83 FR 27609 - Alternative or Streamlined Mechanisms for Complying With the Current Good Manufacturing Practice Requirements for Combination Products; Proposed List Under the 21st Century Cures Act

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration

Federal Register Volume 83, Issue 114 (June 13, 2018)

As required by the 21st Century Cures Act (Cures Act), the Food and Drug Administration (FDA or Agency) is proposing a list of alternative or streamlined mechanisms for complying with the current good manufacturing practice (CGMP) requirements for combination products. Combination products are products composed of two or more different types of medical products (drug, device, and/or biological product).

[Federal Register Volume 83, Number 114 (Wednesday, June 13, 2018)]
[Notices]
[Pages 27609-27614]
From the Federal Register Online  [www.thefederalregister.org]
[FR Doc No: 2018-12634]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2018-N-2065]


Alternative or Streamlined Mechanisms for Complying With the 
Current Good Manufacturing Practice Requirements for Combination 
Products; Proposed List Under the 21st Century Cures Act

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: As required by the 21st Century Cures Act (Cures Act), the 
Food and Drug Administration (FDA or Agency) is proposing a list of 
alternative or streamlined mechanisms for complying with the current 
good manufacturing practice (CGMP) requirements for combination 
products. Combination products are products composed of two or more 
different types of medical products (drug, device, and/or biological 
product).

DATES: Submit either electronic or written comments on this notice by 
September 11, 2018 to ensure that the Agency considers your comment on 
this proposed list before it begins work on the final list.

ADDRESSES: You may submit comments as follows. Please note that late, 
untimely filed comments will not be considered. Electronic comments 
must be submitted on or before September 11, 2018. The https://www.regulations.gov electronic filing system will accept comments until 
midnight Eastern Time at the end of September 11, 2018. Comments 
received by mail/hand delivery/courier (for written/paper submissions) 
will be considered timely if they are postmarked or the delivery 
service acceptance receipt is 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, 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

[[Page 27610]]

identified, as confidential, if submitted as detailed in 
``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2018-N-2065 for ``Alternative or Streamlined Mechanisms for 
Complying with Current Good Manufacturing Practice (CGMP) Requirements 
for Combination Products.'' 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.
     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.thefederalregister.org/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents 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.

FOR FURTHER INFORMATION CONTACT: Melissa Burns, Office of Combination 
Products, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 
32, Rm. 5125, Silver Spring, MD 20993, 301-795-5616, 
[email protected].

SUPPLEMENTARY INFORMATION: 

I. Background

    In December 2016, the Cures Act (Pub. L. 114-255) was signed into 
law. Section 3038(c) of the Cures Act mandated that FDA publish in the 
Federal Register a list identifying types of combination products and 
manufacturing processes for which ``good manufacturing processes'' may 
be adopted that vary from the requirements set forth in Sec.  4.4 (21 
CFR 4.4) or that FDA proposes can satisfy the requirements in Sec.  4.4 
through ``alternative or streamlined mechanisms,'' and to review this 
list periodically. In accordance with this statutory mandate, FDA is 
publishing a proposed list in section II of this document, which 
addresses processes for single-entity and co-packaged combination 
products that can satisfy requirements in Sec.  4.4 through alternative 
or streamlined mechanisms (hereafter ``mechanisms'').
    On January 22, 2013, FDA issued a final rule on CGMP requirements 
for combination products (see 78 FR 4307 and part 4 (21 CFR part 4, 
subpart A)). Prior to issuance of the final rule, although CGMP 
regulations were in place to establish requirements for drugs, devices, 
biological products, and human cells, tissues, or cellular or tissue-
based products (HCT/Ps), there were no regulations to clarify and 
explain the application of these CGMP requirements to combination 
products. The final rule clarified which CGMP requirements apply to 
combination products. It also established a transparent and streamlined 
regulatory framework for combination product manufacturers to use when 
demonstrating compliance with applicable CGMP requirements.
    A combination product is a product composed of two or more 
different types of medical products (i.e., a combination of a drug, 
device, and/or biological product). The drugs, devices, and biological 
products included in combination products are referred to as 
``constituent parts'' of the combination product. Combination products 
include ``single-entity'' combination products that are physically, 
chemically, or otherwise combined or mixed and produced as a single 
entity (Sec.  3.2(e)(1) (21 CFR 3.2(e)(1)) (e.g., prefilled syringes 
and drug-eluting stents) and ``co-packaged'' combination products where 
two or more separate products are packaged together in a single package 
or as a unit and composed of drug and device products, device and 
biological products, or biological and drug products (Sec.  3.2(e)(2)) 
(e.g., a surgical or first-aid kit).\1\ Section 4.4 outlines how 
manufacturers of single-entity and co-packaged combination products 
(hereafter ``CP manufacturers'') can demonstrate compliance with 
applicable CGMP requirements, including through implementation of a 
streamlined approach to meet the requirements of both the drug CGMP and 
the device Quality System (QS) regulation by designing and implementing 
a CGMP operating system that demonstrates compliance with either of the 
following:
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    \1\ There are also ``cross-labeled'' combination products (Sec.  
3.2(e)(3) and (4)). With respect to cross-labeled combination 
products, part 4, subpart A was intended to clarify only that the 
CGMP requirements applicable to the drugs, devices, or biological 
products also apply to these types of articles when they are 
constituent parts of such combination products. Constituent parts of 
cross-labeled combination products need only comply with the 
requirements otherwise applicable to that type of product (e.g., 21 
CFR parts 210 and 211 for a drug constituent part or 21 CFR part 820 
for a device constituent part). The ``streamlined approach'' and 
related mechanisms described in this notice are generally not 
relevant or applicable to cross-labeled combination products. 
However, to the extent that the constituent parts of a cross-labeled 
combination product are manufactured at the same facility, the 
manufacturing process would be akin to when the manufacture of the 
constituent parts of a co-packaged combination product occurs at the 
same facility. Accordingly, as discussed in the combination product 
CGMP guidance (Ref. 1), for cross-labeled combination products 
manufactured at the same facility, the Agency does not intend to 
object to the use of a streamlined CGMP operating system for the 
manufacture of the combination product rather than distinct systems 
for the manufacture of each constituent part that is occurring at 
that facility.
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     The drug CGMP regulations in parts 210 and 211 (21 CFR 
parts 210 and 211) and the following specified provisions from the 
device QS regulation (Sec.  4.4(b)(1), ``drug CGMP-based streamlined 
approach''): (1) Sec.  820.20 (21 CFR 820.20) Management 
responsibility, (2) Sec.  820.30 (21 CFR 820.30) Design controls, (3) 
Sec.  820.50 (21 CFR 820.50) Purchasing controls, (4) Sec.  820.100 (21 
CFR 820.100) Corrective and preventive action, (5) Sec.  820.170 (21 
CFR 820.170) Installation, and (6) Sec.  820.200 (21 CFR 820.200) 
Servicing; or
     The device QS regulation in part 820 (21 CFR part 820) and 
the following specified provisions from the drug CGMP regulations 
(Sec.  4.4(b)(2), ``device QS regulation-based streamlined approach''): 
(1) Sec.  211.84 (21 CFR 211.84) Testing and approval or rejection of 
components, drug product containers, and closures; (2) Sec.  211.103 
(21 CFR 211.103) Calculation of yield; (3) Sec.  211.132 (21 CFR 
211.132) Tamper-evident packaging requirements for

[[Page 27611]]

over-the-counter (OTC) human drug products; (4) Sec.  211.137 (21 CFR 
211.137) Expiration dating; (5) Sec.  211.165 (21 CFR 211.165) Testing 
and release for distribution; (6) Sec.  211.166 (21 CFR 211.166) 
Stability testing; (7) Sec.  211.167 (21 CFR 211.167) Special testing 
requirements; and (8) Sec.  211.170 (21 CFR 211.170) Reserve samples.
    If the combination product includes a biological product 
constituent part, the CGMP operating system must also demonstrate 
compliance with applicable CGMP requirements for biological products in 
parts 600 through 680 (21 CFR parts 600 through 680), and if the 
combination product includes an HCT/P, the CGMP operating system must 
also demonstrate compliance with the applicable current good tissue 
practice requirements in part 1271 (21 CFR part 1271).
    Following publication of the final rule, FDA reviewed data and 
rationales provided by manufacturers who proposed various means of 
addressing CGMP considerations for combination products. FDA also 
considered feedback on its draft guidance on CGMP requirements for 
combination products, published in January 2015, in which stakeholders 
requested further guidance on circumstances in which flexible 
approaches may be available and how to engage with FDA on them. The 
final ``Guidance for Industry and FDA Staff: Current Good Manufacturing 
Practice Requirements for Combination Products'' includes discussion of 
existing mechanisms to comply with the final rule and of circumstances 
in which FDA did not intend to object to manufacturers applying 
practices that vary from the requirements set forth in the rule (Ref. 
1). The Agency continues to apply a risk-based approach to evaluating 
methods for ensuring the quality of combination products and to welcome 
proposals from manufacturers for how to enhance the efficiency of 
development and manufacturing activities, while ensuring the safety and 
effectiveness of the combination products produced.

II. Proposed List of Mechanisms for Complying With Sec.  4.4 CGMP 
Requirements for Combination Products

A. Introduction

    The following is a proposed list of mechanisms for demonstrating 
compliance with relevant combination product CGMP requirements, as 
described below. Where applicable, reference is made to sections of the 
``Guidance for Industry and FDA Staff: Current Good Manufacturing 
Practice Requirements for Combination Products'' for additional 
information (Ref. 1). FDA will continue to evaluate this list in light 
of Agency experience and stakeholder input. Manufacturers are welcome 
to propose other approaches not described, and FDA continues to 
encourage dialogue with the Agency on various means of demonstrating 
CGMP compliance for combination products.
    For each mechanism described below, CP manufacturers should 
consider what documentation would be sufficient to support that the 
mechanism, including the specific approach for implementing it, assures 
appropriate control of the manufacture of the combination product to 
ensure safety and effectiveness of the product. Appropriate evidence 
and an explanation of the rationale to support the approach should be 
accessible at the manufacturing facility for review during facility 
inspections. For additional discussion on how to interact with FDA 
regarding the mechanisms described below, see section III.

B. Mechanisms for Complying With Drug CGMP Requirements (Part 211) 
Specified in Sec.  4.4 2
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    \2\ Several drug CGMP mechanisms included in this proposed list 
depend upon use of a more broadly defined batch. FDA notes that 
approaches that depend upon broadly defined batches may increase the 
number of distributed products implicated when corrective actions 
are necessary to address postmarket issues.
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    FDA interprets the mechanisms identified in the sections below as a 
means to demonstrate compliance with the specified part 211 
requirements identified in Sec.  4.4:
1. Section 211.165 Testing and Release for Distribution
    Use of product samples that are not finished combination products 
(but that are representative of the finished combination product with 
respect to the characteristics and attributes being tested) when 
performing testing required by Sec.  211.165 to determine whether the 
drug constituent part meets final specifications. To meet the 
requirements of Sec.  211.165, the CP manufacturer would need to 
establish, including where appropriate through bridging studies and 
other quantitative means, that any differences in the manufacturing 
process for the representative samples as compared to the finished 
combination product do not affect the drug constituent part. For 
example, as part of product release testing, drug-eluting lead 
manufacturers could perform release testing for identity, potency, or 
other quality attributes on a representative lead tip assembly that 
contains the drug constituent part, but does not contain the full 
electronic and mechanical assembly, so long as they can establish that 
the differences in the manufacturing process do not impact the drug 
constituent part and the sample is representative of the finished 
combination product with respect to the quality attributes being 
tested.
    (See also Section IV.B.5 of Reference 1 for additional information 
on testing and release for combination products.)
2. Section 211.166 Stability Testing
    Use of bracketing and matrixing approaches to stability studies for 
combination products. Principles for bracketing and matrixing 
approaches to meet the requirements of Sec.  211.166 have already been 
addressed by the Agency with regard to drug products (Ref. 2), and such 
principles can also be applied to combination products. For example, 
when assessing stability for a prefilled syringe that is marketed in 
various fill volumes, one of the approaches that a CP manufacturer 
could utilize, if appropriate, is bracketing based on the smallest and 
the largest fill volume of product configurations. In determining the 
extremes for a bracketing approach and/or when justifying the use of a 
matrix design for single-entity combination products, it is important 
that the drug-device interactions and variations in the manufacturing 
processes are considered. For co-packaged combination products, such 
approaches can be applied to the drug constituent part of the product.
    Leveraging stability data for an already marketed combination 
product. Such mechanisms can be considered when the new combination 
product is a modification of an already marketed product and the 
modification does not impact the stability of the drug constituent 
part. For example, when developing new lengths of a drug-coated 
catheter product for which the catheter materials, drug coating, 
manufacturing process, and packaging configurations are largely 
unchanged from existing marketed sizes, the CP manufacturer would 
generally be able to leverage existing stability data to establish 
initial product shelf life or to support reduced stability data 
requirements, so long as characteristics of the product that could 
impact stability (materials, packaging configuration, etc.) remain the 
same. However, if the device constituent part of a drug-coated catheter 
includes a new material that is in contact with the drug coating, for 
example, new stability studies would generally be needed under Sec.  
211.166.

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    (See also Section IV.B.6 of Reference 1 for additional information 
on stability requirements for combination products.)
3. Section 211.167 Special Testing Requirements
    Defining ``batch'' based on the drug constituent part rather than 
the finished combination product for purposes of special testing 
requirements for pyrogens and endotoxins. For example, a manufacturer 
of a combination product that has a sub-assembly coated with a drug, 
which is then incorporated into several ``batches'' or ``lots'' of the 
overall combination product, may be able to define a batch for purposes 
of pyrogen and endotoxin testing as a batch of that sub-assembly for 
purposes of meeting the requirements of Sec.  211.167. As with the 
other mechanisms described in this list, this mechanism would only 
potentially be available if there would be no impact on the drug 
constituent part from subsequent manufacturing processes, including 
when the constituent parts are combined to produce the final 
combination product. CP manufacturers should consider whether such 
risks may be introduced later in the production process (after the 
batch has been defined). This approach will most frequently apply for 
co-packaged combination products or single-entity combination products 
for which only a component or sub-assembly of the overall product is in 
contact with the drug constituent part.
    (See also Section IV.B.7 of Reference 1 for additional information 
on special testing requirements for combination products.)
4. Section 211.170 Reserve Samples
    Keeping reserve samples that are representative of the finished 
combination product. CP manufacturers may use validated surrogates as 
representative samples to meet the requirements of Sec.  211.170, 
provided the surrogate is appropriate, both in terms of the 
manufacturing process and the characteristics of the container closure. 
For example, maintaining only a sub-assembly of a coated single-entity 
combination product or only the drug constituent part of a co-packaged 
combination product as a reserve sample would generally be permissible 
under the regulation when: (1) All manufacturing process steps after 
the coating step or the fill for the drug constituent part are shown 
not to affect the drug constituent part, (2) the immediate container 
closure has essentially the same characteristics as that for the drug 
constituent part as packaged in the combination product for 
distribution, and (3) the representative samples are suitable for all 
required testing of the drug constituent part for which the reserve 
samples are being kept.
    Using samples from representative lots of a larger batch for 
retention of reserve samples. To meet the requirements of Sec.  
211.170, CP manufacturers may be able to use bracketing and matrixing 
approaches to retain reserve samples from certain lots to adequately 
represent the broadly defined batch of the combination product. For 
example, CP manufacturers might be able to retain reserve samples of 
appropriately varied sizes of a drug-coated combination product from 
within a broadly defined batch that includes multiple lots of different 
sizes.
    (See also Section IV.B.8 of Reference 1 for additional information 
on reserve sample requirements for combination products.)

C. Mechanisms for Complying With Device Quality System Requirements 
(Part 820) Specified in Sec.  4.4

    FDA interprets the mechanisms identified in the sections below as a 
means to demonstrate compliance with the specified part 820 
requirements identified in Sec.  4.4:
1. Section 820.30 Design Controls
    Using existing pharmaceutical development practices and 
documentation that align with the design control principles and 
requirements of Sec.  820.30. Robust pharmaceutical development 
practices would address many design control requirements to assure 
compliance with Sec.  820.30, where applicable. CP manufacturers need 
to demonstrate how development processes and terminology align with 
design control principles and requirements in Sec.  820.30, when 
required, including, where necessary, developing additional design 
control elements. When evaluating the adequacy of existing 
pharmaceutical development processes, particular attention should be 
given to postmarket management of design changes to the combination 
product and the alignment of change control practices with the 
principles and requirements of Sec.  820.30, as applicable.
2. Exemption of Combination Products From Device QS Regulation
    Exemption of the combination product from all or certain provisions 
of the device QS regulation (part 820) if the device constituent part 
of the combination product is itself exempt from such requirements and 
use of the device constituent part falls within the scope of the 
relevant exemption, including with respect to the device constituent 
part's intended use. Some devices are exempt from all or certain 
provisions of the device QS regulation (see, for example, liquid 
medication dispensers such as cups and droppers that fall within the 
scope of Sec.  880.6430 (21 CFR 880.6430), provided the use of the 
device is not a new intended use or does not otherwise raise different 
safety and effectiveness questions (see, for example, limitations to 
the exemption under 21 CFR 880.9). Consistent with this, for the 
combination product to be exempt from the associated provisions of the 
device QS regulation, we interpret this exemption to mean that the use 
of the device in the combination product must not be a new intended use 
or otherwise raise different safety and effectiveness questions for the 
device. This circumstance will most frequently apply to co-packaged 
combination products. For example, an oral dosing syringe (a liquid 
medication dispenser under Sec.  880.6430) that is co-packaged with a 
drug may be exempt from certain provisions of the device QS regulation 
(and hence the combination product may also be exempt from such 
provisions); however, incorporation of such a dispenser into a primary 
container closure system or co-packaging of such a dispenser with an 
emergency-use product, for example, may constitute a new intended use 
for the dispenser or raise different safety and effectiveness questions 
for the dispenser, such that the relevant exemption would not apply.
    (See also Section III.C.3 of Reference 1 for additional information 
on the exemption from provisions of the device QS regulation for 
combination products.)

III. Interacting With FDA on Mechanisms for Complying With CGMP for 
Combination Products

1. Process for Interacting With FDA

    In some cases, CP manufacturers may interact with FDA to gain 
approval or otherwise notify FDA of a manufacturing change. In other 
cases, although a submission or notification is not required, CP 
manufacturers may want to discuss potential use of CGMP mechanisms with 
FDA. CP manufacturers are encouraged to interact early with FDA on 
contemplated CGMP mechanisms.
     Pre-Submissions and Meeting Requests. CP manufacturers who 
want to obtain FDA feedback prior to submitting a premarket application 
or a postmarket supplement or who otherwise want to obtain feedback on

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their approach may interact with FDA via the existing established 
process applicable to the lead Center \3\ for the combination product. 
For combination products reviewed under a new drug application (NDA) or 
a biologics license application (BLA), such interactions will generally 
be through Type C meetings (Ref. 3).\4\ For combination products 
reviewed under an abbreviated new drug application (ANDA), these 
interactions will generally be through pre-ANDA meetings (Ref. 4).\5\ 
For combination products reviewed under a device premarket submission 
(e.g., a premarket approval application (PMA), de novo classification, 
or premarket notification (510(k)), these interactions will generally 
be via the pre-submission process (Ref. 5).
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    \3\ A combination product is assigned to an Agency center 
(Center for Biologics Evaluation and Research, Center for Drug 
Evaluation and Research, or Center for Devices and Radiological 
Health) that will have primary jurisdiction (i.e., the ``lead 
Center'') for that combination product's review and regulation. 
Assignment of a combination product to a lead Center is based on a 
determination of which constituent part provides the primary mode of 
action of the combination product (21 U.S.C. 353(g)).
    \4\ When final, this guidance will represent the FDA's current 
thinking on this topic.
    \5\ When final, this guidance will represent the FDA's current 
thinking on this topic.
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    Regardless of the type of submission, such interactions should be 
focused on a general discussion of the mechanism and CGMP approach the 
CP manufacturer wishes to pursue and associated justification to 
support the approach. Only representative data is typically appropriate 
in these interactions; complete data should be included in the 
subsequent premarket submission or postmarket supplement, if required, 
and/or be maintained at the manufacturing facility, as appropriate.\6\
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    \6\ Note that when discussing a mechanism for complying with 
CGMP requirements for which the CP manufacturer is leveraging 
information in master file(s), the master file holder must submit a 
letter of authorization to permit FDA to review such information 
(see 21 CFR 314.420(d) and 21 CFR 814.20(c)). The specific 
information within the master file that is being leveraged should be 
clearly identified to FDA.
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     Premarket Review. CP manufacturers should include in their 
original submission for NDAs, BLAs, ANDAs, and PMAs information on any 
mechanisms for complying with CGMP requirements. For PMAs, this 
information should be included in the manufacturing section of the PMA. 
For information regarding where to place information in NDAs, BLAs, or 
ANDAs, refer to ``eCTD Technical Conformance Guide'' (Ref. 6).
     Postmarket Supplements or Notifications to FDA. Postmarket 
changes to implement a combination product CGMP mechanism for NDAs, 
ANDAs, BLAs, and PMAs, may require submission of a supplement or 
notification to FDA.\7\ CP manufacturers should consult related 
guidances relevant to the type of constituent part of the combination 
product (Refs. 7 to 9).\8\ If a CP manufacturer has questions on the 
appropriate submission type or the need for a submission, they can 
contact the lead Center for assistance.
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    \7\ Requirements for postmarket supplements are contained, for 
example, in 21 CFR 314.70 (NDAs), 21 CFR 601.12 (BLAs), and 21 CFR 
814.39 (PMAs). Any questions on whether FDA review is required for a 
postmarket CGMP mechanism should be directed to the lead Center.
    \8\ With reference to Ref. 8, when final, this guidance will 
represent the FDA's current thinking on this topic.
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2. Content Suggestions
    When submitting information on a CGMP mechanism, along with any 
submission requirements applicable to the submission type, the 
following content should be included:
     Applicable CGMP regulation. Identify the CGMP regulation 
applicable to the described mechanism. For example, if a submission 
includes a mechanism related to stability testing, indicate that Sec.  
211.166 is the applicable CGMP requirement.
     Applicable Products. If the mechanism is to be applied to 
multiple products and/or product configurations, list all related 
sizes, strengths, etc., as well as all related application numbers.
     Related Interactions with FDA. If the CP manufacturer has 
had previous interactions with FDA relevant to the proposed mechanism, 
either for the product addressed in the submission or for related 
products, the CP manufacturer should provide reference to those 
interactions. Where applicable, the CP manufacturer may cross-reference 
previously submitted information.
     Justification and Scientific Data. Include a rationale to 
support that the proposed mechanism assures adequate manufacturing 
control to ensure product safety and effectiveness. When describing a 
CGMP mechanism in a premarket or postmarket submission, the description 
should be accompanied by data necessary to support the approach. When 
proposing a change from a CGMP approach that was reviewed previously by 
FDA, such justification should include analysis of how the proposed 
approach compares to the previously reviewed approach as an effective 
manufacturing control, including representative data, as appropriate, 
to substantiate the analysis.
3. FDA Engagement
    CP manufacturers are encouraged to discuss combination product CGMP 
mechanisms with FDA. Any questions on how to engage FDA in such 
discussions should be directed to the lead Center for the product or 
the Office of Combination Products, as needed.
4. FDA Review
    FDA may review information from a CP manufacturer related to a 
mechanism for complying with CGMP requirements for combination products 
in premarket applications, postmarket supplements or notifications, 
pre-submissions and meetings, and during facility inspections. FDA may 
determine that the data and rationale presented by a CP manufacturer 
for a particular mechanism are insufficient to demonstrate that the 
mechanism, as proposed or implemented, meets the applicable CGMP 
requirement. FDA generally will notify the CP manufacturer and/or 
applicant in writing of any such determination.

IV. Other Issues for Consideration

    We have developed this proposed list of mechanisms based on 
information submitted to FDA by CP manufacturers as well as FDA 
experience with manufacturing processes and CGMP compliance approaches 
that have been shown through appropriate data and rationales to support 
the manufacture of safe and effective products. FDA requests comment 
from stakeholders who believe there are additional types of combination 
products and/or manufacturing processes where different approaches may 
be appropriate. When providing such feedback, the suggested approach 
should be:
     Applicable to a type or range of combination products 
(e.g., not just a single CP manufacturer's product). Commenters should 
indicate to which types of combination products or manufacturing 
processes they believe the suggested approach should apply.
     Supported by adequate data and rationales to demonstrate 
that such an approach would continue to support manufacturing of safe 
and effective combination products. Commenters should summarize the 
data and rationale that support the suggested approach.

Any confidential information submitted to FDA via the docket should be 
appropriately identified (see Instructions above, in ADDRESSES).

V. Paperwork Reduction Act

    This notice refers to previously approved collections of 
information

[[Page 27614]]

found in FDA regulations. These collections of information are subject 
to review by the Office of Management and Budget (OMB) under the 
Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). We note that the 
information collected under the underlying CGMP regulations for drugs, 
devices, and biological products, including current good tissue 
practices for HCT/Ps, found in parts 211, 820, 600 through 680, and 
1271, have already been approved and are in effect. The provisions of 
part 211 are approved under the OMB control number 0910-0139. The 
provisions of part 820 are approved under OMB control number 0910-0073. 
The provisions of parts 606 and 640 are approved under OMB control 
number 0910-0116. The provisions of part 610 are approved under OMB 
control number 0910-0116 and OMB control number 0910-0338 (also for 
part 680). The provisions of part 1271, subparts C and D, are approved 
under OMB control number 0910-0543.
    We note that the information collected under the related submission 
types have already been approved and are in effect. The collections of 
information regarding formal meetings with sponsors and applicants have 
been approved under OMB control number 0910-0429. The collections of 
information regarding new drug approvals (NDA) and abbreviated new drug 
applications (ANDA) have been approved under OMB control number 0910-
0001. The collections of information regarding pre-ANDAs have been 
approved under OMB control number 0910-0797. The collections of 
information regarding pre-submissions have been approved under OMB 
control number 0910-0756. The collections of information regarding PMAs 
have been approved under OMB control number 0910-0231. The collections 
of information for premarket notification (510(k)) have been approved 
under OMB control number 0910-0120. The collections of information for 
the de novo classification process have been approved under OMB control 
number 0910-0844. The collections of information regarding biologics 
license applications have been approved under OMB control number 0910-
0338.

VI. References

    The following references are on display in 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. ``Guidance for Industry and FDA Staff: Current Good Manufacturing 
Practice Requirements for Combination Products,'' January 2017. 
https://www.fda.gov/RegulatoryInformation/Guidances/ucm126198.htm.
2. ``Guidance for Industry: Q1D Bracketing and Matrixing Designs for 
Stability Testing of New Drug Substances and Products,'' January 
2003. https://www.fda.gov/downloads/Drugs/Guidances/ucm073379.pdf.
3. ``Draft Guidance for Industry: Formal Meetings Between the FDA 
and Sponsors or Applicants of PDUFA Products,'' December 2017. 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM590547.pdf.
4. ``Draft Guidance for Industry: Formal Meetings Between FDA and 
ANDA Applicants of Complex Products Under GDUFA,'' October 2017. 
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm578366.pdf.
5. ``Guidance for Industry and Food and Drug Administration Staff: 
Requests for Feedback on Medical Device Submissions: The Pre-
Submission Program and Meetings with Food and Drug Administration 
Staff,'' September 2017. https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm311176.pdf.
6. ``eCTD Technical Conformance Guide,'' November 2017. https://www.fda.gov/downloads/Drugs/UCM465411.pdf.
7. ``Guidance for Industry: Changes to an Approved NDA or ANDA,'' 
April 2004. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm077097.pdf.
8. ``Draft Guidance for Industry: Chemistry, Manufacturing, and 
Controls Changes to an Approved Application: Certain Biological 
Products,'' December 2017. https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/General/UCM590118.pdf.
9. ``Guidance for Industry and FDA Staff: 30-Day Notices, 135-Day 
Premarket Approval (PMA) Supplements and 75-Day Humanitarian Device 
Exemption (HDE) Supplements for Manufacturing Method or Process 
Changes,'' April 2011. https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM080194.pdf.


    Dated: June 7, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018-12634 Filed 6-12-18; 8:45 am]
 BILLING CODE 4164-01-P