[Federal Register Volume 87, Number 198 (Friday, October 14, 2022)]
[Notices]
[Pages 62417-62419]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2022-22334]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2016-D-0973]


Comparability Protocols for Postapproval Changes to the 
Chemistry, Manufacturing, and Controls Information in a New Drug 
Application, Abbreviated New Drug Application, or Biologics License 
Application; Guidance for Industry; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of availability.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing 
the availability of a final guidance for industry entitled 
``Comparability Protocols for Postapproval Changes to the Chemistry, 
Manufacturing, and Controls Information in an NDA, ANDA, or BLA.'' This 
final guidance is intended to assist original applicants and holders of 
approved new drug applications (NDAs), abbreviated new drug 
applications (ANDAs), and biologics

[[Page 62418]]

license applications (BLAs) on implementing a chemistry, manufacturing, 
and controls (CMC) postapproval change(s) through the use of a 
comparability protocol (CP). In many cases, submission and approval of 
a CP will facilitate the subsequent implementation and reporting of CMC 
changes, which could result in moving a drug or biological product into 
distribution or facilitating a proactive approach to reinforcing the 
supply of a product sooner than if a CP were not used. This final 
guidance recommends a framework to promote continuous improvement in 
the manufacturing of quality drug and biological products. This 
document finalizes a revised draft guidance that published on April 20, 
2016, entitled ``Comparability Protocols for Human Drugs and Biologics: 
Chemistry, Manufacturing, and Controls Information.'' A related draft 
guidance entitled ``Comparability Protocols--Protein Drug Products and 
Biological Products--Chemistry, Manufacturing, and Controls 
Information'' that published in September 2003, was withdrawn on May 6, 
2015.

DATES: The announcement of the guidance is published in the Federal 
Register on October 14, 2022.

ADDRESSES: You may submit either electronic or written comments on 
Agency guidances at any time as follows:

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 identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2016-D-0973 for ``Comparability Protocols for Postapproval Changes 
to the Chemistry, Manufacturing, and Controls Information in an NDA, 
ANDA, or BLA.'' Received comments 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://govinfo.gov/content/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, 240-402-7500.
    You may submit comments on any guidance at any time (see 21 CFR 
10.115(g)(5)).
    Submit written requests for single copies of this guidance to the 
Division of Drug Information, Center for Drug Evaluation and Research, 
Food and Drug Administration, 10001 New Hampshire Ave., Hillandale 
Building, 4th Floor, Silver Spring, MD 20993-0002 or the Center for 
Biologics Evaluation and Research, Office of Communication, Outreach, 
and Development, 10903 New Hampshire Ave., WO71, Room 3128, Silver 
Spring, MD 20903. Send one self-addressed adhesive label to assist that 
office in processing your requests. See the SUPPLEMENTARY INFORMATION 
section for electronic access to the guidance document.

FOR FURTHER INFORMATION CONTACT: Stephen Moore, Center for Drug 
Evaluation and Research, Food and Drug Administration, Bldg. 51, Rm. 
4159, 10903 New Hampshire Ave., Silver Spring, MD, 20993-0002, 301-796-
7579 or Stephen Ripley, Center for Biologics Evaluation and Research, 
Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 71, Rm. 
7301, Silver Spring, MD 20993, 240-402-7911.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a guidance for industry 
entitled ``Comparability Protocols for Postapproval Changes to the 
Chemistry, Manufacturing, and Controls Information in an NDA, ANDA, or 
BLA.'' The final guidance is intended to assist original applicants and 
holders of approved applications for human drugs and biological 
products on implementing a CMC postapproval change(s) through the use 
of a CP. In this guidance, a comparability protocol is synonymous with 
a postapproval change management protocol in the International Council 
for Harmonisation (ICH) Q12 guidance ``Technical and Regulatory 
Considerations for Pharmaceutical Product Lifecycle Management'' (May 
2021). The final guidance is not applicable to blood and blood 
components; biological products that also meet the definition of a 
device in section 201(h) of the Federal Food,

[[Page 62419]]

Drug, and Cosmetic Act; or human cells, tissues, or cellular or tissue-
based products regulated solely under section 361 of the Public Health 
Service Act (42 U.S.C. 264) and 21 CFR part 1271.
    On April 20, 2016, (81 FR 23303), FDA announced the availability of 
a revised draft guidance entitled ``Comparability Protocols for Human 
Drugs and Biologics: Chemistry, Manufacturing, and Controls 
Information.'' This was a revised draft of a draft guidance published 
in February 2003. We revised the February 2003 draft guidance in 2016 
for the following reasons:
     To include current pharmaceutical quality concepts.
     To provide more flexibility regarding filing procedures 
for a notification of modifications to an approved CP in less 
burdensome reporting categories than a prior approval supplement.
     To add an appendix to address commonly asked questions.
    The Center for Veterinary Medicine, which was included in the 
February 2003 draft guidance, published recommendations for animal 
drugs in a separate guidance.
    We received a number of comments on the revised draft guidance, 
which the Agency considered carefully as it prepared this final 
guidance. Additional information has been included in the final 
guidance on proposing an appropriate reporting category for 
implementation of changes under a CP once approved. Additional examples 
have been included for notification of modifications to an approved CP 
in less burdensome reporting categories than a prior approval 
supplement. Information has been included in the appendix on cross-
referencing of a master file, including a Drug Master File, in a CP and 
submitting a CP to a master file. Also, the recommendations in the 
guidance for industry ICH Q12 have been carefully considered when 
revising this guidance to maximize consistency. We also have made 
clarifications and editorial changes to the final guidance document.
    This final guidance provides recommendations to original applicants 
and holders of approved applications for human drugs and certain 
biological products on implementing CMC postapproval change(s) through 
the use of a CP. In many cases, submission and approval of a CP will 
facilitate the subsequent implementation and reporting of CMC changes, 
which could result in moving a drug or biological product into 
distribution or facilitating a proactive approach to reinforcing the 
supply of a product sooner than if a CP were not used.
    The final guidance recommends a framework to promote continuous 
improvement in the manufacturing of quality drug and biological 
products by encouraging applicants to employ the following:
     Effective use of knowledge and understanding of the 
product and manufacturing process;
     Risk management activities over the life cycle of a 
product; and
     An effective pharmaceutical quality system
    This final guidance incorporates the modern regulatory concepts 
stated in the guidance for industry entitled ``PAT--A Framework for 
Innovative Pharmaceutical Development, Manufacturing, and Quality 
Assurance,'' the Pharmaceutical Quality for the 21st Century--A Risk 
Based Approach, the Critical Path Initiative, and the quality by design 
principles described in the guidance for industry entitled ``Q8(R2) 
Pharmaceutical Development.''
    This guidance is being issued consistent with FDA's good guidance 
practices regulation (21 CFR 10.115). The guidance represents the 
current thinking of FDA on ``Comparability Protocols for Postapproval 
Changes to the Chemistry, Manufacturing, and Controls Information in an 
NDA, ANDA, or BLA.'' It does not establish any rights for any person 
and, with the exception of section V, is not binding on FDA or the 
public. You can use an alternative approach if it satisfies the 
requirements of the applicable statutes and regulations.
    As noted, insofar as section V of this guidance sets forth that 
certain modifications to an approved CP must be submitted in a changes 
being effected supplement or annual report rather than a prior approval 
supplement, it has binding effect, as indicated by the use of the words 
must, shall, or required. Such binding effect derives from section 506A 
of the FD&C Act, as implemented in 21 CFR 314.70 and 601.12.

II. Paperwork Reduction Act of 1995

    While this guidance contains no collection of information, it does 
refer to previously approved FDA collections of information. Therefore, 
clearance by the Office of Management and Budget (OMB) under the 
Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 3501-3521) is not 
required for this guidance. The previously approved collections of 
information are subject to review by OMB under the PRA. The collections 
of information in 21 CFR part 314 have been approved under OMB control 
number 0910-0001. The collections of information in 21 CFR part 601 
have been approved under OMB control number 0910-0338. The collections 
of information in 21 CFR parts 210 and 211 relating to current good 
manufacturing practices have been approved under OMB control number 
0910-0139. The collections of information relating to section 351(k) of 
the PHS Act have been approved under OMB control number 0910-0718.

III. Electronic Access

    Persons with access to the internet may obtain the guidance at 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs, https://www.fda.gov/regulatory-information/search-fda-guidance-documents, or https://www.regulations.gov.

    Dated: October 7, 2022.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2022-22334 Filed 10-13-22; 8:45 am]
BILLING CODE 4164-01-P


