
[Federal Register Volume 80, Number 207 (Tuesday, October 27, 2015)]
[Notices]
[Pages 65770-65774]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-27270]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2015-N-3469]


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

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of availability; 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) (the 503B 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

[[Page 65771]]

receive nominations of bulk drug substances that were not previously 
nominated for consideration for inclusion on the 503B 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-3469 for ``Bulk Drug Substances That Can Be Used To Compound 
Drug Products in Accordance With Section 503B 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

    Under the Drug Quality and Security Act (Pub. L. 113-54), which 
added a new section 503B to the FD&C Act (21 U.S.C. 353b), outsourcing 
facilities \1\ may qualify for certain exemptions from the FD&C Act if 
the conditions set forth in the statute are satisfied. Those conditions 
include that an outsourcing facility does not compound drug products 
using a bulk drug substance unless the bulk drug substance appears on a 
list established by the Secretary identifying bulk drug substances for 
which there is a clinical need (the 503B bulks list), or the drug 
product compounded from such bulk drug substance appears on the drug 
shortage list in effect under section 506E of the FD&C Act (21 U.S.C. 
356e) (FDA drug shortage list) at the time of compounding, 
distribution, and dispensing, and each of the following conditions are 
met: (1) If an applicable monograph exists under the United States 
Pharmacopeia (USP), the National Formulary, or another compendium or 
pharmacopeia recognized by the Secretary for purposes of this 
paragraph, the bulk drug substance complies with the monograph; (2) the 
bulk drug substance is manufactured by an establishment that is 
registered under section 510 of the FD&C Act (21 U.S.C. 360); and (3) 
the bulk drug substance is accompanied by a valid certificate of 
analysis (see section 503B(a)(2) of the FD&C Act).
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    \1\ ``Outsourcing facilities'' are facilities that meet certain 
conditions described in section 503B of the FD&C Act, including 
registering with FDA as an outsourcing facility.
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    Section 503B 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 
503B(a)(2) 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 Sec.  210.3(b)(7) (21 CFR 210.3(b)(7)).)

[[Page 65772]]

    Any component other than an active ingredient is an ``inactive 
ingredient.'' (See Sec.  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 document dated November 27, 2013, published in the Federal 
Register of December 4, 2013 (78 FR 72838), FDA invited all interested 
persons to nominate bulk drug substances for inclusion on the 503B 
bulks list. Over 2,000 substances were nominated. However, many of the 
nominations were not for bulk drug substances used in compounding as 
active ingredients, or they did not include sufficient information to 
allow FDA to evaluate the nominated substances for placement on the 
list. To improve the efficiency of the process for developing the 503B 
bulks list, FDA reopened the nomination process in July 2014 (79 FR 
37747, 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 further 
considered unless they were renominated 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 2,590 unique substances were nominated. Of the nominated 
substances, approximately 1,750 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 (CSA) (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 biological products subject to licensure in a 
BLA, finished drug products, radiopharmaceuticals, do not appear on 
Schedule I in the CSA, and do not appear on the withdrawn or removed 
list, approximately 650 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 503B 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 503B 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-1524 is 
closed for comment. Therefore, this new docket can be used for 
commenting on nominations previously submitted to that docket as well 
as for submitting new nominations.
    In the Federal Register document seeking nominations, FDA stated 
that the following information about clinical need is necessary to 
provide adequate support for nominations to the 503B bulks list:
     A statement describing the medical condition(s) that the 
drug product to be compounded with the nominated bulk drug substances 
is intended to treat;
     A list of FDA-approved drug products, if any, that address 
the same medical condition;
     If there are any FDA-approved drug products that address 
the same medical condition, an explanation of why a compounded drug 
product is necessary;
     If the approved drug product is not suitable for a 
particular patient population, an estimate of the size of the 
population that would need a compounded drug product;
     A bibliography of safety and efficacy data for the drug 
product compounded using the nominated substance, if available, 
including any relevant peer-reviewed medical literature; and
     If there is an FDA-approved drug product that includes the 
bulk drug substance nominated, an explanation of why the drug product 
proposed to be compounded must be compounded from bulk rather than with 
the FDA-approved drug product.
    Therefore, to be considered for placement on the 503B bulks list, 
this information should be submitted for each nominated substance.
    Interested groups and individuals may nominate specific bulk drug 
substances for inclusion on the 503B 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 meet the definition of a bulk drug 
substance in Sec.  207.3(a)(4). Nominated substances that do not meet 
this definition will not be included on the list. To fully evaluate a 
bulk drug substance using the criteria identified in this document, 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. Active Ingredients

1. Confirmation That the Nominated Substance Is a Bulk Drug Substance
     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 compounded drug 
products, citing specific sources that describe the active properties 
of the substance.
2. General Background on the Bulk Drug Substance
     Ingredient name;
     chemical name;
     common name(s); and
     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 USP for 
consideration of monograph development.

B. Clinical Need To Compound

    For FDA to be able to meaningfully evaluate a substance, the 
information provided regarding the clinical need for compounding with a 
bulk drug substance must be specific to the particular substance 
nominated and

[[Page 65773]]

drug product to be compounded. A ``boilerplate'' or general explanation 
of clinical need for compounding with bulk drug substances will not 
enable FDA to conduct an adequate review. Prescribers of the compounded 
drug products who may be in the best position to explain why there is a 
clinical need for a compounded drug product may provide data in support 
of a nomination. The following information about clinical need is 
necessary to provide adequate support for nominations to the 503B bulks 
list:
     A statement describing the medical condition(s) that the 
drug product to be compounded with the nominated bulk drug substances 
is intended to treat (i.e., what patient need is met by the drug 
product compounded with the bulk drug substance);
     a list of FDA-approved drug products, if any, that address 
the same medical condition;
     if there are FDA-approved drug products that address the 
same medical condition, an explanation of why a compounded drug product 
is necessary (i.e., why the approved drug product is not suitable for a 
particular patient population);
     if the approved drug product is not suitable for a 
particular patient population, an estimate of the size of the 
population that would need a compounded drug product (e.g., for a drug 
product compounded from bulk because of patient allergies or other 
intolerances to excipients in FDA-approved drug products, FDA expects 
the supporting information to include a good faith estimate of the 
patient population with the specific medical condition that suffers 
from the allergy or intolerance, with citations to the literature 
regarding the incidence of the condition or a statement that a search 
was conducted and no references were found); \2\
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    \2\ For example, if there is a need to compound a drug product 
from bulk drug substances due to patient sensitivity to a 
preservative or other excipient in the approved drug product, the 
supporting data is expected to set forth the number of patients for 
whom the drug product is prescribed that are allergic or sensitive 
to that particular excipient.
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     a bibliography of safety and efficacy data for the drug 
compounded using the nominated substance,\3\ if available, including 
any relevant peer-reviewed medical literature; and
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    \3\ 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. Note that data regarding 
safety and efficacy, while relevant, is not indicative of a clinical 
need for a particular bulk drug substance, and additional 
information regarding the clinical need must be provided.
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     if there is an FDA-approved drug product that includes the 
bulk drug substance nominated, an explanation of why the drug product 
proposed to be compounded must be compounded from bulk rather than with 
the FDA-approved drug product.
    General or boilerplate statements regarding the need to compound 
from the bulk drug substance or the benefits of compounding generally 
will not be considered sufficient. Note that the Agency does not 
consider supply issues, such as backorders, that do not rise to the 
level of a drug shortage listed on FDA's drug shortage Web site as 
evidence of a clinical need for compounding with a bulk drug substance, 
and section 503B of the FD&C Act already allows compounding from bulk 
drug substances if the compounded drug product is on the FDA drug 
shortage list. Similarly, considerations of cost and convenience will 
not be considered indicators of clinical need.

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 drug product(s); and
     information about the previous use(s) of the compounded 
drug product(s).

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 503B 
bulks list. Bulk drug substances that were previously nominated and for 
which inadequate information was provided \4\ need to be renominated 
with the information identified in this document to be considered for 
inclusion on the 503B 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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    \4\ As referenced in this document, 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:

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     Column A--What information is        Column B--Put data specific to
               requested?                    the nominated substance
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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.
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.
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 monograph               monograph, if known.
 development?

[[Page 65774]]

 
What medical condition(s) is the drug    Describe the medical
 product compounded with the bulk drug    condition(s) that the drug
 substances intended to treat?            product compounded with the
                                          bulk drug substances is
                                          intended to treat.
Are there other drug products approved   List the other approved
 by FDA to treat the same medical         treatments.
 condition?
If there are FDA-approved drug products  Provide a justification for
 that address the same medical            clinical need, including an
 condition, why is there a clinical       estimate of the size of the
 need for a compounded drug product?      population that would need the
                                          compounded drug.
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.
If there is an FDA-approved drug         Provide an explanation of why
 product that includes the bulk drug      it is necessary to compound
 substance nominated, is it necessary     from the bulk drug substance.
 to compound a drug product from the
 bulk drug substance rather than from
 the FDA-approved drug product?
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).
Has the bulk drug substance been used    Describe previous uses of the
 previously to compound drug              bulk drug substance in
 product(s)?                              compounding.
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 503B bulks 
list that have not yet been addressed in a Federal Register document 
proposing substances for the 503B bulks list. Comments may be submitted 
regarding nominations submitted to both this docket and nominations 
previously submitted to Docket No. FDA-2013-N-1524. 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 503B bulks list. However, comments 
submitted should not address the 503B 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 a 
Federal Register document proposing substances for the 503B bulks list 
should be submitted to the docket for the document 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. 2015-27270 Filed 10-26-15; 8:45 am]
BILLING CODE 4164-01-P


