
[Federal Register Volume 79, Number 127 (Wednesday, July 2, 2014)]
[Notices]
[Pages 37743-37747]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2014-15370]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2014-D-0779]


Draft Guidance for Industry on Current Good Manufacturing 
Practice--Interim Guidance for Human Drug Compounding Outsourcing 
Facilities Under the Federal Food, Drug and Cosmetic Act; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing the 
availability of a draft guidance for industry entitled ``Current Good 
Manufacturing Practice--Interim Guidance for Human Drug Compounding 
Outsourcing Facilities under Section 503B of the FD&C Act.'' This draft 
guidance describes FDA's current expectations regarding compliance with 
current good manufacturing practice (CGMP) requirements for facilities 
that compound human drugs and register with FDA as outsourcing 
facilities under the Federal Food, Drug, and Cosmetic Act (the FD&C 
Act), in accordance with provisions added by the Drug Quality and 
Security Act (DQSA). FDA is also soliciting public input on specific 
potential alternative approaches regarding certain CGMP requirements. 
These potential approaches are explained in detail in the draft 
guidance.

DATES: Although you can comment on any guidance at any time (see 21 CFR 
10.115(g)(5)), to ensure that the Agency considers your comment on this 
draft guidance before it begins work on the final version of the 
guidance, submit either electronic or written comments on the draft 
guidance by September 2, 2014.

ADDRESSES: Submit written requests for single copies of the draft 
guidance to the Division of Drug Information, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 2201, Silver Spring, MD 20993-0002. Send 
one self-addressed adhesive label to assist that office in processing 
your requests. See the SUPPLEMENTARY INFORMATION section for electronic 
access to the draft guidance document.
    Submit electronic comments on the draft guidance to http://www.regulations.gov. Submit written comments to the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Brian Hasselbalch, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 4364, Silver Spring, MD 20993-0002, 301-
796-3279.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a draft guidance for industry 
entitled ``Current Good Manufacturing Practice-Interim Guidance for 
Human Drug Compounding Outsourcing Facilities under Section 503B of the 
FD&C Act.'' On November 27, 2013, President Obama signed the DQSA 
(Public Law 113-54), which added section 503B to the FD&C Act (21 
U.S.C. 353b). Under section 503B(b) of the FD&C Act, a compounder can 
register as an outsourcing facility with FDA. Drug products compounded 
in a registered outsourcing facility can qualify for exemptions from 
the FDA approval requirements in section 505 of the FD&C Act (21 U.S.C. 
355) and the requirement to label products with adequate directions for 
use under section 502(f)(1) of the FD&C Act (21 U.S.C. 352(f)(1)) if 
the requirements in section 503B are met. Outsourcing facilities will 
be inspected by FDA and must comply with other provisions of the FD&C 
Act, including CGMP requirements under section 501(a)(2)(B) (21 U.S.C. 
351(a)(2)(B)).
    Under section 501(a)(2)(B) of the FD&C Act, a drug is deemed to be 
adulterated if it is not produced in accordance with CGMP. FDA's 
regulations regarding CGMP requirements for the preparation of drug 
products have been established in 21 CFR parts 210 and 211. FDA intends 
to issue more specific CGMP regulations for outsourcing facilities. 
Until final regulations are issued, this draft guidance describes FDA's 
expectations regarding outsourcing facilities and the CGMP requirements 
in parts 210 and 211 during this interim period. This draft guidance 
reflects FDA's intent to recognize the differences between compounding 
outsourcing facilities and conventional drug manufacturers, and to 
tailor CGMP requirements to the nature of the specific compounding 
operations conducted by outsourcing facilities while maintaining the 
minimum standards necessary to protect patients from the risks of 
contaminated or otherwise substandard compounded drug products. This 
draft guidance is only applicable to drugs compounded in accordance 
with section 503B of the FD&C Act.
    FDA intends to focus its inspectional and enforcement efforts on 
those aspects of compounding operations that pose the highest risk to 
patient safety. In particular, the primary focus of this draft guidance 
is on those aspects of part 211 that relate to sterility assurance of 
sterile drug products and the safety of compounded drug products more 
generally, with respect to strength (e.g., subpotency, superpotency), 
and labeling or drug product mix-ups.

II. Specific Request for Comments and Information

    In addition to comments on the draft guidance generally, FDA is 
requesting comments and related supporting information on the following 
specific issues: (1) alternative approaches that would enable an 
outsourcing facility to have confidence in the quality of incoming 
components from sources used by multiple outsourcing facilities without 
each individual outsourcing facility having to conduct periodic 
laboratory testing to confirm the information in the third-party 
supplier's certificate of analysis and (2) alternative approaches that 
would minimize the need for outsourcing facilities to establish an in-
house laboratory while providing confidence about the accuracy of 
testing performed by a third party used by more than one outsourcing 
facility. FDA has described these potential alternative approaches in 
the draft guidance and is seeking public comment on these and any other 
alternative approaches.
    This draft guidance is being issued consistent with FDA's good 
guidance practices regulation (21 CFR 10.115). The draft guidance, when 
finalized, will

[[Page 37744]]

represent the Agency's current thinking on ``Current Good Manufacturing 
Practice-Interim Guidance for Human Drug Compounding Outsourcing 
Facilities under Section 503B of the FD&C Act.'' It does not create or 
confer any rights for or on any person and does not operate to bind FDA 
or the public. An alternative approach may be used if such approach 
satisfies the requirements of the applicable statutes and regulations.

III. Comments

    Interested persons may submit electronic comments regarding this 
document to http://www.regulations.gov, or written comments to the 
Division of Dockets Management (see ADDRESSES). It is only necessary to 
send one set of comments. Identify comments with the docket number 
found in brackets in the heading of this document. Received comments 
may be seen in the Division of Dockets Management between 9 a.m. and 4 
p.m., Monday through Friday, and will be posted to the docket at http://www.regulations.gov.

IV. Paperwork Reduction Act of 1995

    This draft guidance contains information collection provisions that 
are subject to review by the Office of Management and Budget (OMB) 
under the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 3501-
3520). The title, description, and respondent description of the 
information collection are given under this section with an estimate of 
the annual recordkeeping, third-party disclosure, and reporting 
burdens. Included in the estimate is the time for reviewing 
instructions, searching existing data sources, gathering and 
maintaining the data needed, and completing and reviewing the 
collection of information.
    We invite comments on these topics: (1) Whether the proposed 
collection of information is necessary for the proper performance of 
FDA's functions, including whether the information will have practical 
utility; (2) the accuracy of FDA's estimate of the burden of the 
proposed collection of information, including the validity of the 
methodology and assumptions used; (3) ways to enhance the quality, 
utility, and clarity of the information to be collected; and (4) ways 
to minimize the burden of the collection of information on respondents, 
including through the use of automated collection techniques, when 
appropriate, and other forms of information technology.
    Title: Guidance for Industry, Current Good Manufacturing Practice--
Interim Guidance for Human Drug Compounding Outsourcing Facilities 
under Section 503B of the FD&C Act.
    Description: The draft guidance describes FDA's expectations 
regarding compliance with CGMP requirements for facilities that 
register with FDA as outsourcing facilities under section 503B of the 
FD&C Act. The primary focus of the draft guidance is on sterility 
assurance of sterile products and the safety of compounded drug 
products with respect to strength (e.g., subpotency, superpotency), and 
labeling or drug product mix-ups. OMB has already approved the 
information collection (recordkeeping) contained in FDA's CGMP 
regulations in part 211 (OMB control number 0910-0139). FDA believes 
that much of the recordkeeping burden that would result from the draft 
guidance is already incurred by outsourcing facilities in the normal 
course of their business activities. Thus, the burden estimates for 
these ``usual and customary'' business practices are not included in 
the calculation of burden that follows (see 5 CFR 1320.3(b)(2).
    The draft guidance contains the following collections of 
information under the PRA:

1. Facility Design

    The draft guidance describes those elements of facility design of 
outsourcing facilities that are considered critical to assuring the 
quality of compounded sterile drug products at those facilities. For 
example, the draft guidance states that sterile drugs should be 
produced only in ISO 5 or better air quality, and that the ISO 5 zone 
or critical area must be qualified (i.e., shown to meet the 
specifications). In section III.A, the draft guidance lists certain 
studies and tests which should be successfully performed for 
outsourcing facilities, and states that the results of these studies 
and tests should be documented.
    We estimate that annually a total of approximately 50 outsourcing 
facilities \1\ (``No. of Recordkeepers'' in table 1, row 1) will 
individually document approximately 20 studies and tests (``Total 
Annual Records'' in table 1, row 1) that are critical to assuring the 
quality of compounded sterile drug products. We also estimate that 
preparing and maintaining each record as described in the draft 
guidance will take on average approximately 1.5 hours for each record 
(``Average Burden per Recordkeeping'' in table 1, row 1).
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    \1\ This is an estimate of the number of facilities that will 
register as outsourcing facilities in fiscal year 2014 (which runs 
from October 1, 2013 to September 30, 2014). As of April 30, 2014, 
40 facilities had registered as outsourcing facilities, and on 
average, 2 facilities have registered each month for the past 3 
months, but these estimates are highly uncertain. Annual 
establishment fees will be assessed for each outsourcing facility 
registered on or after October 1, 2014. It is unknown how many 
facilities will remain as registered outsourcing facilities once 
these fees take effect.
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2. Control Systems and Procedures for Maintaining Suitable Facilities

    The draft guidance describes certain controls, procedures, and 
documentation that should be established and followed for maintaining 
suitable facilities and to prevent contamination and mix-ups during the 
course of aseptic operations at outsourcing facilities. Procedures must 
be established that assign responsibility for and describe cleaning 
schedules, methods, equipment, and materials. In addition, the guidance 
describes that procedures should ensure recording of instances when 
there is a loss of positive pressure in the clean room during 
production.
    We estimate that annually a total of approximately 50 outsourcing 
facilities (``No. of Recordkeepers'' in table 1, row 2) will 
individually establish and maintain approximately 3 records (procedures 
and documentation) for maintaining suitable outsourcing facilities 
(``Total Annual Records'' in table 1, row 2). We also estimate that 
preparing and maintaining each record as described in section III.B of 
the draft guidance will take on average approximately 5 hours for each 
record (``Average Burden per Recordkeeping'' in table 1, row 2).

3. Environmental and Personnel Monitoring

    Under the draft guidance, procedures for environmental and 
personnel monitoring in the aseptic processing area for viable, 
nonviable, and total particulate matter should be established and 
followed in outsourcing facilities. The procedures should include 
establishing the validity of the microbiological media, including the 
preparation, sterilization, and growth potential of the media used in 
performing tests.
    We estimate that annually a total of approximately 50 outsourcing 
facilities (``No. of Recordkeepers'' in table 1, row 3) will 
individually establish approximately 1,200 environmental and personnel 
monitoring procedures and records to document test results (``Total 
Annual Records'' in table 1, row 3) for the aseptic processing areas. 
We also estimate that preparing and maintaining the environmental and 
personnel monitoring procedures as described in section III.C of the 
draft guidance will take on average approximately 0.25

[[Page 37745]]

hours for each record (``Average Burden per Recordkeeping'' in table 1, 
row 3).

4. Equipment, Containers, and Closures

    Procedures and documentation should be established and maintained 
for testing compounding equipment and containers and closures to ensure 
the quality of compounded drug products at outsourcing facilities.
    We estimate that annually a total of approximately 50 outsourcing 
facilities (``No. of Recordkeepers'' in table 1, row 4) will 
individually establish and maintain approximately 1,000 procedures and 
documentation for testing equipment, containers, and closures (``Total 
Annual Records'' in table 1, row 4) in the aseptic processing areas. We 
also estimate that preparing and maintaining these procedures and 
documentation as described in section III.D of the draft guidance will 
take on average approximately 0.25 hours for each record (``Average 
Burden per Recordkeeping'' in table 1, row 4).

5. Components

    Procedures should be established and records maintained concerning 
the source and quality of components such as raw materials or 
ingredients used in producing compounded sterile drug products at 
outsourcing facilities.
    We estimate that annually a total of approximately 50 outsourcing 
facilities (``No. of Recordkeepers'' in table 1, row 5) will 
individually establish and maintain approximately 240 records of 
testing to ensure the quality of components used in producing 
compounded drugs, as recommended in section III.E of the draft guidance 
(``Total Annual Records'' in table 1, row 5). We also estimate that 
preparing and maintaining these records will take on average 
approximately 4 hours for each record (``Average Burden per 
Recordkeeping'' in table 1, row 5).

6. Production and Process Controls

    Production and process documentation and procedures, such as batch 
records, must be established to assure the quality of compounded 
sterile drug products at outsourcing facilities. Training on aseptic 
technique, cleanroom behavior, gowning, and procedures covering aseptic 
manufacturing area operations must be established. Sterilization 
validation of operations (e.g., holding vessels, filling equipment, 
lyophilizer) and periodic verification activities and results must be 
documented.
    We estimate that annually a total of approximately 50 outsourcing 
facilities (``No. of Recordkeepers'' in table 1, row 6) will 
individually establish and maintain approximately 5,000 records 
pertaining to production and process controls, such as validation 
procedures and training, to assure the quality of compounded sterile 
drug products (``Total Annual Records'' in table 1, row 6). We also 
estimate that preparing and maintaining these records, as described in 
section III.F of the draft guidance, will take on average approximately 
0.25 hours for each record (``Average Burden per Recordkeeping'' in 
table 1, row 6).

7. Release Testing

    Compounded drug products produced at outsourcing facilities must be 
tested to determine whether they meet final product specifications 
prior to release for distribution, and procedures for final release 
testing must be established and followed.
    We estimate that annually a total of approximately 50 outsourcing 
facilities (``No. of Recordkeepers'' in table 1, row 7) will 
individually establish and maintain approximately 240 records 
pertaining to final release testing of compounded drug products, 
including release testing procedures and documentation (``Total Annual 
Records'' in table 1, row 7). We also estimate that preparing and 
maintaining these records, as described in section III.G of the draft 
guidance, will take on average approximately 4 hours for each record 
(``Average Burden per Recordkeeping'' in table 1, row 7).
    If sterility testing is not completed prior to release under 
certain conditions described in section III.G of the draft guidance, 
procedures must be established that specify that if the product fails 
to meet a criterion for sterility, all healthcare and other facilities 
that received the product must be immediately notified of the test 
results and provided with any appropriate information and 
recommendations to aid in the treatment of patients; the notification 
must be documented; and FDA must be notified in writing.
    We estimate that annually a total of approximately 10 outsourcing 
facilities (``No. of Respondents'' in table 2, row 1) will individually 
send approximately 1 notification of test results to all healthcare and 
other facilities that received the compounded drug product and provide 
them with any appropriate information and recommendations to aid in the 
treatment of patients (``Total Annual Disclosures'' in table 2, row 1). 
We also estimate that preparing and sending each notification will take 
approximately 5 hours (``Average Burden per Disclosure'' in table 2, 
row 1).
    We also estimate that annually, a total of approximately 10 
outsourcing facilities (``No. of Respondents'' in table 3) will 
individually submit to FDA 1 notification of the test results for any 
compounded drug product that fails to meet a sterility criterion 
(``Total Annual Responses'' in table 3). Preparing and submitting this 
information will take approximately 5 hours per notification (``Average 
Burden per Response'' in table 3).

8. Laboratory Controls

    Each laboratory used to conduct testing of components, in-process 
materials, and finished drug products for outsourcing facilities must 
follow written procedures for the conduct of each test and document the 
results, establish sampling and testing procedures to ensure that 
components, in-process materials, and drug products conform to the 
product specifications, and keep complete records of all tests 
performed to ensure compliance with established specifications and 
standards, including examinations and assays.
    We estimate that annually a total of approximately 50 outsourcing 
facilities (``No. of Recordkeepers'' in table 1, row 8) will 
individually establish and maintain approximately 1,000 laboratory 
records as described in section III.H of the draft guidance (``Total 
Annual Records'' in table 1, row 8). We also estimate that preparing 
and maintaining these records will take on average approximately 0.5 
hours for each record (``Average Burden per Recordkeeping'' in table 1, 
row 8).

9. Stability/Expiration Dating

    Stability testing is used to ensure that a drug product will retain 
its quality (in particular, strength) and remain sterile through the 
labeled expiration date. The draft guidance recommends that procedures 
established by outsourcing facilities for assessing the stability of 
drug products should include: (1) using stability-indicating test 
methods that are reliable, meaningful and specific; (2) evaluating 
samples of the drug product in the same container closure system in 
which the drug product will be marketed; (3) evaluating samples for 
stability that are representative of the lot or batch from which they 
were obtained and are stored under suitable conditions; and (4) testing 
to evaluate antimicrobial effectiveness (resistance to antimicrobial 
contamination) for drug products labeled or intended to be multiple 
dose.
    We estimate that annually a total of approximately 50 outsourcing 
facilities (``No. of Recordkeepers'' in table 1, row

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9) will individually establish and maintain approximately 90 procedures 
for stability studies to determine an expiration date (``Total Annual 
Records'' in table 1, row 9) for compounded drug products. We also 
estimate that preparing and maintaining these procedures as described 
in section III.I of the draft guidance will take approximately 5 hours 
for each record (``Average Burden per Recordkeeping'' in table 1, row 
9).

10. Packaging and Labels

    Packaging of sterile drugs must ensure the sterility and integrity 
of the product until it is administered to a patient, and product 
labels must contain required information and labeling operations must 
include controls to prevent mix-ups. Procedures should be established 
by outsourcing facilities for packaging and labeling operations for 
compounded sterile drug products, including the following: (1) The 
container, closure, and packaging systems should provide adequate 
protection against foreseeable external factors in storage, shipment, 
and use that can cause contamination or deterioration; (2) packaging 
records should include specimens of all labels used; procedures should 
be established for issuance of labels, examination of issued labels, 
reconciliation of used labels to prevent mix-ups; (3) there should be 
physical/spatial separation between different labeling and packaging 
operations to prevent mix-ups; and (4) controls should be established 
that assure proper identification of any filled containers of sterile 
products that are stored unlabeled for any period of time.
    We estimate that annually a total of approximately 50 outsourcing 
facilities (``No. of Recordkeepers'' in table 1, row 10) will 
individually establish and maintain approximately 20 procedures and 
records for packaging operations and labels (``Total Annual Records'' 
in table 1, row 10) for compounded drug products. We also estimate that 
preparing and maintaining these procedures and records as described in 
section III.J of the draft guidance will take approximately 5.5 hours 
for each record (``Average Burden per Recordkeeping'' in table 1, row 
10).

11. Quality Assurance Activities

    A quality control unit must be established by outsourcing 
facilities to oversee various aspects of compounded sterile drug 
production and to monitor quality assurance. The responsibilities of 
the quality control unit must be established in procedures and should 
include investigations and development and oversight of appropriate 
corrective actions and preventive actions regarding: Rejected lots of 
finished product, unexpected results or trends, validation and 
stability failures, and process deviations or equipment malfunctions 
that involve critical equipment. The quality control unit also is 
responsible for ensuring that sampling and testing are conducted to 
ensure that appropriate specifications are met, and for product 
complaint handling.
    We estimate that annually a total of approximately 50 outsourcing 
facilities (``No. of Recordkeepers'' in table 1, row 11) will 
individually establish approximately 8 procedures on the 
responsibilities of the quality control unit (``Total Annual Records'' 
in table 1, row 10) as described in section III.K of the draft 
guidance. We also estimate that preparing and maintaining these 
procedures will take approximately 3 hours for each record (``Average 
Burden per Recordkeeping'' in table 1, row 11).
    The total estimated recordkeeping, third party disclosure, and 
reporting burdens for the draft guidance are as follows:

                               Table 1--Estimated Annual Recordkeeping Burden \1\
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                                                   Number of                     Average burden
     Type of recordkeeping         Number of      records per    Total annual          per          Total hours
                                 recordkeepers   recordkeeper       records       recordkeeping
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Facility Design...............              50              20           1,000  1.5.............           1,500
Control Systems and Procedures              50               3             150  5...............             750
 For Maintaining Suitable
 Facilities.
Environmental and Personnel                 50           1,200          60,000  0.25 (15                  15,000
 Monitoring.                                                                     minutes).
Equipment, Containers, and                  50           1,000          50,000  0.25 (15                  12,500
 Closures.                                                                       minutes).
Components....................              50             240          12,000  4...............          48,000
Production and Process                      50           5,000         250,000  0.25 (15                  62,500
 Controls.                                                                       minutes).
Release Testing...............              50             240          12,000  4...............          48,000
Laboratory Controls...........              50           1,000          50,000  0.5 (30 minutes)          25,000
Stability/Expiration Dating...              50              90           4,500  5...............          22,500
Packaging and Labels..........              50              20           1,000  5.5.............           5,500
Quality Assurance Activities..              50               8             400  3...............           1,200
                               ---------------------------------------------------------------------------------
    Total.....................              50           8,821         441,050  ................         242,450
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.


                           Table 2--Estimated Annual Third-Party Disclosure Burden \1\
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 Type of disclosure & proposed     Number of     Frequency per   Total annual    Average burden
        21 CFR section            respondents     disclosure      disclosures    per disclosure     Total hours
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Notification that a compounded              10               1              10  5...............              50
 drug product fails to meet a
 sterility criterion.
An expiration date is added to              50             540          27,000  0.25 (15                   6,750
 the compounded drug product's                                                   minutes).
 label.
                               ---------------------------------------------------------------------------------
    Total.....................           6,800
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.


[[Page 37747]]


                                 Table 3--Estimated Annual Reporting Burden \1\
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                                                     Number of                        Average
 Type of reporting & proposed 21     Number of     responses per   Total annual     burden per      Total hours
           CFR section              respondents     respondent       responses       response
----------------------------------------------------------------------------------------------------------------
Notification to FDA that a                    10               1              10               5              50
 compounded drug product fails
 to meet a sterility criterion..
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

V. Electronic Access

    Persons with access to the Internet may obtain the document at 
either http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm or http://www.regulations.gov.

    Dated: June 25, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-15370 Filed 7-1-14; 8:45 am]
BILLING CODE 4164-01-P


