:31853pt;width:93pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:251pt;top:31853pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:252pt;top:31853pt;width:62pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:314pt;top:31853pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:315pt;top:31853pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:391pt;top:31853pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:391pt;top:31853pt;width:71pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:463pt;top:31853pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:463pt;top:31853pt;width:74pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:537pt;top:31853pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:73pt;top:31853pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:157pt;top:31853pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:251pt;top:31853pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:314pt;top:31853pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:391pt;top:31853pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:463pt;top:31853pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:537pt;top:31853pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:79.15pt;top:31883.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Identity</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:73pt;top:31881pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:74pt;top:31881pt;width:83pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:157pt;top:31881pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:157pt;top:31881pt;width:93pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:251pt;top:31881pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:252pt;top:31881pt;width:62pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:314pt;top:31881pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:315pt;top:31881pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:391pt;top:31881pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:391pt;top:31881pt;width:71pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:463pt;top:31881pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:463pt;top:31881pt;width:74pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:537pt;top:31881pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:73pt;top:31882pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:157pt;top:31882pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:251pt;top:31882pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:314pt;top:31882pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:391pt;top:31882pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:463pt;top:31882pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:537pt;top:31882pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:79.15pt;top:31897.85pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Potency</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:73pt;top:31896pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:74pt;top:31896pt;width:83pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:157pt;top:31896pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:157pt;top:31896pt;width:93pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:251pt;top:31896pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:252pt;top:31896pt;width:62pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:314pt;top:31896pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:315pt;top:31896pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:391pt;top:31896pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:391pt;top:31896pt;width:71pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:463pt;top:31896pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:463pt;top:31896pt;width:74pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:537pt;top:31896pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:73pt;top:31897pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:157pt;top:31897pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:251pt;top:31897pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:314pt;top:31897pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:391pt;top:31897pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:463pt;top:31897pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:537pt;top:31897pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:79.15pt;top:31912.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Others (cell</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:79.15pt;top:31926.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">dose)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:73pt;top:31911pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:74pt;top:31911pt;width:83pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:157pt;top:31911pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:157pt;top:31911pt;width:93pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:251pt;top:31911pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:252pt;top:31911pt;width:62pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:314pt;top:31911pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:315pt;top:31911pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:391pt;top:31911pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:391pt;top:31911pt;width:71pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:463pt;top:31911pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:463pt;top:31911pt;width:74pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:537pt;top:31911pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:73pt;top:31912pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:157pt;top:31912pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:251pt;top:31912pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:314pt;top:31912pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:391pt;top:31912pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:463pt;top:31912pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:537pt;top:31912pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:79.15pt;top:31941.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Others (cell</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:79.15pt;top:31955.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">viability)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:73pt;top:31940pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:74pt;top:31940pt;width:83pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:157pt;top:31940pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:157pt;top:31940pt;width:93pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:251pt;top:31940pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:252pt;top:31940pt;width:62pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:314pt;top:31940pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:315pt;top:31940pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:391pt;top:31940pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:391pt;top:31940pt;width:71pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:463pt;top:31940pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:463pt;top:31940pt;width:74pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:537pt;top:31940pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:73pt;top:31940pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:73pt;top:31968pt;width:83pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:157pt;top:31940pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:157pt;top:31968pt;width:93pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:251pt;top:31940pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:252pt;top:31968pt;width:62pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:314pt;top:31940pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:315pt;top:31968pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:391pt;top:31940pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:391pt;top:31968pt;width:71pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:463pt;top:31940pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:463pt;top:31968pt;width:74pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:537pt;top:31940pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:537pt;top:31968pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:31984.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Description of Test Methods</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:32012.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">FINAL PRODUCT RELEASE CRITERIA/SPECIFICATIONS</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:32040.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Tabulation of Final Product Release Criteria Tests, Test Methods, Criteria, Test Sensitivity </FONT><FONT STYLE="font-size: 10.98pt">&</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:32053.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">Specificity</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:68.40pt;top:32081.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Test</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:157.25pt;top:32081.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Method</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.90pt;top:32081.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Criteria</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:293.40pt;top:32081.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Sensitivity</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:360.90pt;top:32081.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Specificity</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:428.40pt;top:32081.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Results Available</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:428.40pt;top:32095.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Prior to Release</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:62pt;top:32080pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:62pt;top:32080pt;width:88pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:63pt;top:32080pt;width:88pt;height: 1pt;background-color:#e4e4e4;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:151pt;top:32080pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:152pt;top:32080pt;width:59pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:152pt;top:32080pt;width:59pt;height: 1pt;background-color:#e4e4e4;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:211pt;top:32080pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:211pt;top:32080pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:211pt;top:32080pt;width:75pt;height: 1pt;background-color:#e4e4e4;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:287pt;top:32080pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:288pt;top:32080pt;width:66pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:288pt;top:32080pt;width:66pt;height: 1pt;background-color:#e4e4e4;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:355pt;top:32080pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:355pt;top:32080pt;width:66pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:355pt;top:32080pt;width:66pt;height: 1pt;background-color:#e4e4e4;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:422pt;top:32080pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:423pt;top:32080pt;width:121pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:423pt;top:32080pt;width:121pt;height: 1pt;background-color:#e4e4e4;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:32080pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:32080pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:62pt;top:32080pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:62pt;top:32108pt;width:88pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:151pt;top:32080pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:152pt;top:32108pt;width:59pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:211pt;top:32080pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:211pt;top:32108pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:287pt;top:32080pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:288pt;top:32108pt;width:66pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:355pt;top:32080pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:355pt;top:32108pt;width:66pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:422pt;top:32080pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:423pt;top:32108pt;width:121pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:32080pt;width: 1pt;height:28pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:32108pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:32124.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Description of Test Methods</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:32152.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">PRODUCT STABILITY</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:90.00pt;top:32180.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">In-Process Stability Testing</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:32208.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Cryopreserved Cells</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:32236.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Other Intermediate Holding Steps</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:90.00pt;top:32264.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Final Product Stability Testing</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:32292.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Product Formulation to Patient Infusion</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:32320.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Shipping Conditions</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:32348.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">OTHER ISSUES</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:32376.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Product Tracking</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:32422.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">38</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:31680.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile1414621255.htm_files\outputfile1414621255_background40.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:32472.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:32508.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:32544.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Labeling and Containers</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:32558.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">In-Process Labeling</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:32586.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Final Product Labeling</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:32614.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Container Closure & Integrity</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:32642.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Environmental Impact</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:32670.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Validation and Qualification of the Manufacturing Process</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:90.00pt;top:32698.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">QA/QC Program</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:90.00pt;top:32726.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Manufacturing Process Validation</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:32754.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Biostatistics</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:32782.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">PRECLINICAL STUDIES</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:32810.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">CLINICAL STUDIES</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:32838.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Protocol Title</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:32866.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Subject Population</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:32894.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Route of Administration</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:32922.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Dose</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:32950.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Frequency</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:32978.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Genetic, Biochemical, and Immunological Testing</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:33006.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Informed Consent</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:33034.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">RECOMMENDATION</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:33062.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">COMMENTS TO SPONSOR</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:33090.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Clinical Hold</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:33104.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Non-Clinical Hold</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:87.00pt;top:33146.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><u><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Signature</FONT></FONT></i></u></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:198.00pt;top:33146.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Date:____________________</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:33160.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Reviewer Name</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:33214.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">39</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:33264.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:33300.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:33336.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">APPENDIX B – CONSIDERATIONS FOR DEVELOPMENT OF FINAL PRODUCT</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:33350.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">RELEASE CRITERIA SPECIFICATIONS AND STABILITY PROTOCOLS</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:33378.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Specifications are the quality standards (i.e., tests, analytical procedures, and acceptance criteria)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:33392.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">that confirm the quality of products and other materials used in the production of a product.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:33406.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Acceptance criteria are the numerical limits, ranges, or other criteria for the tests described.  For</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:33420.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">additional information, see ICH Guideline Q6B:  “Test Procedures and Acceptance Criteria for</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:33434.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Biotechnological/Biological Products”.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:261.55pt;top:33432.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">4</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:272.10pt;top:33434.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">We believe that certain release specifications, such as</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:33448.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">those related to product safety, should be in place prior to initiating Phase 1 clinical studies.  As</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:33462.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">product development proceeds, additional specifications for product quality and manufacturing</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:33476.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">consistency are developed and implemented.  For additional discussion of manufacturing quality</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:33490.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">control, see “Guidance for Industry: Guideline on the Preparation of Investigational New Drug</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:33504.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Products” and “Guidance for Industry: IND Meetings for Human Drugs and Biologics;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:119.95pt;top:33502.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">5</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:33518.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Chemistry, Manufacturing and Controls Information”.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:333.30pt;top:33516.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">6</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:33546.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">A.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:33546.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Development of Release Acceptance Criteria</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:33574.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">We recommend that proposed release acceptance criteria for the final product be based</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:33588.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">on scientific data and manufacturing experience obtained during development of the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:33602.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">product as described below:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:33629.75pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:33631.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Phase 1 – Based on data from lots used in preclinical studies.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:33644.55pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:33645.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Phase 2 – Refine and tighten based on data generated during Phase 1.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:33659.30pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:33660.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Phase 3 – Based on information collected during product development.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:33674.05pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:33675.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Licensure – Based on information collected during product development</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:33689.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">using validated assays.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:33717.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">B.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:33717.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Development of Acceptance Criteria Analytical Procedures</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:33745.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">We recommend that proposed analytical procedures be based on scientific data and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:33759.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">manufacturing experience as described below:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:33786.75pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:33788.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Phase 1-3 – Usually based on Code of Federal Regulation (CFR) methods</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:33802.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">or alternative methods, if appropriate.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:33815.45pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:33816.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Phase 2 – If an alternative to the CFR method is used, we recommend that</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:33830.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the sponsor initiate validation of the alternative by Phase 3.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:33844.20pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:33845.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Licensure – The product specification should be in place and established</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:33859.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">under a validated assay.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:72pt;top:33891pt;width:144pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:33898.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 6.48pt">4</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:77.75pt;top:33900.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Guidance for Industry:  Q6B Specifications:  Test Procedures and Acceptance Criteria for</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:33912.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Biotechnological/Biological Products, August 1999, http://www.fda.gov/cder/guidance/Q6Bfnl.pdf.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:33922.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 6.48pt">5</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:77.75pt;top:33923.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Guidance for Industry: Guideline on the Preparation of Investigational New Drug Products (Human and Animal),</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:33935.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">dated March 1991, reprinted November 1992, http://www.fda.gov/cder/guidance/old042fn.pdf.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:33945.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 6.48pt">6</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:77.75pt;top:33947.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Guidance for Industry: IND Meetings for Human Drugs and Biologics; Chemistry, Manufacturing and Controls</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:33958.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Information, May 2001, http://www.fda.gov/cber/gdlns/ind052501.htm</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:34006.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">40</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:34056.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:205.25pt;top:34092.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Contains Nonbinding Recommendations</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:34142.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">C.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:34142.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Development of Stability Protocols</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:34170.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">In order to develop adequate stability data for timely submission in a license application,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:34184.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">we recommend that a sponsor implement and expand the stability program as described</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:34198.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">below:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:34225.95pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:34227.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Phase 1 - 3 – Preliminary data on product stability must indicate whether</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:34241.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the product or components are likely to remain stable for the duration of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:34255.25pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the clinical trial.  Note:  the regulations require that the IND contain these</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:34269.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">data at each stage of the clinical trial (21 CFR 312.23(a)(7)(ii)).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:34282.65pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:34284.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Phase 2 – We recommend that the sponsor initiate a stability protocol to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:34297.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">accumulate additional data.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:162.00pt;top:34311.35pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">x</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:34312.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Phase 3 – We recommend that the sponsor begin to establish the dating</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:34326.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">period, storage conditions, and shipping conditions based on data derived</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:34340.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">from the stability protocol.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:34798.60pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">41</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:34848.00pt"> </SPAN>
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