
[Federal Register Volume 79, Number 127 (Wednesday, July 2, 2014)]
[Notices]
[Pages 37747-37750]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2014-15367]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2013-N-1525]


Bulk Drug Substances That May Be Used To Compound Drug Products 
in Accordance With Section 503A of the Federal Food, Drug, and Cosmetic 
Act; Revised Request for Nominations

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice; revised request for nominations.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is preparing 
to develop a list of bulk drug substances (active ingredients) that may 
be used to compound drug products in accordance with section 503A of 
the Federal Food, Drug, and Cosmetic Act (the FD&C Act), although they 
are neither the subject of a United States Pharmacopeia (USP) or 
National Formulary (NF) monograph nor components of FDA-approved drugs. 
In response to a notice published in the Federal Register of December 
4, 2013, interested groups and individuals previously nominated a wide 
variety of substances for this list. However, many of those nominations 
either were for a substance that is already the subject of a USP 
monograph or a component of an FDA-approved drug, were not for bulk 
drug substances used in compounding as active ingredients, or did not 
include sufficient information to justify inclusion of the nominated 
substance on the list. To improve the efficiency of the process for 
developing the list of bulk drug substances that may be used to 
compound drug products under section 503A, FDA is providing more 
detailed information on what it needs to evaluate a nomination. Because 
the deadline for nominations has passed, FDA is reopening the 
nomination process so that interested persons can submit nominations of 
bulk drug substances that are not the subject of a USP or NF monograph 
or a component of an FDA-approved drug. Interested persons will also 
have the opportunity to provide adequate support to justify placement 
of the substances on the list. Bulk drug substances that were 
previously nominated will not be further considered unless they are 
renominated and those nominations are adequately supported. Substances 
that are already eligible for use in compounding or that are not 
adequately supported will not be placed on the list.

DATES: Submit written or electronic nominations for the bulk drug 
substances list by September 30, 2014.

ADDRESSES: You may submit nominations, identified by Docket No. FDA-
2013-N-1525, by any of the following methods.

Electronic Submissions

    Submit electronic nominations in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting ``comments.''

Written Submissions

    Submit written nominations in the following ways:
     Mail/Hand delivery/Courier (for paper submissions): 
Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    Instructions: All submissions received must include the Agency name 
and Docket No. FDA-2013-N-1525 for this request for nominations. All 
nominations received may be posted without change to http://www.regulations.gov, including any personal information provided. For 
additional information on submitting nominations, see the ``Request for 
Nominations'' heading of the SUPPLEMENTARY INFORMATION section of this 
document.
    Docket: For access to the docket to read background documents or 
nominations 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: Emily Helms Williams, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 6280, Silver Spring, MD 20993-0002, 301-
796-3381.

SUPPLEMENTARY INFORMATION:

I. Background

    Section 503A of the FD&C Act (21 U.S.C. 353a) describes the 
conditions under which a compounded drug product may be entitled to an 
exemption from certain sections of the FD&C Act. Those conditions 
include that the licensed pharmacist or 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), 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.''
    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

[[Page 37748]]

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 requested nominations for specific bulk drug substances for 
the Agency to consider placing on the list. In response to that 
request, 115 comments were submitted to the docket, most of which 
nominated substances for inclusion on the bulk drug substances list. 
Some comments nominated several hundred substances, and approximately 
10 comments nominated thousands of substances, including en bloc 
nominations of substances listed in the British Pharmacopeia, the 
European Pharmacopeia, the Japanese Pharmacopeia, the Food Chemicals 
Codex, the Homeopathic Pharmacopeia of the United States, and the USP 
Dietary Supplements Compendium. Several submissions referenced a 
spreadsheet entitled ``OTC Active Ingredients,'' available on FDA's Web 
site at http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/UCM135688.pdf. Those submissions nominated all of the ingredients on 
the spreadsheet, which numbered over 1,700 entries.\1\
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    \1\ The total number of unique ingredients on the spreadsheet 
available on FDA's Web site and the nominations that mirrored that 
document is lower than this total because the same substances were 
listed separately for different indications, according to how they 
are listed in the over-the-counter (OTC) monographs and regulations.
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    However, many of the nominated substances are typically inactive 
ingredients or foods. Some commonly used inactive ingredients are 
occasionally used as the active ingredient in a drug product. See 55 FR 
46914 at 46916, November 7, 1990 (noting that 21 CFR 310.545 only 
affects the use of the listed ingredients as active ingredients for the 
specific indications, and that some of the ingredients listed in the 
rule, such as sorbitol, sugars, and eucalyptol, have valid uses as 
inactive ingredients). Ingredients commonly used as inactive 
ingredients in compounded drug products, such as flavorings, dyes, 
diluents, or other excipients, need not appear on the Secretary's list 
of bulk drug substances to be eligible for use as an inactive 
ingredient in compounded drug products, should not be nominated, and 
will not be included on the list. All nominations must demonstrate how 
the ingredient is used as an active ingredient in a particular 
compounded drug product.
    Additionally, many of the nominated substances are already eligible 
for use in compounded drug products, namely, those that are components 
of approved products or are the subject of a USP or NF monograph. 
Substances that are in one of those two categories need not appear on 
the list of bulk drug substances to be used in compounded drug 
products.
    Further, many of the nominations did not include sufficient 
information for the Agency to evaluate whether the substance is 
appropriate for use in compounded drug products. 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 prior consultations with the USP and the Pharmacy 
Compounding Advisory Committee,\2\ FDA is proposing to examine the 
following four criteria when determining whether a bulk drug substance 
is appropriate for use in compounded drug products: (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 qualify for placement on the list, it is 
necessary to identify this information about the nominated substances. 
FDA will evaluate the nominated substances in consultation with the 
Pharmacy Compounding Advisory Committee.
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    \2\ 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.
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    The November 27, 2013, notice requested that nominations include 
``[i]nformation about the past and proposed use(s) of the compounded 
product(s), including the rationale for its use or why the compounded 
product(s), as opposed to an FDA-approved product, is necessary.'' 
However, many comments to the docket did not provide any information in 
response to this request. The nominators of the en bloc submissions 
provided no justification for listing any of the specific substances on 
the list. To the extent information about the rationale for compounding 
with a bulk drug substance was provided in individual nominations, many 
of the comments to the docket included only a brief statement about the 
use of the compounded drug product and a statement that the product is 
not available as a commercially made drug. Such statements do not 
provide sufficient information for FDA to determine whether the 
nominated bulk drug substance is appropriate for use in compounded drug 
products. Because the information submitted with previous nominations 
was insufficient, FDA is unable to determine whether those substances 
should be included on the list.
    To improve the efficiency of the process for developing the list of 
bulk drug substances that may be used to compound drug products under 
section 503A, and because the deadline for submitting nominations has 
passed, FDA is reopening the nomination process so that interested 
persons have the opportunity to submit nominations of bulk drug 
substances and provide adequate support for placing them on the list. 
FDA will be able to evaluate only those bulk drug substances submitted 
in response to this notice that are supported with adequate data and 
information, as described in section II.
    Bulk drug substances that were previously nominated will not be

[[Page 37749]]

further considered unless they are renominated and adequately 
supported. Substances that are not adequately supported will not be 
placed on the list. FDA expects the submissions for each bulk drug 
substance to provide the information described in section II. For 
example, nominations must include sufficient information to demonstrate 
that a particular ingredient meets the definition of ``bulk drug 
substance,'' as defined in Sec.  207.3(a)(4). See section 503A(b)(1)(A) 
of the FD&C Act. The identification of an ingredient as an ``active 
ingredient'' in a regulation, or on a spreadsheet such as the one 
listing ``OTC Active Ingredients,'' is not sufficient to demonstrate 
that a substance is a bulk drug substance for purposes of the 503A 
list. En bloc nominations of substances listed in compendia, 
pharmacopeia, or similar reference materials cannot be placed on the 
list unless the Agency receives adequate information for each bulk drug 
substance to justify its placement on the list. FDA will only be able 
to consider bulk drug substances that are supported with the 
information requested.
    In section II, FDA identifies the type of information needed to 
support a nomination to the 503A list.

II. Request for Nominations

    Interested groups and individuals may nominate specific bulk 
substances for inclusion on the list. 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), are not for 
components of approved products, and are not for the subject of a USP 
or NF monograph. To fully evaluate a bulk drug substance, FDA needs the 
following information about both the bulk drug substance being 
nominated 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 USP and NF 
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;
     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.

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,\3\ 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.
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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. Nomination Process

    Because the deadline for submitting nominations has passed, FDA is 
reopening the nomination process so that interested persons can submit 
nominations of bulk drug substances and have the opportunity to provide 
adequate support for placing them on the list. Bulk drug substances 
that were previously nominated need to be renominated. 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. Individuals and organizations will be able to 
comment on nominated substances after the nomination period has closed 
or petition FDA to make additional list amendments after the list is 
published, in accordance with 21 CFR 10.30.
    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
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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.

[[Page 37750]]

 
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 monographs for the ingredient   Confirm whether the ingredient
 found in the USP or NF monographs?       is the subject of a 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.
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.
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?
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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    Interested persons may submit either electronic nominations to 
http://www.regulations.gov or written nominations to the Division of 
Dockets Management (see ADDRESSES). It is only necessary to send one 
set of nominations. Identify nominations with the docket number found 
in the brackets in the heading of this document. Received nominations 
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.

    Dated: June 25, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-15367 Filed 7-1-14; 8:45 am]
BILLING CODE 4164-01-P


