[Federal Register Volume 87, Number 176 (Tuesday, September 13, 2022)]
[Notices]
[Pages 56066-56070]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2022-19713]


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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; 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, Agency, or we) is finalizing a list 
of alternative or streamlined mechanisms for complying with the current 
good manufacturing practice (CGMP) requirements for combination 
products. A combination product is a product composed of any 
combination of a drug, a device, and/or a biological product.

DATES: This notice is published in the Federal Register on September 
13, 2022.

ADDRESSES: For access to the docket, 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, between 9 a.m. and 4 p.m., Monday through Friday, 240-402-
7500. Publicly available submissions may be seen in the docket.

FOR FURTHER INFORMATION CONTACT: John Barlow Weiner, Office of 
Combination Products, Food and Drug Administration, 10903 New Hampshire 
Ave., Bldg. 32, Rm. 5130, Silver Spring, MD 20993, 301-796-8930, 
[email protected] or [email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    On January 22, 2013, FDA issued a final rule on CGMP requirements 
for combination products (see 78 FR 4307 and part 4, subpart A (21 CFR 
part 4, subpart A)) (CGMP Rule). 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, the constituent parts 
of which are physically, chemically, or otherwise combined or mixed and 
produced as a single entity (see 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 the constituent parts are packaged together 
in a single package or as a unit (see Sec.  3.2(e)(2)) (e.g., a 
surgical or first-aid kit).\1\ Section 4.4 (21 CFR 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) regulations.
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    \1\ There are also ``cross-labeled'' combination products (Sec.  
3.2(e)(3) and (4)). See Ref. 1 for additional information regarding 
CGMP requirements for them, as well as use of the ``streamlined 
approach'' if a device and drug or biological product constituent 
part of a cross-labeled combination product are manufactured at the 
same facility.
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    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, 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 published 
a proposed list on June 13, 2018 (83 FR 27609).
    FDA received six comments on this proposed list, has considered 
them, and is now publishing a list after such consideration (see 
section II of this document). In response to the comments, FDA added 
and refined examples and provided additional clarity regarding FDA's 
expectations for CP manufacturers when applying mechanisms presented in 
this list. FDA also added reference to a guidance on how to request FDA 
feedback on combination products, which provides additional detail on 
interacting with

[[Page 56067]]

FDA, including with respect to CGMP issues addressed in this list.
    While FDA has provided examples in this notice of the types of 
mechanisms that may be appropriate, CP manufacturers should consider 
the suitability of an approach in the context of their product and 
manufacturing process. For these examples, we have recommended engaging 
the Agency before adoption of some, whereas others may be evaluated on 
inspection as appropriate. Additional approaches may be permissible as 
well for evaluation on a case-by-case basis for a particular product 
and CP manufacturer. FDA continues to apply a risk-based approach to 
evaluating alternative or streamlined mechanisms for ensuring the 
quality of combination products, and as FDA and CP manufacturers 
develop additional data and rationales, this list may be expanded, 
including to provide additional examples or to identify types of 
combination products for which alternative or streamlined mechanisms 
may be applicable.

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

A. Introduction

    Sections II.B and II.C present mechanisms for demonstrating 
compliance with relevant combination product CGMP requirements. 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. CP manufacturers are welcome to 
propose other approaches not described, including approaches to other 
requirements set forth in Sec.  4.4 for which FDA is not currently 
describing mechanisms for demonstrating compliance in the sections 
below.
    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 regardless of whether the approach has been discussed with 
FDA.
    In some cases, CP manufacturers may need to interact with FDA to 
gain approval or otherwise notify FDA of a manufacturing change (see 
section III.A). For example, if a CP manufacturer utilizes a 
bracketing/matrixing design for stability studies, this approach should 
be submitted to FDA either as a proposal at the time of premarket 
review or as a postmarket change.
    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 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 
means to demonstrate compliance with the following part 211 (21 CFR 
part 211) requirements specified in Sec.  4.4:
1. Section 211.165 Testing and Release for Distribution
    Use of 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 (21 CFR 211.165) to determine whether 
the drug constituent part, and thus the combination product, meets 
relevant final specifications. To meet the requirements of Sec.  
211.165, the CP manufacturer using this mechanism 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 (i.e., to 
establish that there is no difference in the quality attributes related 
to the drug constituent part in the representative sample as compared 
to the attributes related to the drug constituent part in the finished 
combination product). For example, as part of product release testing, 
drug-eluting lead CP manufacturers could perform release testing for 
identity, potency, or other quality attributes on a representative lead 
tip assembly that contains the drug constituent part, rather than on 
the finished combination product containing the full electronic and 
mechanical assembly, so long as they can establish that the 
representative lead tip assemblies meet the relevant acceptance 
criteria and there are no statistically significant differences in the 
test results for the representative lead tip assemblies compared to the 
finished combination product.
    (See also section IV.B.5 of Ref. 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 (21 CFR 211.166) 
have already been addressed by the Agency, including in The 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) guidelines with regard to drug 
products (Refs. 2 and 3), and such principles can also be applied to 
combination products. CP manufacturers could utilize a bracketing/
matrixing design, if appropriate, for stability studies. 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 only be applied to the drug constituent part of the 
product.
    Leveraging stability data for an already marketed combination 
product. Mechanisms that use prior stability knowledge, data, or 
information for an existing product to support stability assessment for 
a modification to that product may be appropriate when a new 
combination product is a modification of an already marketed product 
and the modification does not have the potential to 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 (e.g., materials, packaging configuration) 
remain the same. However, if the device constituent

[[Page 56068]]

part of a drug-coated catheter includes a new material that is in 
contact with the drug coating or is a new design with a different drug-
coated area or geometry, for example, new stability studies would 
generally be needed under Sec.  211.166.
    (See also section IV.B.6 of Ref. 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 CP 
manufacturer of a combination product consisting of a device that is 
coated with a drug, where a larger batch of coating is used to 
manufacture 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 set of combination products that were all 
manufactured using the same coating batch for purposes of meeting the 
requirements of Sec.  211.167 (21 CFR 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 endotoxin 
or pyrogen levels for the finished combination product from subsequent 
manufacturing processes, including when the constituent parts are 
combined to produce the final combination product (e.g., there are no 
statistically significant differences in pyrogen or endotoxin test 
results for the combination product immediately following the coating 
process step as compared to the finished combination product). When 
defining the batch, CP manufacturers should consider whether such risks 
may be introduced later in the production process.
    (See also section IV.B.7 of Ref. 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 (21 
CFR 211.170), provided the surrogate is appropriate, both in terms of 
the manufacturing process and the characteristics of the container 
closure. For example, it may be permissible to maintain as a reserve 
sample only the drug-containing subassembly of a single-entity 
combination product, such as only the distal tip subassembly (with 
drug-containing collar) of a pacemaker lead without the associated 
internal electronic components, or the drug constituent part of a co-
packaged combination product, such as the prefilled cartridge of a 
combination product that is distributed as a prefilled cartridge with 
an injector system. Such approaches would generally be permissible 
under the regulation when: (1) all subsequent manufacturing process 
steps to produce the final combination product 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, where relevant lot-release tests, analytical procedures, and 
acceptance criteria are the same for the product matrix and the 
relevant aspects of the manufacturing process are the same, CP 
manufacturers might be able to retain reserve samples of appropriately 
varied sizes of a drug-coated combination product from across that 
matrix.
    (See also section IV.B.8 of Ref. 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 
means to demonstrate compliance with the following part 820 (21 CFR 
part 820) requirements specified 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 (21 CFR 820.30). Robust pharmaceutical 
development practices would address many design control requirements to 
assure compliance with Sec.  820.30 where applicable (Ref. 4). CP 
manufacturers need to demonstrate how development processes, 
procedures, and terminology align with design control principles and 
requirements in Sec.  820.30, when applicable, including developing 
additional design control elements, if necessary. When evaluating the 
adequacy of existing pharmaceutical development processes and related 
documentation, 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.
    (See also section IV.A.2 of Ref. 1 for additional information on 
the requirements of Sec.  820.30 as they apply to combination 
products.)
2. Exemption of Combination Products From Device QS Regulation
    Exemption of the combination product from provisions of the device 
QS regulation (part 820) if the device constituent part of the 
combination product is itself exempt from the device QS requirements 
specified in Sec.  4.4(b)(1) (i.e., the intended use of the device as a 
constituent part falls within the scope of the relevant exemption). 
Some devices are exempt from 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); see also, for example, limitations to device exemptions 
under 21 CFR 880.9). Accordingly, a combination product is exempt from 
the associated provisions of the device QS regulation specified in 
Sec.  4.4(b)(1) if the device constituent part falls within the scope 
of the relevant exemption; i.e., if the intended use of the device in 
the combination product is not a new intended use and does not 
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 all provisions of the device QS regulation 
except for 21 CFR 820.180 (general requirements concerning records) and 
21 CFR 820.198 (requirements concerning complaint files) when marketed 
as a stand-alone device (and hence the combination product may also be 
exempt from such provisions). Accordingly, if the CP manufacturer for 
the co-packaged combination product is using a streamlined approach 
based on drug CGMP requirements (see Sec.  4.4(b)(1)), the CP 
manufacturer does not need to demonstrate compliance

[[Page 56069]]

with the device QS requirements because the product is exempt from all 
device QS requirements specified in Sec.  4.4(b)(1) and, therefore, 
must only be compliant with the drug CGMP requirements. However, 
incorporating such a dispenser into a primary container closure system 
or co-packaging of such a dispenser with a drug with a narrow 
therapeutic index, for example, each may constitute a new intended use 
for the dispenser or raise different safety and effectiveness questions 
related to performance of the dispenser, such that the relevant 
exemption would not apply.
    (See also section III.C.3 of Ref. 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

A. Process for Interacting With FDA

    In some cases, CP manufacturers may need to 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 any 
such contemplated use of alternative or streamlined CGMP mechanisms for 
combination products (see also Ref. 5 regarding interactions with FDA 
on combination products).
     Pre-Submissions and Meeting Requests. CP manufacturers who 
want to obtain FDA feedback prior to making a premarket submission or 
submitting a postmarket supplement or who otherwise want to obtain 
feedback on their CGMP approach, may interact with FDA via the 
processes available for such questions at the lead Center \3\ for the 
combination product (see Ref. 5). 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. 6). For combination products reviewed under an abbreviated new 
drug application (ANDA), such interactions will generally be through 
the pre-ANDA program or controlled correspondence for a premarket 
application (Refs. 7 and 8). 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. 9). Regardless of the type of submission or meeting, such 
interactions should be focused on a general discussion of the CGMP 
approach the CP manufacturer wishes to pursue and associated 
justification to support the approach.\4\ Only representative data is 
typically appropriate in these interactions; complete data should be 
included in the subsequent premarket submission or postmarket 
supplement and/or be maintained at the manufacturing facility, as 
appropriate.
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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., be 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)). Manufacturers 
who are unsure of the lead Center for their combination product or 
of whether their product is a combination product, should contact 
the Office of Combination Products.
    \4\ Note that to discuss a mechanism for complying with CGMP 
requirements for which the CP manufacturer is referencing 
information in a master file, the CP manufacturer must have the 
appropriate authorization from the master file holder (see, e.g., 21 
CFR 314.420 and 814.20(c)). The authorization should clearly 
identify the specific information within the master file that is 
being made available to reference. For more information on 
biologics, device, and drug master files, see CBER's master files 
for CBER-Regulated Products web page (available at https://www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/master-files-cber-regulated-products), CDRH's master files web 
page (available at https://www.fda.gov/medical-devices/premarket-approval-pma/master-files), and CDER's drug master files web page 
(available at https://www.fda.gov/drugs/forms-submission-requirements/drug-master-files-dmfs), respectively.
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     Premarket Review. CP manufacturers should include in their 
original submission for NDAs, BLAs, ANDAs, and PMAs information on any 
alternative or streamlined mechanisms for complying with combination 
product 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. 10).
     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.\5\ CP manufacturers should consult related 
guidances relevant to the type of constituent part(s) included in the 
combination product (e.g., Refs. 11 to 13, as appropriate). 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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    \5\ Requirements for postmarket supplements are contained, for 
example, in 21 CFR 314.70 and 314.97 (NDAs and ANDAs), 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 generally 
be directed to the lead Center.
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B. Submission Content

    When submitting information on a CGMP mechanism, CP manufacturers 
should refer to applicable guidance (see section V below) as the 
primary reference regarding what information to provide. Along with 
other information indicated in relevant guidance (see section V), the 
following content should be included:
     Applicable CGMP Regulation. Identify the applicable CGMP 
regulation to which the described mechanism relates. 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.
     Prior, 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 justification 
to support that the proposed mechanism assures adequate manufacturing 
control to ensure product safety and effectiveness. When describing a 
CGMP alternative or streamlined mechanism in a premarket or postmarket 
submission, the description should be accompanied by such data as may 
be 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.
     Exemption from Part 820. For interactions with FDA 
regarding whether a combination product is exempt from the provisions 
of part 820 specified in Sec.  4.4(b)(1), the submission should include 
a description of the device constituent part and justification

[[Page 56070]]

that: (1) the intended use of the device in the combination product is 
consistent with the intended use of a separately marketed device that 
has been exempted from the requirements of part 820 specified in Sec.  
4.4(b)(1), and (2) the use of the device constituent part in the 
combination product does not raise any different device performance-
related safety and effectiveness questions as compared to a separately 
marketed device.

C. FDA Engagement

    CP manufacturers are encouraged to discuss combination product CGMP 
mechanisms with FDA. In some cases, CP manufacturers may need to 
interact with FDA to gain approval or otherwise notify FDA of a 
manufacturing change (see III.A above). Any questions on how to engage 
FDA in such discussions should generally be directed to the lead Center 
for the product (see Ref. 5). The lead Center will engage appropriate 
expertise from within the lead Center and from other FDA Centers and 
the Office of Combination Products, as needed, to support review (see 
Ref. 14), and FDA will provide appropriate feedback (see section III.D 
below).

D. FDA Review

    FDA may review information from a CP manufacturer related to 
alternative or streamlined mechanisms in pre-submissions and meetings, 
premarket applications, postmarket supplements or notifications, and 
during facility inspections. FDA may determine whether the data and 
rationale presented by a CP manufacturer for a particular mechanism are 
sufficient to demonstrate that the mechanism, as proposed or 
implemented, is acceptable. In such cases, FDA generally will notify 
the CP manufacturer and/or applicant regarding acceptability of the 
mechanism, consistent with existing policies and practices for the 
submission type and, if the Agency finds the approach insufficient, FDA 
intends to provide the scientific and/or regulatory basis for this 
determination.

IV. Paperwork Reduction Act

    This notice refers to previously approved collections of 
information 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. 3501-3521). We 
note that the information collected under the underlying CGMP 
regulations for drugs, devices, and biological products, including 
current good tissue practices for human cells, tissues, and cellular 
and tissue-based products, found in parts 211, 820, 600 through 680, 
and 1271 (21 CFR 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 are 
approved under OMB control number 0910-0429. The collections of 
information regarding NDA and ANDA are approved under OMB control 
number 0910-0001. The collections of information regarding the pre-ANDA 
program and controlled correspondence are approved under OMB control 
number 0910-0797. The collections of information regarding pre-
submissions are approved under OMB control number 0910-0756. The 
collections of information regarding PMAs are approved under OMB 
control number 0910-0231. The collections of information for premarket 
notification (510(k)) are approved under OMB control number 0910-0120. 
The collections of information for the de novo classification process 
are approved under OMB control number 0910-0844. The collections of 
information regarding BLAs are approved under OMB control number 0910-
0338. The collections of information regarding combination product 
agreement meetings are approved under OMB control number 0910-0523.

V. 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/media/90425/download.
2. ``Guidance for Industry Q1D Bracketing and Matrixing Designs for 
Stability Testing of New Drug Substances and Products,'' January 
2003. https://www.fda.gov/media/71720/download.
3. ``Guidance for Industry Quality of Biotechnological Products: 
Stability Testing of Biotechnological/Biological Products'' Q5C, 
July 1996. https://www.fda.gov/media/71441/download.
4. ``Guidance for Industry Q8(R2) Pharmaceutical Development,'' 
November 2009. https://www.fda.gov/media/71535/download.
5. ``Guidance for Industry and FDA Staff: Requesting FDA Feedback on 
Combination Products,'' December 2020. https://www.fda.gov/media/133768/download.
6. ``Draft Guidance for Industry Formal Meetings Between the FDA and 
Sponsors or Applicants of PDUFA Products,'' December 2017. https://www.fda.gov/media/109951/download.
7. ``Guidance for Industry Formal Meetings Between FDA and ANDA 
Applicants of Complex Products Under GDUFA,'' November 2020. https://www.fda.gov/media/107626/download.
8. ``Guidance for Industry Controlled Correspondence Related to 
Generic Drug Development,'' December 2020. https://www.fda.gov/media/109232/download.
9. ``Guidance for Industry and FDA Staff Requests for Feedback and 
Meetings for Medical Device Submissions: The Q-Submission Program,'' 
January 2021. https://www.fda.gov/media/114034/download.
10. ``eCTD Technical Conformance Guide,'' March 2022. https://www.fda.gov/media/93818/download.
11. ``Guidance for Industry Changes to an Approved NDA or ANDA,'' 
April 2004. https://www.fda.gov/media/71846/download.
12. ``Guidance for Industry Chemistry, Manufacturing, and Controls 
Changes to an Approved Application: Certain Biological Products,'' 
June 2021. https://www.fda.gov/media/109615/download.
13. ``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,'' December 2019. https://www.fda.gov/media/72663/download.
14. FDA Staff Manual Guide SMG 4101 ``Inter-Center Consult Request 
Process,'' June 2018. https://www.fda.gov/media/81927/download.

    Dated: September 7, 2022.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2022-19713 Filed 9-12-22; 8:45 am]
BILLING CODE 4164-01-P