
[Federal Register Volume 80, Number 207 (Tuesday, October 27, 2015)]
[Notices]
[Pages 65765-65768]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-27271]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2015-N-3534]


Bulk Drug Substances That Can Be Used To Compound Drug Products 
in Accordance With Section 503A of the Federal Food, Drug, and Cosmetic 
Act; Establishment of a Public Docket

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice; establishment of public docket.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is developing 
a list of bulk drug substances (active ingredients) that can be used to 
compound drug products in accordance with the Federal Food, Drug, and 
Cosmetic Act (the FD&C Act), although they are neither the subject of 
an applicable United States Pharmacopeia (USP) or National Formulary 
(NF) monograph nor components of FDA-approved drugs (503A bulks list). 
The Agency previously solicited nominations for the list, but some of 
the nominated substances were not supported by sufficient information 
for FDA to evaluate them. FDA is establishing a public docket where 
these substances can be renominated with sufficient supporting 
information or to receive nominations of bulk drug substances that were 
not previously nominated for consideration for inclusion on the 503A 
bulks list. Interested parties can also submit comments on nominated 
substances via this docket.

DATES: Nominations and comments may be submitted to this docket at any 
time.

ADDRESSES: You may submit comments as follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to http://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on http://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand delivery/Courier (for written/paper 
submissions): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Division of 
Dockets Management, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2015-N-3534 for ``Bulk Drug Substances That Can Be Used To Compound 
Drug Products in Accordance With Section 503A of the Federal Food, 
Drug, and Cosmetic Act; Establishment of a Public Docket.'' Received 
comments will be placed in the docket and, except for those submitted 
as ``Confidential Submissions,'' publicly viewable at http://www.regulations.gov or at the Division of Dockets Management between 9 
a.m. and 4 p.m., Monday through Friday.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on http://www.regulations.gov. 
Submit both copies to the Division of Dockets Management. If you do not 
wish your name and contact information to be made publicly available, 
you can provide this information on the cover sheet and not in the body 
of your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: http://www.fda.gov/regulatoryinformation/dockets/default.htm.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to http://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Division of Dockets Management, 5630 Fishers 
Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Philantha Bowen, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 5175, Silver Spring, MD 20993-0002, 301-
796-2466.

SUPPLEMENTARY INFORMATION:

I. Background

    Section 503A of the FD&C Act (21 U.S.C. 353a) describes the 
conditions under which a compounded drug

[[Page 65766]]

product may be entitled to an exemption from certain sections of the 
FD&C Act. Those conditions include that a licensed pharmacist in a 
State licensed pharmacy or Federal facility or a licensed physician 
compounds the drug product using bulk drug substances that: (1) Comply 
with the standards of an applicable USP or NF monograph, if a monograph 
exists, and the USP chapter on pharmacy compounding; (2) if such a 
monograph does not exist, are drug substances that are components of 
drugs approved by the Secretary; or (3) if such a monograph does not 
exist and the drug substance is not a component of a drug approved by 
the Secretary, that appear on a list developed by the Secretary through 
regulations issued by the Secretary under subsection (c) of section 
503A. See section 503A(b)(1)(A)(i) of the FD&C Act. Under section 
503A(c)(2) of the FD&C Act, the criteria for determining which 
substances should appear on the 503A bulks list ``shall include 
historical use, reports in peer reviewed medical literature, or other 
criteria the Secretary may identify.''
    Section 503A refers to the definition of ``bulk drug substance'' in 
FDA regulations at Sec.  207.3(a)(4) (21 CFR 207.3(a)(4)). See section 
503A(b)(1)(A) of the FD&C Act. As defined in Sec.  207.3(a)(4), a 
``bulk drug substance'' is any substance that is represented for use in 
a drug and that, when used in the manufacturing, processing, or 
packaging of a drug, becomes an active ingredient or a finished dosage 
form of the drug, but the term does not include intermediates used in 
the synthesis of such substances.
    An ``active ingredient'' is any component that is intended to 
furnish pharmacological activity or other direct effect in the 
diagnosis, cure, mitigation, treatment, or prevention of disease, or to 
affect the structure or any function of the body of man or other 
animals. The term includes those components that may undergo chemical 
change in the manufacture of the drug product and be present in the 
drug product in a modified form intended to furnish the specified 
activity or effect. See 21 CFR 210.3(b)(7).
    Any component other than an active ingredient is an ``inactive 
ingredient.'' See 21 CFR 210.3(b)(8). Inactive ingredients used in 
compounded drug products, which commonly include flavorings, dyes, 
diluents, or other excipients, need not appear on the Secretary's list 
of bulk drug substances to be eligible for use in compounding drug 
products and will not be included on the list.
    In a notice dated November 27, 2013 (the November 27, 2013, 
notice), published in the Federal Register of December 4, 2013 (78 FR 
72841), FDA invited all interested persons to nominate bulk drug 
substances for inclusion on a list of bulk drug substances that can be 
used for compounding under section 503A of the FD&C Act. Over 2,000 
substances were nominated. However, many of the nominations were for 
substances that can be used for compounding without being on the list 
because they are the subject of an applicable USP or NF monograph or 
are a component of an FDA-approved drug. In addition, many of the 
nominations were not for bulk drug substances used in compounding as 
active ingredients, or did not include sufficient information to allow 
FDA to evaluate the substance for inclusion on the list. To improve the 
efficiency of the process for developing the 503A bulks list, FDA 
reopened the nomination process in July 2014 (79 FR 37742, July 2, 
2014) and provided more detailed information on what it needs to 
evaluate nominations for the list. FDA stated that bulk drug substances 
that were previously nominated would not be considered further unless 
they were re-nominated with adequate support to permit a meaningful 
evaluation. Substances that were already eligible for use in 
compounding or that were not adequately supported would not be 
evaluated for placement on the list.
    In response to the July 2, 2014, request for nominations, 
approximately 740 unique substances were nominated. Of the nominated 
substances, approximately 275 are already eligible for use in 
compounding because they are either components of an approved drug or 
the subject of an applicable USP or NF monograph. At least nine of the 
nominated substances are not eligible for inclusion on the list because 
they are either a finished drug product, a biological product subject 
to licensure in a biologics license application (BLA), a 
radiopharmaceutical drug product, a substance with no currently 
accepted medical use that is included on Schedule I of the Controlled 
Substances Act (21 U.S.C. 812(c)), or they appear on the list published 
by FDA of substances that have been withdrawn or removed from the 
market because such drug products or components of such drug products 
have been found to be unsafe or not effective. Of the substances that 
are not components of an FDA-approved drug or the subject of an 
applicable USP or NF monograph, not biological products subject to 
licensure in a BLA, not radiopharmaceuticals, do not appear on Schedule 
I, and do not appear on the withdrawn or removed list, approximately 
390 substances were nominated with insufficient supporting evidence for 
FDA to evaluate them.

II. Establishment of a Docket

    As described in section III.B of the draft guidance entitled, 
``Interim Policy on Compounding Using Bulk Drug Substances Under 
Section 503A of the Federal Food, Drug, and Cosmetic Act,'' FDA is 
establishing a public docket so that interested parties can comment on 
nominated bulk drug substances, nominate bulk drug substances that were 
not previously nominated for the 503A bulks list, or renominate with 
adequate supporting information bulk drug substances that were 
previously nominated but that were not supported by sufficient 
information for FDA to evaluate them. Docket No. FDA-2013-N-1525 is 
closed for comment. Therefore, this new docket can be used for 
commenting on nominations submitted to that docket as well as for 
submitting new nominations.
    As stated previously, under section 503A(c)(2) of the FD&C Act, the 
criteria for determining which substances should appear on the 503A 
bulk drugs list shall include historical use, reports in peer reviewed 
medical literature, or other criteria the Secretary may identify. Based 
on this statutory language and consultations with the USP and the 
Pharmacy Compounding Advisory Committee (PCAC),\1\ FDA is considering 
the use of the following four criteria to determine whether a bulk drug 
substance is appropriate for use in compounding: (1) The physical and 
chemical characterization of the substance; (2) any safety issues 
raised by the use of the substance in compounded drug products; (3) 
historical use of the substance in compounded drug products, including 
information about the medical condition(s) the substance has been used 
to treat and any references in peer-reviewed medical literature; and 
(4) the available evidence of effectiveness or lack of effectiveness of 
a drug product compounded with the substance, if any such evidence 
exists. Therefore, to be considered for placement on the 503A bulks 
list, this information should be submitted for each nominated 
substance. FDA will

[[Page 65767]]

evaluate the nominated substances in consultation with the USP and the 
PCAC.
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    \1\ See 64 FR 996, January 7, 1999 (proposed rule listing bulk 
drug substances that may be used in pharmacy compounding). This 
proposed rule was withdrawn in the November 27, 2013, notice but 
sets forth additional background about the criteria used in the 
evaluation of nominated bulk drug substances. The criteria were 
discussed with the PCAC, the membership of which includes a USP 
representative, at its meeting on February 22, 2015.
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    Interested groups and individuals may nominate specific bulk drug 
substances for inclusion on the 503A bulks list, renominate previously 
nominated substances with additional information, or comment on 
nominated substances. Nominations will only be evaluated if they are 
for specific active ingredients that: (1) Meet the definition of a bulk 
drug substance in Sec.  207.3(a)(4); (2) are not components of FDA-
approved drug products; and (3) are not substances that are the subject 
of an applicable USP or NF monograph. To fully evaluate a bulk drug 
substance using the criteria identified above, FDA needs the following 
information about both the nominated bulk drug substance and the drug 
product(s) that will be compounded using such substance:

A. Confirmation That the Nominated Substance Is a Bulk Drug Substance 
and Is Not Already Eligible for 503A Compounding

     A statement that the nominated substance is an active 
ingredient that meets the definition of ``bulk drug substance'' in 
Sec.  207.3(a)(4), and an explanation of why the substance is 
considered an active ingredient when it is used in the identified 
compounded drug product(s), citing to specific sources that describe 
the active properties of the substance.
     A statement that the nominator has searched for the active 
ingredient in all three sections of the Orange Book (for prescription 
drug products, over-the-counter drug products, and discontinued drug 
products), available at http://www.accessdata.fda.gov/scripts/cder/ob/docs/queryai.cfm, and the drug substance did not appear in any of those 
searches, confirming that the substance is not a component of any FDA-
approved product.
     A statement that the nominator has searched applicable USP 
and NF drug monographs, available at http://www.uspnf.com, and the drug 
substance is not the subject of such a monograph.

B. General Background on the Bulk Drug Substance

     Ingredient name;
     Chemical name;
     Common name(s);
     Identifying codes, as available, from FDA's Unique 
Ingredient Identifiers (UNII) used in the FDA/USP Substance 
Registration System, available at http://fdasis.nlm.nih.gov/srs/. 
Because substance names can vary, this code, where available, will be 
used by the Agency to confirm the exact substance nominated and to 
identify multiple nominations of the same substance so the information 
can be reviewed together.
     Chemical grade of the ingredient;
     Description of the strength, quality, stability, and 
purity of the ingredient, and a copy of a certificate of analysis that 
is representative of the characteristics of the nominated ingredient;
     Information about how the ingredient is supplied (e.g., 
powder, liquid); and
     Information about recognition of the substance in foreign 
pharmacopeias and the status of its registration(s) in other countries, 
including whether information has been submitted to the USP for 
consideration of monograph development.

C. Information on the Drug Product That Will Be Compounded With the 
Bulk Drug Substance

     Information about the dosage form(s) into which the bulk 
drug substance will be compounded;
     Information about the strength(s) of the compounded drug 
product(s);
     Information about the anticipated route(s) of 
administration of the compounded product(s);
     A bibliography of safety and efficacy data for the drug 
compounded using the nominated substance, if available,\2\ including 
any relevant peer-reviewed medical literature; and
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    \2\ FDA recognizes that the available safety and efficacy data 
supporting consideration of a bulk drug substance for inclusion on 
the list may not be of the same type, amount, or quality as is 
required to support a new drug application.
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     Information about the past and proposed use(s) of the 
compounded drug product(s), including the rationale for its use and why 
the compounded product(s), as opposed to an FDA-approved product, is 
necessary. Information on the rationale for use of the bulk drug 
substance and why a compounded drug product is necessary must be 
specific to the compounded drug product at issue. General or 
boilerplate statements regarding the need for compounded drug products 
or the benefits of compounding generally will not be considered 
sufficient to address this issue.

D. Process for Submitting Nominations and Comments

    Because the prior deadline for submitting nominations has passed, 
FDA is opening this docket so that interested persons can submit 
nominations of bulk drug substances and provide adequate support for 
FDA to evaluate whether those substances should be placed on the 503A 
bulks list. Bulk drug substances that were previously nominated and for 
which inadequate information was provided \3\ need to be renominated 
with the information identified above to be considered for inclusion on 
the 503A bulks list. Nominators are encouraged to submit as much of the 
information identified in this document as possible. Unless adequate 
supporting data is received for a bulk drug substance, FDA will be 
unable to consider it further for inclusion on the list.
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    \3\ As referenced above, a list of the substances in this 
category is available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/UCM467373.pdf.
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    For efficient consolidation and review of nominations, nominators 
are encouraged to submit their nominations in an editable Excel file. 
Specifically, nominators are encouraged to format their nominations as 
follows:

------------------------------------------------------------------------
     Column A--What information is        Column B--Put data specific to
               requested?                    the nominated substance
------------------------------------------------------------------------
What is the name of the nominated        Provide the ingredient name.
 ingredient?
Is the ingredient an active ingredient   Provide an explanation for why
 that meets the definition of ``bulk      it is considered an active
 drug substance'' in Sec.                 ingredient when it is used in
 207.3(a)(4)?                             specific compounded drug
                                          products, and provide
                                          citations to specific sources
                                          that describe its active
                                          properties.
Is the ingredient listed in any of the   Confirm whether the ingredient
 three sections of the Orange Book?       is a component of an FDA-
                                          approved product.
Were any drug monographs for the         Confirm whether the ingredient
 ingredient found in the USP or NF        is the subject of an
 monographs?                              applicable USP or NF
                                          monograph.
What is the chemical name of the         Chemical name.
 substance?
What is the common name of the           Common name.
 substance?
Does the substance have a UNII code?     UNII code.

[[Page 65768]]

 
What is the chemical grade of the        Provide the chemical grade.
 substance?
What is the strength, quality,           Provide the strength, quality,
 stability, and purity of the             stability, and purity
 ingredient?                              information and attach a
                                          certificate of analysis.
How is the ingredient supplied?          Describe how the ingredient is
                                          supplied (e.g., powder,
                                          liquid).
Is the substance recognized in foreign   List the foreign pharmacopeias
 pharmacopeias or registered in other     or other countries in which it
 countries?                               is registered.
Has information been submitted about     Put yes, no, or unknown. If
 the substance to the USP for             yes, state the status of the
 consideration of drug monograph          monograph, if known.
 development?
What dosage form(s) will be compounded   State the dosage form(s).
 using the bulk drug substance?
What strength(s) will be compounded      List the strength(s) of the
 from the nominated substance?            drug product(s) that will be
                                          compounded from the nominated
                                          substance, or a range of
                                          strengths, if known.
What are the anticipated route(s) of     List the route(s) of
 administration of the compounded drug    administration of the
 product(s)?                              compounded drug product(s).
Are there safety and efficacy data on    Provide a bibliography of
 compounded drugs using the nominated     safety and efficacy data for
 substance?                               the drug compounded using the
                                          nominated substance, if
                                          available, including any
                                          relevant peer-reviewed medical
                                          literature.
Has the bulk drug substance been used    Describe past uses of the bulk
 previously to compound drug              drug substance in compounding.
 product(s)?
What is the proposed use for the drug    Provide information on the
 product(s) to be compounded with the     proposed use of the compounded
 nominated substance?                     drug product.
What is the reason for use of a          Provide a rationale for the use
 compounded drug product rather than an   of a compounded drug product.
 FDA-approved product?
Is there any other relevant              Provide any other information
 information?                             you would like FDA to consider
                                          in evaluating the nomination.
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    In addition to nominating new substances or renominating substances 
previously nominated without sufficient supporting information, 
individuals and organizations will be able to comment via the docket 
established by this notice on substances nominated for the 503A bulks 
list that have not yet been addressed in a Notice of Proposed 
Rulemaking (NPRM). Comments may be submitted regarding nominations 
submitted to both this docket and Docket No. FDA-2013-N-1525. Comments 
may provide any relevant information about particular bulk drug 
substances, including that in support of, or in opposition to, the 
placement of a nominated bulk drug substance on the 503A bulks list. 
However, comments submitted should not address the 503A bulks list 
generally or other matters related to the Agency's regulation of 
compounding. Comments about nominated substances that have been 
addressed by the Agency in an NPRM should be submitted to the docket 
for the proposed rulemaking in which the substance is addressed.
    Please do not submit comments that have already been submitted to 
other dockets. Such submissions are duplicative and not helpful to the 
Agency. If comments on particular documents or issues are submitted to 
this docket rather than the docket specifically opened for the 
particular document or issue, the comment might not be considered as 
the specific documents are being finalized and issues considered. FDA 
will not respond to questions submitted to this docket.
    Information in the docket will be publicly available. Therefore, we 
remind nominators and commenters not to submit personal or confidential 
information.

    Dated: October 21, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015-27271 Filed 10-26-15; 8:45 am]
BILLING CODE 4164-01-P


