Drug Products or Categories of Drug Products That Present Demonstrable Difficulties for Compounding Under Sections 503A or 503B of the Federal Food, Drug, and Cosmetic Act
| Published date | 20 March 2024 |
| Record Number | 2024-05801 |
| Citation | 89 FR 19776 |
| Court | Food And Drug Administration |
| Section | Proposed rules |
Federal Register, Volume 89 Issue 55 (Wednesday, March 20, 2024)
[Federal Register Volume 89, Number 55 (Wednesday, March 20, 2024)]
[Proposed Rules]
[Pages 19776-19788]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2024-05801]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 216
[Docket No. FDA-2023-N-0061]
RIN 0910-AI31
Drug Products or Categories of Drug Products That Present
Demonstrable Difficulties for Compounding Under Sections 503A or 503B
of the Federal Food, Drug, and Cosmetic Act
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration is proposing to establish
criteria for the lists of drug products or categories of drug products
that present demonstrable difficulties for compounding (Demonstrable
Difficulties for Compounding Lists or DDC Lists) under certain sections
of the Federal Food, Drug, and Cosmetic Act. Additionally, the Agency
is proposing to identify the first three categories of drug products on
both DDC Lists. Drug products or categories of drug products that
appear on the DDC Lists cannot qualify for certain statutory
exemptions, and therefore may not be compounded under, either section
503A or section 503B, respectively.
DATES: Either electronic or written comments on the proposed rule must
be submitted by June 18, 2024.
ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. The https://www.regulations.gov electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of June 18, 2024. Comments received
by mail/hand delivery/courier (for written/paper submissions) will be
considered timely if they are received on or before that date.
Electronic Submissions
Submit electronic comments in the following way:
Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://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,
[[Page 19777]]
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 https://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): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
For written/paper comments submitted to the Dockets
Management Staff, 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-2023-N-0061 for ``Drug Products or Categories of Drug Products That
Present Demonstrable Difficulties for Compounding Under Sections 503A
or 503B of the Federal Food, Drug, and Cosmetic Act.'' Received
comments, those filed in a timely manner (see ADDRESSES), will be
placed in the docket and, except for those submitted as ``Confidential
Submissions,'' publicly viewable at https://www.regulations.gov or at
the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through
Friday, 240-402-7500.
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 https://www.regulations.gov.
Submit both copies to the Dockets Management Staff. 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: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
Docket: For access to the docket to read background documents, the
plain language summary of the proposed rule of not more than 100 words
as required by the ``Providing Accountability Through Transparency
Act,'' or the electronic and written/paper comments received, go to
https://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 Dockets Management Staff, 5630
Fishers Lane, Rm. 1061, Rockville, MD 20852, 240-402-7500.
FOR FURTHER INFORMATION CONTACT: Dorcas Ann Taylor, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Silver Spring, MD 20993-0002, 301-796-0611.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Executive Summary
A. Purpose of the Proposed Rule
B. Summary of the Major Provisions of the Proposed Rule
C. Legal Authority
D. Costs and Benefits
II. Table of Abbreviations/Commonly Used Acronyms in This Document
III. Background
A. FDA's Current Regulatory Framework and Need for DDC Lists
B. History of This Rulemaking and Request for Nominations
IV. Legal Authority
V. Description of the Proposed Rule
A. Criteria for Evaluating Drug Products or Categories of Drug
Products for the DDC Lists (Proposed Sec. 216.25(a))
B. Description of Criteria for the Evaluation of Drug Products
or Categories of Drug Products for Inclusion on the DDC Lists
C. Evaluation of Drug Products or Categories of Drug Products
Proposed for Inclusion on the DDC Lists
D. Drug Products or Categories of Drug Products Proposed for
Inclusion on the DDC Lists
VI. Proposed Effective Date
VII. Preliminary Economic Analysis of Impacts
VIII. Analysis of Environmental Impact
IX. Paperwork Reduction Act of 1995
X. Federalism
XI. Consultation and Coordination With Indian Tribal Governments
XII. References
I. Executive Summary
A. Purpose of the Proposed Rule
The Food and Drug Administration (FDA, Agency, or we) is proposing
to implement parts of the Federal Food, Drug, and Cosmetic Act (FD&C
Act) to establish criteria the Agency will use in evaluating drug
products or categories of drug products considered for inclusion on the
lists of drug products or categories of drug products that present
demonstrable difficulties for compounding (DDC Lists) under each
section. FDA also proposes to identify three categories of drug
products on both DDC Lists. Drug products or categories of drug
products that appear on the DDC Lists cannot qualify for the statutory
exemptions under the applicable section. Additional drug products or
categories of drug products are under consideration and may be
addressed in future rulemaking.
B. Summary of the Major Provisions of the Proposed Rule
FDA is proposing to amend its regulations to add two lists
identifying drug products or categories of drug products that present
demonstrable difficulties for compounding under the FD&C Act. FDA is
also proposing to establish criteria for evaluating drug products or
categories of products for inclusion on one or both of these lists.
For evaluating drug products or categories of drug products for
inclusion on the DDC Lists, FDA is proposing to establish the following
criteria: the formulation complexity, drug delivery mechanism
complexity, dosage form complexity, complexity of achieving or
assessing bioavailability, compounding process complexity, and
complexity of physicochemical or analytical testing of the drug product
or category of drug products. FDA proposes to consider these criteria
and the risks and benefits to patients of the compounded drug product
or category of drug products in determining whether to add the drug
product or category of drug products to one or both lists.
Based on the results of FDA's evaluation of certain categories of
drug products that the public has nominated for consideration as
presenting demonstrable difficulties for compounding, as well as in
consultation with the Pharmacy Compounding Advisory Committee (PCAC),
FDA is proposing to include the following three categories of drug
products on the DDC Lists: (1) oral solid modified-release
[[Page 19778]]
drug products that employ coated systems (MRCs), (2) liposome drug
products (LDPs), and (3) drug products produced using hot melt
extrusion (HMEs). Before finalizing this rulemaking, FDA intends to
consider whether any changes to the proposed criteria would alter FDA's
analysis of whether the categories of drug products addressed in this
notice of proposed rulemaking present demonstrable difficulties for
compounding within the meaning of sections 503A or 503B of the FD&C
Act. As discussed below, the final rule may include some or all of the
categories of drug products proposed here for inclusion on the DDC
Lists, depending on the comments received.
C. Legal Authority
Sections 503A and 503B of the FD&C Act, in conjunction with our
general rulemaking authority in the FD&C Act, serve as our principal
legal authority for this proposed rule.
D. Costs and Benefits
FDA evaluated three categories of drug products for this proposed
rule (MRCs, LDPs, and HMEs) and is currently proposing to place all
three of these categories of drug products on the DDC Lists. We expect
that this proposed rule may create benefits for compounders by reducing
regulatory uncertainty. At this time, we are not aware of any
compounding and marketing of the three proposed categories of drug
products for human use. Therefore, we expect that the proposed rule
would only create administrative costs to read and understand the rule.
We estimate that, over 10 years, the annualized costs of the proposed
rule would equal $0.42 million at a 7 percent discount rate and $0.36
million at a 3 percent discount rate.
II. Table of Abbreviations/Commonly Used Acronyms in This Document
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Abbreviation/ acronym What it means
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ANDA................................ Abbreviated New Drug Applications.
API................................. Active Pharmaceutical Ingredient.
CGMP................................ Current Good Manufacturing
Practice.
CFR................................. Code of Federal Regulations.
DDC................................. Demonstrable Difficulties for
Compounding.
FD&C Act............................ Federal Food, Drug, and Cosmetic
Act.
FDA................................. Food and Drug Administration.
GI.................................. Gastrointestinal.
HME................................. Hot Melt Extrusion.
LDP................................. Liposome Drug Product.
MRC................................. Oral Solid Modified-Release Drug
Product That Employs Coated
Systems.
PCAC................................ Pharmacy Compounding Advisory
Committee.
NDA................................. New Drug Application.
PEG................................. Polyethylene Glycol.
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III. Background
A. FDA's Current Regulatory Framework and Need for DDC Lists
Under sections 503A and 503B of the FD&C Act (21 U.S.C. 353a and
353b), certain conditions must be satisfied for compounded drug
products to qualify for the exemptions set forth in each section from
statutory requirements that may otherwise apply. Section 503A of the
FD&C Act describes the conditions that must be satisfied for a human
drug product compounded by a licensed pharmacist in a State licensed
pharmacy or a Federal facility, or by a licensed physician, to qualify
for exemptions from section 501(a)(2)(B) (concerning current good
manufacturing practice (CGMP) requirements), section 502(f)(1)
(concerning the labeling of drugs with adequate directions for use),
and section 505 (concerning the approval of drugs under new drug
applications (NDAs) or abbreviated new drug applications (ANDAs)) of
the FD&C Act (21 U.S.C. 351(a)(2)(B), 352(f)(1), and 355). Section 503B
of the FD&C Act describes the conditions that must be satisfied for a
drug product compounded by or under the direct supervision of a
licensed pharmacist in an outsourcing facility to qualify for
exemptions from section 502(f)(1) (concerning the labeling of drugs
with adequate directions for use), section 505 (concerning the approval
of drugs under NDAs or ANDAs), and section 582 (concerning drug supply
chain security requirements) of the FD&C Act (21 U.S.C. 360eee-1). Both
sections contain conditions that concern whether the compounded drug
product is one identified by the Secretary of Health and Human Services
(the Secretary) as presenting demonstrable difficulties for compounding
(see generally sections 503A(b)(3)(A) and 503B(a)(6) of the FD&C
Act).\1\ A drug product that the Secretary has identified as presenting
demonstrable difficulties for compounding pursuant to section
503A(b)(3)(A) or section 503B(a)(6) may not be compounded under either
section 503A or section 503B.
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\1\ The functions of the Secretary described herein have been
delegated to FDA. Delegations of authority are available on FDA's
website at https://www.fda.gov/about-fda/staff-manual-guides/delegations-authority-volume-ii-1400. Please see Delegations of
Authority to the Commissioner of Food and Drugs in Staff Manual
Guide 1410.10.
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Specifically, a condition for the statutory exemptions in section
503A of the FD&C Act is that a drug product is not identified by the
Secretary by regulation as a drug product that presents demonstrable
difficulties for compounding that reasonably demonstrate an adverse
effect on the safety or effectiveness of that drug product (see section
503A(b)(3)(A) of the FD&C Act). Section 503A(c)(1) of the FD&C Act
provides that before issuing regulations to implement paragraph
(b)(3)(A), the Secretary shall convene and consult an advisory
committee on compounding unless the Secretary determines that the
issuance of such regulations before consultation is necessary to
protect the public health.
Similarly, a condition for the statutory exemptions in section 503B
of the FD&C Act is that a drug compounded by an outsourcing facility is
not identified (directly or as part of a category of drugs) on a list
published by the Secretary of drugs or categories of drugs that present
demonstrable difficulties for compounding that are reasonably likely to
lead to an adverse effect on the safety or effectiveness of the drug or
category of drugs, taking into account the risks and benefits to
patients, or the drug is compounded in accordance with all applicable
conditions identified on the list as conditions that are necessary to
prevent the drug or category of drugs from presenting such demonstrable
difficulties (see section 503B(a)(6) of the FD&C Act). Section 503B(c)
of the FD&C Act provides that the Secretary will implement the list
described in paragraph (a)(6) through regulations and that before
issuing regulations to implement paragraph (a)(6), the Secretary will
convene and consult an advisory committee on compounding.
This proposed rule, if finalized, would implement sections
503A(b)(3)(A) and 503B(a)(6) of the FD&C Act.
B. History of This Rulemaking and Request for Nominations
In July 2000, the PCAC discussed and provided FDA with advice about
the Agency's efforts to develop a list of drugs that present
demonstrable difficulties for compounding. FDA published a notice of
that meeting in the Federal Register of June 29, 2000 (65 FR 40104).
However, before a list could be developed, the constitutionality of
provisions of section 503A of the FD&C Act concerning restrictions on
the advertising or promotion of the compounding of any particular drug,
class of drug, or type of drug and the solicitation of prescriptions
for compounded drugs were challenged in court. These provisions were
held unconstitutional by the U.S. Supreme Court in 2002 (see Thompson
v. Western
[[Page 19779]]
States Med. Ctr., 535 U.S. 357 (2002)). After the court decision, FDA
suspended its efforts to develop the difficult-to-compound list.
The Drug Quality and Security Act, enacted in 2013, removed from
section 503A of the FD&C Act the provisions that had been held
unconstitutional and added new section 503B to the FD&C Act. In the
Federal Register of December 4, 2013 (78 FR 72840), FDA established a
docket and invited interested persons to nominate drug products or
categories of drug products to be identified as ones that present
demonstrable difficulties for compounding under sections 503A and 503B
of the FD&C Act. Approximately 70 unique drug products or categories of
drug products were nominated. In the Federal Register of July 28, 2017
(82 FR 35214), FDA established another public docket so that interested
parties could nominate drug products or categories of drug products
that were not previously nominated, resubmit previous nominations with
additional supporting information, or submit comments. Since
establishing the new public docket, several new unique drug products or
categories of drug products have been nominated and additional
information regarding previous nominations and general comments has
been submitted.
On June 18, 2015, March 9, 2016, November 3, 2016, May 9, 2017, and
November 21, 2017, FDA consulted with the PCAC (see sections 503A(c)(1)
and 503B(c)(2) of the FD&C Act) about criteria for evaluating whether
drug products and categories of drug products present demonstrable
difficulties for compounding under sections 503A and 503B of the FD&C
Act and the three categories of drug products that are addressed in
this proposed rule (Refs. 1 to 10). The criteria were presented and
discussed at the June 2015 PCAC meeting. The criteria were subsequently
revised to clarify the description of each factor and were then
presented and discussed at the March 2016 PCAC meeting (Ref. 7). In
general, the PCAC agreed with the proposed criteria and the approach
taken by the Agency in evaluating the proposed categories of products
that present demonstrable difficulties for compounding under sections
503A and 503B. In addition, the PCAC agreed with FDA's recommendation
to identify each of the categories of drug products described in this
proposed rule as ones that present demonstrable difficulties for
compounding. Since the PCAC meetings, FDA is not aware of information
regarding the difficulties presented by compounding the categories of
drug products addressed in this proposed rule that would change the
analysis the Agency last presented to the PCAC. The Agency has
considered the PCAC's recommendations in developing this proposed rule,
and the Agency intends to continue to consult with the PCAC in
evaluating drug products or categories of drug products for the DDC
Lists.
IV. Legal Authority
Section 503A of the FD&C Act describes the conditions that must be
satisfied for a human drug product compounded by a licensed pharmacist
in a State licensed pharmacy or a Federal facility, or by a licensed
physician, to qualify for exemptions from section 501(a)(2)(B)
(concerning CGMP requirements), section 502(f)(1) (concerning the
labeling of drugs with adequate directions for use), and section 505
(concerning the approval of drugs under NDAs or ANDAs) of the FD&C Act.
Section 503B of the FD&C Act describes the conditions that must be met
for a drug product compounded by or under the direct supervision of a
licensed pharmacist in a facility registered as an outsourcing facility
to qualify for exemptions from section 502(f)(1) (concerning the
labeling of drugs with adequate directions for use), section 505
(concerning the approval of drugs under NDAs or ANDAs), and section 582
(concerning drug supply chain security requirements) of the FD&C Act.
Sections 503A and 503B of the FD&C Act contain conditions concerning
drug products that have been identified as presenting demonstrable
difficulties for compounding and address how lists of drug products or
categories of drug products that present demonstrable difficulties for
compounding must be established under each section. Specifically,
section 503A(c)(1) of the FD&C Act requires that FDA issue regulations
to implement paragraph (b)(3)(A), which refers to the DDC List under
section 503A, and section 503B(c)(1) of the FD&C Act states that FDA
must implement the list described in paragraph (a)(6) that refers to
the DDC List under section 503B, through regulations. Thus, sections
503A and 503B of the FD&C Act, in conjunction with our general
rulemaking authority in section 701(a) of the FD&C Act (21 U.S.C.
371(a)), serve as our principal legal authority for this proposed rule.
V. Description of the Proposed Rule
FDA is proposing to add Sec. 216.25 to title 21 of the Code of
Federal Regulations (CFR) (21 CFR 216.25) to establish criteria to
evaluate drug products and categories of drug products for inclusion on
one or both of the DDC Lists in Sec. 216.25(a), and to codify the
initial DDC List for section 503A and the initial DDC List for section
503B of the FD&C Act in Sec. 216.25(b) and (c), respectively. FDA is
proposing to create two separate DDC Lists, a 503A DDC List and a 503B
DDC List, that would implement the DDC statutory provisions and reflect
the differences in compounding standards under each section. Having two
separate lists will make it easier to address situations that could
arise where a drug product or category of drug products would present
demonstrable difficulties for compounding under section 503A but may
not present demonstrable difficulties for compounding under section
503B of the FD&C Act. For example, in certain situations, FDA may
determine in its consideration of the DDC criteria that a drug product
or category of drug products presents demonstrable difficulties for
compounding unless it is made in accordance with the manufacturing
controls over safety, identity, strength, quality, and purity required
under CGMP. In such cases, because drug products compounded in
accordance with the conditions of section 503A, but not section 503B,
are exempt from CGMP requirements, FDA may decide to include a drug
product or category of drug products on the DDC List for section 503A
but not the DDC List for section 503B of the FD&C Act.\2\ The initial
lists, if finalized as proposed, would include three categories of drug
products that present demonstrable difficulties for compounding under
both sections 503A and 503B of the FD&C Act and, therefore, would not
qualify for the exemptions in either section. The proposed criteria and
categories of drug products are described below.
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\2\ See section 501(a)(2)(B) of the FD&C Act.
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As discussed below, to determine whether a drug product or category
of drug products presents demonstrable difficulties for compounding FDA
may consider the criteria in this proposed rule individually and
collectively, and take into account the risks and benefits to patients
of the compounded drug product or categories of drug products.
Additionally, FDA is proposing three categories of drug products that
were, independently of each other, evaluated by FDA and presented to
the PCAC to be included on the DDC List for section 503A and the DDC
List for section 503B of the FD&C Act. In the event of a stay or
invalidation of any criterion or of any entry on a DDC List, those
criteria and entries that remain in effect would
[[Page 19780]]
continue to function sensibly \3\ to advance the statutory objectives.
It is FDA's intent to preserve each of the criteria and entries on the
DDC Lists, if finalized, to the fullest possible extent, to help
advance the objectives described in section III.A.
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\3\ See, e.g., Belmont Mun. Light Dep't v. FERC, 38 F.4th 173,
188 (D.C. Cir. 2022) (finding severability of portion of an
administrative action, applying principle that severability is
appropriate where ``the agency prefers severability to overturning
the entire regulation'' and where the remainder of the regulation
``could function sensibly without the stricken provision'')
(citations omitted).
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A. Criteria for Evaluating Drug Products or Categories of Drug Products
for the DDC Lists (Proposed Sec. 216.25(a))
FDA has identified six criteria it proposes to consider in
determining whether drug products or categories of drug products
present demonstrable difficulties for compounding under sections 503A
and 503B of the FD&C Act:
1. Complex formulation,
2. Complex drug delivery mechanism,
3. Complex dosage form,
4. Bioavailability achievement complexity,
5. Compounding process complexity, and
6. Physicochemical or analytical testing complexity.
In evaluating drug products or categories of drug products for the
DDC Lists, the Agency proposes to consider these criteria individually
and collectively, and to take into account the risks and benefits to
patients of the compounded drug product or categories of drug products.
The criteria are not mutually exclusive. A drug product or category of
drug products may meet one or more of these criteria that indicate it
presents demonstrable difficulties for compounding. FDA proposes to
apply the same criteria when considering drug products or categories of
drug products for inclusion on either the DDC List for section 503A or
the DDC List for section 503B of the FD&C Act, although the application
of the criteria may lead to different conclusions for each list. The
three categories of drug products identified in this proposed rule are
proposed to be included on both the initial 503A and 503B DDC Lists,
but this may not always be the case given the differences in the
statutory standards that apply to compounding under sections 503A and
503B of the FD&C Act. We also note that these criteria for determining
whether a drug product presents demonstrable difficulties for
compounding are not intended to provide FDA's interpretation of which
drugs are considered complex products in other circumstances, including
for purposes of determining whether a proposed generic drug is a
complex product as defined in the Generic Drug User Fee Amendments
Commitment Letters and which, as appropriate, may use scientifically
valid in vivo or in vitro test methods to demonstrate bioequivalence.
In its evaluations for the DDC Lists, FDA intends to take into
account the risks and benefits to patients of the compounded drug
product or category of drug products under consideration. In doing so,
FDA may use available information such as reports submitted to FDA
about adverse drug experiences and FDA's scientific and medical
expertise to inform its analysis, as well as information about FDA-
approved drug products. FDA may consider actual or potential risks and
benefits to patients posed by a drug product or category of drug
products. In particular, FDA intends to consider actual or potential
risks to patients in connection with the six criteria described in this
proposed rule.
The Agency does not intend to consider cost and convenience as
factors that would be relevant to the risk-benefit analysis for the DDC
Lists.
There may be situations in which FDA's findings, with respect to
whether a drug product or category of drug products presents
demonstrable difficulties for compounding, indicate that the difficulty
in compounding is limited to a subset of such drug products or
categories of drug products. In those cases, the Agency may tailor the
entry on the DDC Lists to reflect its findings and conditions that the
Agency determines are necessary to prevent the drug or category of
drugs from presenting the demonstrable difficulties. For example, if
the Agency were to find a drug product or category of drug products
presents demonstrable difficulties for compounding at a specific
strength for topical use, it could choose to limit the entry of that
drug product or category of drug products on the DDC Lists to a
specified strength for topical use.
B. Description of Criteria for the Evaluation of Drug Products or
Categories of Drug Products for Inclusion on the DDC Lists 4
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\4\ These proposed descriptions of terms apply only to those
terms when used in proposed 21 CFR part 216 for purposes of
determining whether drug products or categories of drug products
present demonstrable difficulties for compounding.
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The following is a discussion of the criteria the Agency proposes
to codify, in proposed Sec. 216.25(a), for including a drug product or
category of drug products on the section 503A or section 503B DDC List.
A drug product or category of drug products that meets one or more of
the criteria may present demonstrable difficulties for compounding
under section 503A or 503B of the FD&C Act.
1. Complex Formulation
Complex formulation refers to a formulation in which the
ingredients (active pharmaceutical ingredients (APIs) or excipients)
possess (or are required to possess) certain physicochemical
characteristics or properties that are necessary to achieve or maintain
the proper performance of the drug product. Generally, these attributes
may include the solid state (crystalline, amorphous, or a combination
thereof), chirality, molecular weight (dispersity/distributions), or
particle size distribution of ingredients. For example, for some APIs,
the solid state, chirality, or particle size might be critical to the
safety and efficacy of certain drug products, whereas for some
excipients, the molecular weight, intrinsic viscosity, or relative
proportion of the release controlling polymer to an API might be
critical to the safety and efficacy of certain drug products. The
compatibility or stability (physical and chemical) of the API(s) or
excipients in the final dosage form may also contribute to determining
whether the compounded drug product has a complex formulation.
2. Complex Drug Delivery Mechanism
Complex drug delivery mechanism refers to the way in which the drug
is released from the dosage form or targeted for delivery in the body
to achieve the desired therapeutic effect. Complex drug delivery
mechanisms include, for example, formulations designed to release the
drug at specific onset, rate, and extent through specific region(s)
within the gastrointestinal (GI) tract; formulations designed to
achieve permeation through the skin at a specific rate; and
formulations containing coated beads or liposomes.
3. Complex Dosage Form
Complex dosage form refers to physical dosage units with unique
characteristics that are difficult to consistently achieve or maintain.
Complex dosage form also refers to container closure systems that may
interact with the compounded drug and affect its intended use, either
through physical (inconsistent dose administration) or chemical
interactions between the compounded drug and the
[[Page 19781]]
container closure system. Drug products may have very simple
formulations, such as a single API, and a simple delivery mechanism,
such as an injection, but the drug product may be complex because the
physical properties of the dosage form are difficult to achieve or
maintain. Examples of complex dosage forms include coated beads,
osmotic-controlled release systems, and liposomes.
4. Bioavailability Achievement Complexity
Bioavailability refers to the rate and extent to which the active
ingredient or active moiety is absorbed from a drug product and becomes
available at the site of action. Drug products may present demonstrable
difficulties for compounding if bioavailability is challenging to
achieve because of the characteristics of the API or compounded
formulation such as low permeability or low solubility. Examples of
drug products for which consistent bioavailability is difficult to
achieve include Biopharmaceutics Classification System Class 2 drugs
(e.g., naproxen, lansoprazole, rifampin, and carbamazepine) and Class 4
drugs (e.g., azathioprine, clarithromycin, oxcarbazepine, and
modafinil).
5. Compounding Process Complexity
Compounding process complexity refers to whether compounding the
drug requires multiple, complicated, or interrelated steps or
specialized facilities or equipment to achieve the appropriate drug
product. An example of a complex compounding process includes multistep
and highly interrelated processes such as wet granulation, extrusion,
spheronization, fluid bed drying, coating, compression, or curing
before processing into the final dosage form.
6. Physicochemical or Analytical Testing Complexity
Physicochemical or analytical testing complexity refers to the
challenges presented with confirming the drug product will perform as
expected with regard to certain characteristics. Drug products may
demonstrate testing complexity when specialized analytical instruments
or special training is necessary to show that the drug product will
perform as expected. Some examples of complex testing include cell-
based assays and use of nuclear magnetic resonance, mass spectrometry,
or X-ray powder diffraction to identify constituents of complex
formulations.
C. Evaluation of Drug Products or Categories of Drug Products Proposed
for Inclusion on the DDC Lists
FDA is proposing three categories of drug products that were
evaluated by FDA and presented to the PCAC to be included on the
initial DDC List for section 503A and the initial DDC List for section
503B of the FD&C Act. The following three categories of drug products
are being proposed to be included in Sec. 216.25(b) and (c): MRCs,
LDPs, and HMEs. FDA may propose additional drug products or categories
of drug products for inclusion on the DDC Lists as it continues its
evaluations.
The information that FDA assessed under each of the proposed
evaluation criteria for each of the categories of drug products
included in this proposed rule was obtained from publicly available
sources, including peer-reviewed medical literature. Some of this
information was referenced in the nominations, and the remainder was
gathered through independent searches of medical and pharmaceutical
databases. The nature, quantity, and quality of the information FDA
assessed varied considerably from drug product category to drug product
category. For some categories of drug products, reports in the
literature were more plentiful and sometimes comprised hundreds or
thousands of articles. In those cases, generally, the Agency limited
its review to a sample of the best literature sources available (e.g.,
review articles in widely known, peer-reviewed journals; meta-analyses;
reports of randomized controlled trials). The Agency intends to use a
similar process when evaluating other drug products or categories of
drug products for inclusion on the DDC Lists in future rulemakings.
Three categories of drug products that were nominated as presenting
demonstrable difficulties for compounding under sections 503A and 503B,
and that FDA evaluated in consultation with the PCAC, are not included
in this proposed rule: (1) drug products that employ transdermal or
topical delivery systems; (2) metered-dose inhalers; and (3) dry powder
inhalers. FDA may address these categories in future rulemaking.
After evaluating the comments on this proposed rule, FDA intends to
issue the evaluation criteria and DDC Lists as a final rule, which will
be codified at Sec. 216.25. The final rule may include some or all of
the categories of drug products proposed here for inclusion on the DDC
Lists, depending on the comments received.
Individuals and organizations may nominate drug products or
categories of drug products for the DDC Lists or comment on nominated
categories of products. For access to the docket to nominate products
or comment on nominated products, go to https://www.regulations.gov and
insert Docket No. FDA-2017-N-2562 into the ``Search'' box and follow
the prompts.
FDA intends to consider reevaluating products or categories of
products for the DDC Lists if there is a change in circumstances that
alters the Agency's analysis. FDA may consider reevaluating products or
categories of products for the DDC Lists at any time on its own
initiative. Requests for updates to the DDC Lists may be submitted to
FDA at any time. With respect to a drug product or category of drug
products that has not been addressed in rulemaking, individuals and
organizations may submit nominations of new substances or comments on
nominated substances to Docket No. FDA-2017-N-2562. With respect to a
drug product or category of drug products addressed in a final rule,
individuals and organizations may petition FDA to amend the DDC Lists
(see 21 CFR 10.30). FDA will review the section 503B DDC List at least
once every 4 years and update the DDC List as necessary.\5\
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\5\ See section 503B(c)(4) of the FD&C Act.
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D. Drug Products or Categories of Drug Products Proposed for Inclusion
on the DDC Lists
1. Oral Solid Modified-Release Drug Products That Employ Coated Systems
(MRCs)
For purposes of this proposed rule, the Agency defines MRCs as oral
solid drug products that consist of, or are intended to consist of, a
drug-containing core enclosed within a polymeric coating to release an
API at specified rates, patterns, or onsets through the GI tract to
produce systemic, enteric, or local action.\6\ There are two types of
[[Page 19782]]
MRCs that affect the rate of API release: diffusion and osmotic
systems. The diffusion systems consist of a hydrophilic and/or water-
insoluble polymeric coating enclosing a core tablet or multiple cores
of active ingredient and excipient. The osmotic systems consist of a
semipermeable polymeric membrane coating enclosing a compressed core
that is composed of active ingredient, osmotic agent, and other
excipients, and one or more mechanical or laser drilled orifices for
drug release.
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\6\ Modified release solid oral dosage forms include both
delayed and extended release drug products. See FDA's guidance for
industry on ``(SUPAC-MR) Scale-Up and Postapproval Changes for
Modified Release Solid Oral Dosage Forms.'' For this proposed
rulemaking, the Agency does not consider matrix-type tablets and
capsules to be MRCs, provided that drug release and delivery of an
active ingredient from such products is controlled solely by
disintegration or dissolution through the polymeric matrix.
Moreover, with regard to certain fillable capsules, the Agency does
not consider enteric coated capsules of immediate release
formulations to be MRCs because of the fact that such enteric
coating is designed to control disintegration onset of the coated
capsule and not the release rate of active ingredient at a targeted
location in the GI tract. In addition, as noted above, this proposed
rule is not intended to provide FDA's interpretation of which drugs
are considered complex products in other circumstances, including
for purposes of determining whether a proposed generic drug is a
complex product.
---------------------------------------------------------------------------
MRCs were evaluated using the six criteria that FDA proposes to use
to determine whether drug products or categories of drug products
present demonstrable difficulties for compounding under sections 503A
and 503B of the FD&C Act explained in section V.A. above. MRC
formulations are complex because they are required to release a
specified amount of active ingredient over a specified period of time
for a given therapy. Developed properly, MRCs must be physically stable
and exhibit consistent functional properties of active ingredient
release rate, pattern, and location within the GI tract. If MRCs are
not produced correctly, sub- or supra-therapeutic release, GI mucosa
irritation, and variability in performance within and across batches
may occur. The mechanism by which active ingredient is released from
the MRCs throughout the GI tract is complex because, to perform
properly, it requires the design and formation of a system that
delivers a specific amount of active ingredient per unit time and, in
some cases, in specific regions of the GI tract. Depending on the type
of MRC systems, the drug (API) delivery mechanism for an MRC can either
be diffusion controlled through polymeric coating or osmotic controlled
through a polymeric semipermeable membrane, and, in either case, the
delivery mechanism depends on several factors, including the intended
time/location of API release in the GI tract and the types of materials
used for coating. In addition, because the dose-release profile is
impacted by several factors, precise control of the attributes of raw
materials, the manufacturing process, and the final product is
necessary for ensuring the specifications of the drug product are met.
MRCs' complex formulations and complex drug delivery mechanisms
also affect the complexity of their dosage forms for compounding. They
require well-designed controls of component attributes and process
parameters for predictable release of the active ingredient. In
addition, MRCs are designed to maintain their integrity in vivo to
minimize local irritation to the GI tract and to ensure that dose
dumping does not occur. Various components play a critical role in the
dosage form performance. Extensive product development and precise
control over raw material selection and the production process are
essential for evaluating the active ingredient release mechanism and
profile, and overall MRC performance characteristics. Characterizing
and controlling bioavailability of MRCs are also critical. Subtle
changes to any of the product's components or manufacturing processes
could significantly impact its bioavailability and performance
characteristics. In general, for MRCs, in vitro assessments, such as in
vitro dissolution testing, alone are insufficient to accurately predict
bioavailability and overall clinical effect; rather, in vivo
assessments are needed.
Because specialized equipment under appropriate controls is
critical for the automated processing and precise control over the
manufacturing process, the compounding processes for MRCs are also
complex. These processes include technically complex mixing,
fluidization coating and drying, compression, filling, and orifice
drilling. Poor technique or control during any of these processes will
likely result in variable performance of the drug product. MRCs
additionally require complex physicochemical and analytical testing of
raw material, product quality/performance, and stability because
evaluating the physical and chemical properties of the raw materials
and finished dosage form, as well as the product-critical performance
parameters, requires specialized analytical devices and procedures for
accurate measurement. Furthermore, to assess and ensure consistent
purity of the drug product, chemical impurities must be quantitated
through various sensitive analytical techniques developed specifically
for these impurities.
With respect to the risks and benefits to patients, compounded MRCs
present a significant safety risk given the complexities described
above. MRC design and the relationship between excipient and active
ingredient directly impact release rate and pattern and performance.
Release rate and pattern and performance in turn affect drug product
effectiveness and safety. Substituting or removing excipients, such as
release retarding polymers, plasticizers, solubilizers, and permeation
enhancers, would likely change the release characteristics of the
product and, in turn, may adversely impact product performance. Also,
precise and consistent quality controls of raw materials, the
manufacturing process, and final product are essential for predictable
and reproducible active ingredient release, performance, and safety
profiles. MRCs are designed to release a specified amount of active
ingredient to a specific region of the GI tract over a specified period
of time, for a given therapy. MRCs are designed to maintain their
integrity in vivo to minimize local irritation to the GI tract and to
ensure that dose dumping does not occur. The complexities associated
with the manufacture of MRCs create a heightened risk that compounded
products would not deliver the active ingredient as intended, which
would present a safety concern to patients. The Agency is not aware of
compounded MRCs for human use. However, FDA requests comments regarding
availability of and potential access to compounded MRCs. FDA is also
not aware of a rationale for why a patient would have a medical need
for compounded MRCs, as opposed to an FDA-approved product, nor is it
aware of any actual or potential benefit that would outweigh the risks
to patient safety that would be presented by compounded MRCs.
Based on an analysis of the evaluation criteria, taking into
account the risks and benefits to patients, FDA proposes to include
MRCs on the lists of drug products or categories of drug products that
present demonstrable difficulties for compounding under sections 503A
and 503B of the FD&C Act. On May 9, 2017, FDA proposed to the PCAC that
MRCs be identified as presenting demonstrable difficulties for
compounding under sections 503A and 503B of the FD&C Act (Ref. 9). The
PCAC voted to agree with FDA's proposal (Ref. 4).
In applying the six criteria discussed above, FDA considered
whether MRCs should be added to the 503A DDC List and to the 503B DDC
List. FDA has tentatively concluded that MRCs meet the statutory
criteria for inclusion on both lists. As discussed above, MRCs are
solid oral dosage form drug products that consist of, or are intended
to consist of, a drug-containing core enclosed within a polymeric
coating to release an active ingredient at specified rates, patterns,
or onsets through the GI tract to produce systemic, enteric, or local
action. The complexities associated with the manufacture of MRCs create
a
[[Page 19783]]
heightened risk that compounded products would not deliver the active
ingredient as intended, which would present a safety concern to
patients. FDA does not believe an outsourcing facility's compliance
with CGMP requirements would address the concerns described above
regarding formulation complexity, drug delivery mechanism complexity,
dosage form complexity, complexity of achieving or assessing
bioavailability, compounding process complexity, and complexity of
physicochemical or analytical testing of the drug product or category
of drug products. FDA's CGMP regulations contain the minimum current
good manufacturing practice for methods to be used in, and the
facilities or controls to be used for, the manufacture, processing,
packing, or holding of a drug to assure that such drug meets the
requirements of the FD&C Act as to safety, and has the identity and
strength and meets the quality and purity characteristics that it
purports or is represented to possess (see 21 CFR 210.1(a)). The
potential quality and safety concerns raised by MRCs would typically be
evaluated as part of the premarket approval process, based on the
assessment of a broader range of drug development data including
certain safety, clinical, and bioavailability or bioequivalence
information as appropriate. Since compounded drug products that meet
the conditions of sections 503A and 503B are exempt from premarket
approval requirements, compounded MRCs would not be subject to such
evaluation based on a broader range of drug development data.
Therefore, compliance with CGMP standards, alone, is unlikely to
provide sufficient assurance that compounded MRCs can deliver product
of intended characteristics with reliable quality and consistent
performance. However, FDA is soliciting comments about whether this
entry should be added to only the 503A DDC List or only the 503B DDC
List.
2. Liposome Drug Products (LDPs)
For this proposed rule, the Agency defines an LDP as a drug product
in which the API is generally contained in or intended to be contained
in liposomes.\7\ The Agency has broadly evaluated LDPs, including those
containing liposomes that would not fall within what is commonly
considered to be the nanoscale-size range, for inclusion on the DDC
Lists.\8\
---------------------------------------------------------------------------
\7\ With respect to FDA-approved liposome drug products, see the
guidance for industry ``Liposome Drug Products: Chemistry,
Manufacturing, and Controls; Human Pharmacokinetics and
Bioavailability; and Labeling Documentation.'' See also FDA's final
guidance for industry ``Drug Products, Including Biological
Products, That Contain Nanomaterials.''
\8\ Within the context of this rule, preparations such as
liposomal creams or gels are not considered LDPs, provided that, the
principal use of amphipathic molecules such as phospholipids in the
form of liposome alone or in combination with other inactive
components (i.e., other than the drug or active pharmaceutical
ingredient) in such preparations is intended for other than cure,
mitigation, treatment or prevention of any underlying human disease;
or intended not to affect, the structure or any function of a human
body.
---------------------------------------------------------------------------
Liposomes are vesicles composed of a bilayer and/or a concentric
series of multiple bilayers separated by aqueous compartments formed by
amphipathic molecules such as phospholipids that enclose a central
aqueous compartment. LDPs were evaluated using the six criteria
explained in section V.A. above. Because of: (1) the attributes of
lipids, including chemistry and structure; (2) the attributes of
inactive ingredients (e.g., cholesterol and polyethylene glycol (PEG)
or PEG derivatives), including grade, ratio, and concentration range;
and (3) the stability of the liposome, which can be affected by a
number of formulation-related factors (e.g., the size and size
distribution of the lipid vesicles, morphology, surface coating, pH,
buffer, or counter ions), LDPs have complex formulations. LDPs also
have a complex drug delivery mechanism. The mechanism by which an API
is released from an LDP is complex because it involves precisely
designing and formulating a system that delivers a specific amount of
API per unit time and, in most cases, in a specific region (e.g., tumor
tissues, intracellular compartments). In addition, because the in vivo
biodistribution and release characteristics are affected by several
factors, precise control of raw materials, the manufacturing process,
and the final product is critical to achieving a safe and effective
drug product.
LDPs are complex dosage forms because they have complex
formulations and mechanisms by which the API is delivered in vivo.
Characteristics of the physical dosage units of liposome suspensions or
lyophilized powders for suspension are difficult to consistently
achieve or maintain, including: (1) well-defined and controlled
particle size and particle size distribution; (2) the status of the API
(e.g., whether it is contained within the liposome); and (3) the
surface chemistry of the liposomes. These characteristics have a
significant impact on the safety and effectiveness of LDPs. In
addition, various formulation components play a critical role in dosage
form performance and product stability. Such components can vary for
different drug products that have different routes of administration.
For example, the components of an injectable drug product may include
different inactive ingredients than potential topical or inhalation
drug products. Extensive product development and precise control over
raw materials and optimization of the process parameters are essential
to produce safe, effective, and high-quality LDPs.
Characterizing and controlling the bioavailability of LDPs is also
a contributing factor to the complexity of LDPs. Subtle changes to the
formulation composition, lipid raw material purity, or manufacturing
processes could significantly impact the biodistribution and release
characteristics of an API from liposomes, which in turn influence the
availability of an API in systemic circulation at tissue or subcellular
targets. Different API forms may have different absorption,
distribution, metabolism, and elimination, and the difficulty in
determining the amount of various forms of API makes it complex to
characterize and control bioavailability. Depending on the types of
lipids used in formulating liposomes, interactions between liposome
surface and blood proteins may affect the drug release and
pharmacological properties of a liposome drug product in vivo. Such
interactions can have safety implications because of ``dose dumping.''
For parenteral LDPs, in vitro assessments (e.g., in vitro drug release
testing) are often used in conjunction with in vivo testing to predict
the availability of drug at its intended target. LDPs involve complex
compounding processes. The production of LDPs is complex because of
unique equipment and unit operations involved and the critical need for
in-process controls to ensure consistent product quality. Poor control
over these unit operations may lead to variability in product quality,
which may potentially lead to a negative impact on product efficacy and
safety. In addition, LDPs involve comprehensive and complex
physicochemical testing to ensure quality of the raw material,
consistency of the product quality, and predictable in vivo
performance. Furthermore, suitable analytical methods need to be
employed to properly characterize LDPs, which can often be difficult
given the complexity of liposome formulations. Use of inappropriate
methods could produce false results,
[[Page 19784]]
thereby calling data reliability and, hence, product quality into
question.
With respect to the risks and benefits to patients, compounded LDPs
present a significant safety risk for compounding given the
complexities described above. Many of the APIs used in LDPs are
cytotoxic. In addition, improper selection of inactive ingredients or
improper mixing of liposomes with APIs present safety risks that the
APIs will not be encapsulated properly or be released prematurely,
causing the drug product to be potentially ineffective or hazardous.
LDPs are used to alter the biodistribution of an API and can improve
drug dissolution, stability, deliverability, biodistribution, and
bioavailability. The Agency is not aware of compounded LDPs for human
use; however, FDA requests comments regarding availability of and
potential access to compounded LDPs for human use. FDA is also not
aware of any actual or potential benefit that would outweigh the risks
to patient safety that would be presented by compounded LDPs.
Based on an analysis of the evaluation criteria, taking into
account the risks and benefits to patients, FDA proposes to include
LDPs on the lists of drug products or categories of drug products that
present demonstrable difficulties for compounding under sections 503A
and 503B of the FD&C Act. On November 21, 2017, FDA proposed to the
PCAC that LDPs be identified as presenting demonstrable difficulties
for compounding under sections 503A and 503B of the FD&C Act (Ref. 10).
The PCAC voted to agree with FDA's proposal (Ref. 5).
In applying the six criteria discussed above, FDA considered
whether LDPs should be added to the 503A DDC List and to the 503B DDC
List. FDA has tentatively concluded that LDPs meet the statutory
criteria for inclusion on both lists. As discussed above, LDPs are drug
products in which the active ingredient is generally contained in or
intended to be contained in liposomes, which are vesicles composed of a
bilayer and/or a concentric series of multiple bilayers separated by
aqueous compartments formed by amphipathic molecules such as
phospholipids that enclose a central aqueous compartment. Among FDA's
concerns are that many of the active ingredients used in LDPs are
cytotoxic and that there is a risk that improper selection of inactive
ingredients or improper mixing of liposomes with active ingredients
could cause the drug product to be potentially ineffective or
hazardous. FDA does not believe an outsourcing facility's compliance
with CGMP requirements would address the concerns described above
regarding formulation complexity, drug delivery mechanism complexity,
dosage form complexity, complexity of achieving or assessing
bioavailability, compounding process complexity, and complexity of
physicochemical or analytical testing of the drug product or category
of drug products. FDA's CGMP regulations contain the minimum current
good manufacturing practice for methods to be used in, and the
facilities or controls to be used for, the manufacture, processing,
packing, or holding of a drug to assure that such drug meets the
requirements of the FD&C Act as to safety, and has the identity and
strength and meets the quality and purity characteristics that it
purports or is represented to possess (see 21 CFR 210.1(a)). The
potential quality and safety concerns raised by LDPs would typically be
evaluated as part of the premarket approval process, based on the
assessment of a broader range of drug development data including
certain safety, clinical, and bioavailability or bioequivalence
information as appropriate.\9\ Since compounded drug products that meet
the conditions of sections 503A and 503B are exempt from premarket
approval requirements, compounded LDPs would not be subject to such
assessment based on a broader range of drug development data.
Therefore, compliance with CGMP standards, alone, is unlikely to
provide sufficient assurance that compounded LDPs can deliver product
of intended characteristics with reliable quality and consistent
performance. However, FDA is soliciting comments about whether this
entry should be added to only the 503A DDC List or only the 503B DDC
List. FDA is aware that certain FDA-approved liposome drug products may
have instructions in their approved labeling for certain manipulations.
Accordingly, FDA is also soliciting comments about whether the entry
for the 503B DDC List should include any limitations, such as, for
example, to address certain LDPs that an outsourcing facility compounds
from FDA-approved liposome drug products.
---------------------------------------------------------------------------
\9\ For more information see the guidance for industry
``Liposome Drug Products: Chemistry, Manufacturing, and Controls;
Human Pharmacokinetics and Bioavailability; and Labeling
Documentation.'' See also FDA's final guidance for industry ``Drug
Products, Including Biological Products, That Contain
Nanomaterials.''
---------------------------------------------------------------------------
3. Drug Products Produced Using HMEs
For this proposed rule, the Agency defines HME as a continuous
process operation that achieves or is intended to achieve the molecular
mixing of APIs and inactive ingredients (e.g., polymers) at
temperatures above their glass transition temperatures and/or melting
temperatures within an extruder. The objective of an HME process is to
enhance the solubility of poorly water-soluble drugs by converting the
formulation components into an amorphous phase (not crystalline)
product with uniform content.
HME is a process by which heat and shear are applied to melt a
mixture of API and inactive ingredients within an extruder that is then
pushed through an orifice with the objective of converting the
ingredients into an amorphous phase material with uniform content,
referred to as the ``extrudate.'' HMEs were evaluated using the six
criteria that FDA proposes to use to determine whether drug products or
categories of drug products present difficulties for compounding under
sections 503A and 503B of the FD&C Act explained in section V.A. above.
HMEs have complex formulations because the extrudate must remain a
stable and amorphous solid solution of API within a matrix throughout
the shelf life of the final drug product in order to achieve proper
product performance. This formulation is necessary to ensure that the
API has higher solubility, resulting in the desired bioavailability of
the drug product. To avoid a negative impact on the safety and efficacy
of the product, the extrudate should have a uniform distribution of API
in the matrix and a controlled level of impurities. It is critical for
these formulations to be thermally stable during the extrusion process
and physically stable afterwards. Raw material selection and control
and ingredient ratios influence several attributes of the extrudate
and, in turn, the final product. If HMEs are not formulated correctly,
taking into account the principles discussed above, it could lead to
significant variability in performance within and across batches, and
may impact bioavailability. The drug delivery mechanism, or the
mechanism by which API is released from the HMEs, can also be complex
because it is dependent on a product design (e.g., immediate or
sustained) that implicates API dissolution and solubility in an
amorphous state within the extrudate to ensure appropriate drug
delivery. Product design involves achieving and maintaining an
amorphous state of the API in the extrudate, extrudate incorporation
into the final dosage form, and selection of a carrier/API matrix that
will release the drug at a predetermined rate. In addition, in order to
achieve a proper dose-release profile, precise control of
[[Page 19785]]
raw materials, the extrusion process, and the final product is
critical.
Some dosage forms of HMEs are complex because of the structural
arrangement or distribution of the extrudate within the dosage form,
the function or role of the extrudate in the dosage form's drug
delivery mechanism, or the interaction of extrudate with other
ingredients within the dosage form. HMEs require well-designed controls
of ingredient attributes and process parameters for predictable API
release from a dosage form. These controls may vary from dosage form to
dosage form, depending on what downstream incorporation steps the
extrudate will undergo. Extensive product development and precise
control over raw material selection and the production process are
essential to evaluating the API release mechanism and profile, and
other product performance characteristics. Characterizing and
controlling the bioavailability of HMEs is also a contributing factor
to the complexity of HMEs. Subtle changes to any components or
production processes could significantly impact a drug product's
solubility and intrinsic dissolution, which may in turn influence local
and systemic bioavailability. In general, for compounded HMEs, in vitro
assessments, such as dissolution testing, alone are insufficient to
accurately predict bioavailability and overall clinical effect. Rather,
in vivo assessments are needed.
The manufacturing process for HMEs typically requires specialized
equipment under sophisticated controls, critical for ensuring product
quality, and thereby making compounding of HMEs complex. To achieve and
maintain critical product quality attributes, the extruder must be
properly calibrated based on the characteristics of the ingredients fed
into the extruder and desired characteristics of the extrudate. Poor
technique or control at any step will likely result in a product that
does not achieve or maintain critical quality attributes.
Physicochemical and analytical testing before, during, and after HME to
evaluate thermal properties, recrystallization, dissolution, and
uniformity requires specialized analytical devices and procedures for
accurate measurement. A rigorous characterization of the ingredients
processed by HME is important to avoid a negative impact on the safety
and effectiveness of HMEs. Physicochemical characterization of the
extrudate formed during HME is complex and necessary to properly assess
its properties and performance in the finished drug product. In
addition, the measurement system to properly characterize the extrudate
is complex because it incorporates multiple complementary methods to
interpret similar properties, such as a limit of detection for
crystallinity and thermal history of amorphous phase. Ensuring the
stability of an HME is a major challenge during production, storage,
and administration.
With respect to the risks and benefits to patients, compounded HMEs
present a significant safety risk given the complexities described
above, which include HME process-design complexities and the
relationship between inactive ingredient and API of HMEs, which
directly impacts bioavailability, release, and performance.
Bioavailability, release, and performance in turn affect drug product
effectiveness and safety. Substituting or removing inactive
ingredients, such as polymers, plasticizers, or surfactants, would
likely change the solubility and release characteristics of the product
and, in turn, may adversely impact product performance. Also,
consistent quality controls for raw materials, the extrusion process,
and final product are essential for predictable and reproducible API
release, which directly affects the safety and effectiveness of the
product. HMEs can have enhanced bioavailability, controlled delivery
rates, and stabilized formulations. Such products can be produced with
taste-masking properties suitable for children or are in dosage forms
that are suitable for patients with swallowing difficulties. The Agency
is not aware of compounded HMEs for human use; however, FDA requests
comments regarding availability of and potential access to compounded
HMEs for human use. FDA is also not aware of a rationale for why
patients would have a medical need for compounded HMEs, as opposed to
an FDA-approved product; or of any actual or potential benefit that
would outweigh the risks to patient safety that would be presented by
compounded HMEs.
Based on an analysis of the evaluation criteria, taking into
account the risks and benefits to patients, FDA proposes to include
HMEs on the lists of drug products or categories of drug products that
present demonstrable difficulties for compounding under sections 503A
and 503B of the FD&C Act. On November 21, 2017, FDA proposed to the
PCAC that HMEs be identified as presenting demonstrable difficulties
for compounding under sections 503A and 503B of the FD&C Act (Ref. 10).
The PCAC voted to agree with FDA's proposal (Ref. 5).
In applying the six criteria discussed above, FDA considered
whether HMEs should be added to the 503A DDC List and to the 503B DDC
List. FDA has tentatively concluded that HMEs meet the statutory
criteria for inclusion on both lists. As discussed above, HME is a
process by which heat and shear are applied to melt a mixture of API
and inactive ingredients within an extruder that is then pushed through
an orifice to convert the ingredients into an amorphous phase material
with uniform content. FDA has identified, among other things, process-
design complexities and found that the relationship between inactive
ingredient and active ingredient of HMEs impacts bioavailability,
release, and performance, which could affect safety and effectiveness.
FDA does not believe an outsourcing facility's compliance with CGMP
requirements would address the concerns described above regarding
formulation complexity, drug delivery mechanism complexity, dosage form
complexity, complexity of achieving or assessing bioavailability,
compounding process complexity, and complexity of physicochemical or
analytical testing of the drug product or category of drug products.
FDA's CGMP regulations contain the minimum current good manufacturing
practice for methods to be used in, and the facilities or controls to
be used for, the manufacture, processing, packing, or holding of a drug
to assure that such drug meets the requirements of the FD&C Act as to
safety, and has the identity and strength and meets the quality and
purity characteristics that it purports or is represented to possess
(see 21 CFR 210.1(a)). The potential quality and safety concerns raised
by HMEs would typically be evaluated as part of the premarket approval
process, based on the assessment of a broader range of drug development
data including certain safety, clinical, and bioavailability or
bioequivalence information as appropriate. Since compounded drug
products that meet the conditions of sections 503A and 503B are exempt
from premarket approval requirements, compounded HMEs would not be
subject to such evaluation based on a broader range of drug development
data. Therefore, compliance with CGMP standards, alone, is unlikely to
provide sufficient assurance that compounded HMEs can deliver product
of intended characteristics with reliable quality and consistent
performance. However, FDA is soliciting comments about whether this
entry should be added to only the
[[Page 19786]]
503A DDC List, or only the 503B DDC List.
VI. Proposed Effective Date
The Agency proposes that any final rule based on this proposal
become effective 30 days after the date of publication of the final
rule in the Federal Register.
VII. Preliminary Economic Analysis of Impacts
We have examined the impacts of the proposed rule under Executive
Order 12866, Executive Order 13563, Executive Order 14094, the
Regulatory Flexibility Act (5 U.S.C. 601-612), and the Unfunded
Mandates Reform Act of 1995 (Pub. L. 104-4). Executive Orders 12866,
13563, and 14094 direct us to assess all benefits, costs, and transfers
of available regulatory alternatives and, when regulation is necessary,
to select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). Rules are
``significant'' under Executive Order 12866 Section 3(f)(1) (as amended
by Executive Order 14094) if they ``have an annual effect on the
economy of $200 million or more (adjusted every 3 years by the
Administrator of the Office of Information and Regulatory Affairs
(OIRA) for changes in gross domestic product); or adversely affect in a
material way the economy, a sector of the economy, productivity,
competition, jobs, the environment, public health or safety, or State,
local, territorial, or tribal governments or communities.'' OIRA has
determined that this proposed rule is not a significant regulatory
action under Executive Order 12866 Section 3(f)(1).
The Regulatory Flexibility Act requires us to analyze regulatory
options that would minimize any significant impact of a rule on small
entities. Because we expect that the proposed rule would have a small
impact, if any, on small entities, we propose to certify that the
proposed rule will not have a significant economic impact on a
substantial number of small entities.
The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires
us to prepare a written statement, which includes an assessment of
anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The 2022 threshold after adjustment for
inflation is $177 million, using the 2022 Implicit Price Deflator for
the Gross Domestic Product. This proposed rule would not result in an
expenditure in any year that meets or exceeds this amount.
We evaluated three categories of drug products for this proposed
rule. We are proposing to place all three of these categories of drug
products on the DDC Lists for sections 503A and 503B of the FD&C Act.
We expect that this proposed rule may create benefits for compounders
by reducing regulatory uncertainty. Currently, we are not aware of any
marketing of compounded drugs in the three proposed categories of drug
products for human use. Therefore, we expect that the proposed rule
would only create administrative costs for compounders to read and
understand the rule. We seek comments on these assumptions.
In table 1, we summarize the impacts of the proposed rule. The
present value of the costs of the proposed rule would equal $4.22
million at a 7 percent discount rate and $4.22 million at a 3 percent
discount rate. The proposed rule would result in annualized costs of
$0.56 million at a 7 percent discount rate, or $0.48 million at a 3
percent discount rate.
Table 1--Summary of Benefits, Costs, and Distributional Effects of the Proposed Rule
--------------------------------------------------------------------------------------------------------------------------------------------------------
Units
------------------------------------
Category Primary Low High Period Notes
estimate estimate estimate Year Discount covered
dollars rate (%) (years)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
Annualized Monetized ($m/year)................................. .......... .......... .......... .......... .......... ..........
.......... .......... .......... .......... .......... ..........
Annualized Quantified.......................................... .......... .......... .......... .......... .......... ..........
------------------------------------------------------------------------------------
Qualitative....................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
Costs:
Annualized Monetized ($m/year)................................. $0.56 $0.51 $0.63 2021 7 10
0.48 0.43 0.54 2021 3 10
Annualized Quantified.......................................... .......... .......... .......... .......... .......... ..........
------------------------------------------------------------------------------------
Qualitative....................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
Transfers:
Federal Annualized Monetized ($m/year)......................... .......... .......... .......... .......... .......... ..........
.......... .......... .......... .......... .......... ..........
------------------------------------------------------------------------------------
From:
To:
------------------------------------------------------------------------------------
Other Annualized Monetized ($m/year)........................... .......... .......... .......... .......... .......... ..........
.......... .......... .......... .......... .......... ..........
------------------------------------------------------------------------------------
From:
To:
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects:
State, Local, or Tribal Government: None.
Small Business: None.
Wages: None.
Growth: None.
--------------------------------------------------------------------------------------------------------------------------------------------------------
[[Page 19787]]
We have developed a comprehensive Preliminary Economic Analysis of
Impacts that assesses the impacts of the proposed rule. The full
preliminary analysis of economic impacts is available in the docket for
this proposed rule (Ref. 11) and at https://www.fda.gov/about-fda/reports/economic-impact-analyses-fda-regulations.
VIII. Analysis of Environmental Impact
We have determined under 21 CFR 25.30(h) that this action is of a
type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
IX. Paperwork Reduction Act of 1995
FDA tentatively concludes that this proposed rule contains no
collection of information as defined by the Paperwork Reduction Act of
1995.
X. Federalism
We have analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. We have determined that
this proposed rule does not contain policies that have substantial
direct effects on the States, on the relationship between the National
Government and the States, or on the distribution of power and
responsibilities among the various levels of government. Accordingly,
we conclude that the rule does not contain policies that have
federalism implications as defined in the Executive Order and,
consequently, a federalism summary impact statement is not required.
XI. Consultation and Coordination With Indian Tribal Governments
We have analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13175. We have tentatively
determined that the rule does not contain policies that would have a
substantial direct effect on one or more Indian Tribes, on the
relationship between the Federal Government and Indian Tribes, or on
the distribution of power and responsibilities between the Federal
Government and Indian Tribes. The Agency solicits comments from tribal
officials on any potential impact on Indian Tribes from this proposed
action.
XII. References
The following references are on display at the Dockets Management
Staff (see ADDRESSES) and are available for viewing by interested
persons between 9 a.m. and 4 p.m., Monday through Friday; they are also
available electronically at https://www.regulations.gov. FDA has
verified the website addresses, as of the date this document publishes
in the Federal Register, but websites are subject to change over time.
1. FDA, Transcript of the June 18, 2015, Meeting of the Pharmacy
Compounding Advisory Committee (available at https://wayback.archive-it.org/7993/20170403224128/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/UCM458514.pdf), accessed
January 10, 2023.
2. FDA, Transcript of the March 9, 2016, Meeting of the Pharmacy
Compounding Advisory Committee (available at https://public4.pagefreezer.com/content/FDA/04-03-2022T19:30/https://www.fda.gov/media/98783/download), accessed January 10, 2023.
3. FDA, Transcript of the November 3, 2016, Meeting of the Pharmacy
Compounding Advisory Committee (available at https://public4.pagefreezer.com/content/FDA/04-03-2022T19:30/https://www.fda.gov/media/105599/download), accessed January 10, 2023.
4. FDA, Transcript of the May 9, 2017, Meeting of the Pharmacy
Compounding Advisory Committee (available at https://public4.pagefreezer.com/content/FDA/04-03-2022T19:30/https://www.fda.gov/media/106182/download), accessed January 10, 2023.
5. FDA, Transcript of the November 21, 2017, Meeting of the Pharmacy
Compounding Advisory Committee (available at https://public4.pagefreezer.com/content/FDA/04-03-2022T19:30/https://www.fda.gov/media/112399/download), accessed January 10, 2023.
6. FDA, Briefing Information for the June 17-18, 2015, Meeting of
the Pharmacy Compounding Advisory Committee (available at https://wayback.archive-it.org/7993/20170404155225/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/UCM449535.pdf), accessed
January 10, 2023.
7. FDA, Briefing Information for the March 8-9, 2016, Meeting of the
Pharmacy Compounding Advisory Committee (available at https://public4.pagefreezer.com/browse/FDA/01-03-2022T00:42/https://www.fda.gov/advisory-committees/pharmacy-compounding-advisory-committee/briefing-information-march-8-9-2016-meeting-pharmacy-compounding-advisory-committee-pcac), accessed January 10, 2023.
8. FDA, Briefing Information for the November 3, 2016, Meeting of
the Pharmacy Compounding Advisory Committee (available at https://public4.pagefreezer.com/content/FDA/01-03-2022T00:42/https://www.fda.gov/media/100283/download), accessed January 10, 2023.
9. FDA, Briefing Information for the May 8-9, 2017, Meeting of the
Pharmacy Compounding Advisory Committee (available at https://public4.pagefreezer.com/content/FDA/01-03-2022T00:42/https://www.fda.govmedia/104134/download), accessed January 10, 2023.
10. FDA, Briefing Information for the November 20-21, 2017, Meeting
of the Pharmacy Compounding Advisory Committee (available at https://public4.pagefreezer.com/browse/FDA/01-03-2022T00:42/https://www.fda.gov/advisory-committees/pharmacy-compounding-advisory-committee/briefing-information-november-20-21-2017-meeting-pharmacy-compounding-advisory-committee-pcac), accessed January 10, 2023.
11. FDA, Preliminary Regulatory Impact Analysis, ``Drug Products
That Present Demonstrable Difficulties for Compounding Under Section
503A or 503B of the Federal Food, Drug, and Cosmetic Act ''
(available at https://www.fda.gov/about-fda/reports/economic-impact-analyses-fda-regulations).
List of Subjects in 21 CFR Part 216
Drugs, Prescription drugs.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, we propose
that 21 CFR part 216 be amended as follows:
PART 216--HUMAN DRUG COMPOUNDING
0
1. The authority citation for part 216 is revised to read as follows:
Authority: 21 U.S.C. 351, 352, 353a, 353b, 355, and 371.
0
2. Add Sec. 216.25 to subpart B to read as follows:
Sec. 216.25 Drug products or categories of drug products that present
demonstrable difficulties for compounding under section 503A or 503B of
the Federal Food, Drug, and Cosmetic Act.
(a) FDA will use the following criteria in evaluating drug products
or categories of drug products considered for inclusion on the lists
set forth in paragraphs (b) and (c) of this section:
(1) The complexity of the drug product or category of drug
products' formulation;
(2) The complexity of the drug product or category of drug
products' drug delivery mechanism;
(3) The complexity of the drug product or category of drug
products' dosage form;
(4) The complexity of achieving or assessing bioavailability of the
drug product or category of drug products;
(5) The complexity of the drug product or category of drug
products' compounding process; and
[[Page 19788]]
(6) The complexity of physicochemical or analytical testing of the
drug product or category of drug products.
(b) After considering the criteria in paragraph (a) of this section
and taking into account risks and benefits to patients, FDA has
determined that the following drug products or categories of drug
products present demonstrable difficulties for compounding that
reasonably demonstrate an adverse effect on the safety or effectiveness
of that drug product and therefore cannot be compounded under section
503A of the Federal Food, Drug, and Cosmetic Act:
(1) Drug products produced using hot melt extrusion.
(2) Liposome drug products.
(3) Oral solid modified-release drug products that employ coated
systems.
(c) After considering the criteria in paragraph (a) of this section
and taking into account risks and benefits to patients, FDA has
determined that the following drug products or categories of drug
products present demonstrable difficulties for compounding that are
reasonably likely to lead to an adverse effect on the safety or
effectiveness of the drug or category of drugs, and therefore cannot be
compounded under section 503B of the Federal Food, Drug, and Cosmetic
Act:
(1) Drug products produced using hot melt extrusion.
(2) Liposome drug products.
(3) Oral solid modified-release drug products that employ coated
systems.
Dated: March 12, 2024.
Robert M. Califf,
Commissioner of Food and Drugs.
[FR Doc. 2024-05801 Filed 3-19-24; 8:45 am]
BILLING CODE 4164-01-P
