[Federal Register Volume 89, Number 29 (Monday, February 12, 2024)]
[Rules and Regulations]
[Pages 9743-9757]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2024-02741]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 601

[Docket No. FDA-2019-N-1363]
RIN 0910-AH50


Biologics License Applications and Master Files

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is 
issuing a final rule to amend its regulations to address the use of 
master files by applications licensed under the Public Health Service 
Act (PHS Act). This final rule codifies FDA's existing approach that 
former approved applications for certain biological products under the 
Federal Food, Drug, and Cosmetic Act (FD&C Act) that have been deemed 
to be licenses for the biological products under the PHS Act may 
continue to incorporate by reference drug substance, drug substance 
intermediate, or drug product (DS/DSI/DP) information contained in a 
drug master file (DMF) if such information was being referenced at the 
time the application was deemed to be a license. This final rule also 
codifies FDA's general practices regarding the referencing of 
information in master files by applications licensed under the PHS Act, 
including applications for combination products licensed under the PHS 
Act, and by investigational new drug applications (INDs) for products 
that would be subject to licensure under the PHS Act.

DATES: This rule is effective March 13, 2024.

ADDRESSES: For access to the docket to read background documents or 
comments received, go to https://www.regulations.gov and insert the 
docket number found in brackets in the heading of this final rule 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.

[[Page 9744]]


FOR FURTHER INFORMATION CONTACT: Natalia Comella, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 3141, Silver Spring, MD 20993-0002, 301-
796-6226, <a href="/cdn-cgi/l/email-protection#6e000f1a0f02070f400d01030b02020f2e080a0f4006061d40090118"><span class="__cf_email__" data-cfemail="e6888792878a8f87c885898b838a8a87a6808287c88e8e95c8818990">[email protected]</span></a>; or James Myers, Center for 
Biologics Evaluation and Research, Food and Drug Administration, 10903 
New Hampshire Ave., Bldg. 71, Rm. 7301, Silver Spring, MD 20993-0002, 
240-402-7911.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Executive Summary
    A. Purpose and Coverage of the Final Rule
    B. Summary of the Major Provisions of the Final Rule
    C. Legal Authority
    D. Costs and Benefits
II. Table of Abbreviations/Commonly Used Acronyms in This Document
III. Background
    A. History of This Rulemaking
    B. Summary of Comments to the Proposed Rule
IV. Legal Authority
V. Comments on the Proposed Rule and FDA Response
    A. Introduction
    B. Specific Comments and FDA Response
VI. Effective/Compliance Date
VII. 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 and Coverage of the Final Rule

    This final rule amends FDA's regulations to codify FDA's existing 
approach that former approved applications for biological products 
under the FD&C Act that have been deemed, pursuant to the Biologics 
Price Competition and Innovation Act of 2009 (BPCI Act), to be licenses 
for the biological products under the PHS Act can continue to 
incorporate by reference DS/DSI/DP information contained in a DMF if 
such information was referenced at the time the application was deemed 
to be a license, in order to avoid the risk of unnecessary disruptions 
and potential drug shortages for these products. This final rule also 
amends the regulations to reflect FDA's longstanding practices 
regarding the referencing of information contained in master files by 
biologics license applications (BLAs). The final rule codifies FDA's 
practice and policy that INDs for products that would be subject to 
licensure under the PHS Act may incorporate by reference any 
information in a master file. The final rule also amends the 
regulations to address the use of master files for the constituent 
parts of combination products licensed under the PHS Act.

B. Summary of the Major Provisions of the Final Rule

    Under this final rule, FDA is amending its regulations to address 
the use of master files by BLAs and INDs for products subject to 
licensure under the PHS Act. This final rule confirms that former 
approved applications for biological products in new drug applications 
(NDAs) under the FD&C Act that have been deemed, pursuant to the BPCI 
Act, to be licenses for the biological products under the PHS Act may 
continue relying on DMFs for information on DS/DSI/DP if such 
information in a master file was relied on at the time the application 
was deemed to be a license under the PHS Act. For BLAs outside the 
scope of the circumstances described in the preceding sentence, the 
final rule also codifies FDA's existing practice that BLAs may not rely 
on a master file for DS/DSI/DP information but may rely on a master 
file for other kinds of information.\1\ This final rule also codifies 
FDA's practice that an IND for a product that would be subject to 
licensure as a BLA may incorporate by reference any information, 
including DS/DSI/DP information, contained in a master file. This final 
rule also provides that, while BLAs under the PHS Act may not 
incorporate by reference DS/DSI/DP information contained in master 
files for biological product constituent parts of combination products, 
they may do so for non-biological product constituent parts.
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    \1\ FDA notes that an applicant may seek guidance from the 
relevant review division at the Agency if the applicant is unsure 
whether information in a master file constitutes DS/DSI/DP 
information in the context of a particular BLA.
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C. Legal Authority

    This final rule amends FDA's regulations, as part of FDA's 
implementation of the BPCI Act, as amended by the Further Consolidated 
Appropriations Act, 2020 (FCA). FDA's authority for this rule also 
derives from the biological product licensing provisions of the PHS Act 
and the provisions of the FD&C Act applicable to drugs; the FD&C Act 
provisions are applicable to biological products under the PHS Act.

D. Costs and Benefits

    By allowing certain BLAs to continue referencing a DMF for DS/DSI/
DP information, FDA avoids imposing a potential new regulatory burden. 
Affected entities will incur minimal costs to read and understand the 
rule. FDA estimates that over 10 years at a discount rate of 7 percent, 
the final rule will generate annualized net cost savings ranging from 
$0.40 million to $5.19 million with a primary estimate of $2.80 
million; at a discount rate of 3 percent, the final rule will generate 
annualized net cost savings ranging from $0.37 million to $5.17 million 
with a primary estimate of $2.77 million.

II. Table of Abbreviations/Commonly Used Acronyms in This Document

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        Abbreviation/acronym                     What it means
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BLA.................................  Biologics License Application.
BPCI Act............................  Biologics Price Competition and
                                       Innovation Act of 2009.
DMF.................................  Drug Master File.
DP..................................  Drug Product.
DS..................................  Drug Substance.
DSI.................................  Drug Substance Intermediate.
FD&C Act............................  Federal Food, Drug, and Cosmetic
                                       Act.
FDA.................................  U.S. Food and Drug Administration.
FCA Act.............................  Further Consolidated
                                       Appropriations Act, 2020.
IND.................................  Investigational New Drug
                                       Application.
IVD.................................  In Vitro Diagnostic.
NDA.................................  New Drug Application.
PHS Act.............................  Public Health Service Act.
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III. Background

A. History of This Rulemaking

    In the proposed rule,\2\ FDA announced its intention to amend its 
regulations to address the use of master files by BLAs. Section 
7002(b)(1) of the BPCI Act revised section 351(i) of the PHS Act (42 
U.S.C. 262(i)), in part, to amend the definition of a ``biological 
product'' to include a ``protein (except any chemically synthesized 
polypeptide).'' Section 605 of the FCA Act (Pub. L. 116-94) later 
amended this definition to remove the parenthetical ``(except any 
chemically synthesized polypeptide).'' \3\ Also, section 7002(e)(4) of 
the BPCI Act provided that, on March 23, 2020, an approved application 
for a biological product under section 505 of the FD&C Act (21 U.S.C. 
355) ``shall be deemed to be a license for the biological product 
under'' section 351 of the PHS Act.\4\ A number of products that were

[[Page 9745]]

approved in NDAs under section 505 of the FD&C Act met the revised 
definition of a biological product and the applications for these 
products were deemed to be biologics license applications on March 23, 
2020 (deemed BLAs). The proposed rule described FDA's interpretation of 
the ``deemed to be a license'' provision of the BPCI Act with respect 
to the use of master files by BLAs.\5\
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    \2\ ``Biologics License Applications and Master Files,'' 84 FR 
30968 (June 28, 2019).
    \3\ See FDA's final rule issued on February 21, 2020, regarding 
its interpretation of the term ``protein'' as used in section 
351(i)(1) of the PHS Act (definition of the term ``Biological 
Product,'' 85 FR 10057).
    \4\ Section 607 of Division N of the FCA Act, 2020 (Pub. L. 116-
94, 133 Stat 3127), amended section 7002(e)(4) of the BPCI Act to 
provide that FDA will continue to review an application for a 
biological product under section 505 of the FD&C Act after March 23, 
2020, so long as that application was submitted under section 505 of 
the FD&C Act, is filed not later than March 23, 2019, and is not 
approved as of March 23, 2020. If such an application is approved 
under section 505 of the FD&C Act before October 1, 2022, it will be 
deemed to be a license for the biological product under section 351 
of the PHS Act upon approval (see section 7002(e)(4)(B)(iii) and 
(vi) of the BPCI Act).
    \5\ For more information about FDA's interpretation of the 
``deemed to be a license'' provision of the BPCI Act, see the 
guidance for industry entitled ``Interpretation of the `Deemed to be 
a License' Provision of the Biologics Price Competition and 
Innovation Act of 2009'' (Ref. 1). We update guidances periodically. 
To make sure you have the most recent version of a guidance, check 
the FDA Drugs guidance web page at https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs.
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    The preamble to the proposed rule described FDA's current 
regulatory framework and practices regarding the use of master files by 
BLAs and INDs. The proposed rule also described a mechanism to provide 
for continued use of DMFs referenced by deemed BLAs. The preamble to 
the proposed rule further noted that there are combination products 
approved in BLAs under the PHS Act and that the rationale described in 
the proposed rule for the Agency's proposed approach to BLAs also 
applied to the biological product constituent part(s) of such 
combination products. FDA sought comments on whether applications for 
combination products submitted in BLAs under the PHS Act should be 
permitted to incorporate by reference DS/DSI/DP information for any 
non-biological product constituent part (for example, the drug 
constituent part of an antibody-drug conjugate).
    In this final rule, FDA is finalizing the approach described in the 
proposed rule with several changes. Based on comments received, FDA is 
adding provisions codifying the use of master files by BLAs under the 
PHS Act for combination products. In addition, FDA is making 
nonsubstantive changes to the structure of the codified language to 
improve its readability.

B. Summary of Comments to the Proposed Rule

    We received fewer than 30 comment letters on the proposed rule. 
Several comments generally support the proposed rule, in whole or in 
part. Several comments recommend revisions to, or disagree with, 
individual provisions in the proposed rule. Some comments address the 
use of master files for combination products in response to FDA's 
request for public comment in the preamble to the proposed rule.

IV. Legal Authority

    We are issuing this final rule under section 7002(e) of the BPCI 
Act, as amended by section 607 of the FCA Act. FDA's authority for this 
final rule also derives from the biological product licensing 
provisions of the PHS Act and the provisions of the FD&C Act (21 U.S.C. 
321, et seq.) applicable to drugs. Under these provisions, FDA has the 
authority to issue regulations designed to ensure, among other things, 
that biological products are safe, pure, and potent and manufactured in 
accordance with current good manufacturing practice. FDA also has 
general authority to issue regulations for the efficient enforcement of 
the FD&C Act under section 701 of the FD&C Act, which is applicable to 
biological products pursuant to section 351(j) of the PHS Act.

V. Comments on the Proposed Rule and FDA Response

A. Introduction

    We received fewer than 30 comment letters on the proposed rule by 
the close of the comment period, each addressing one or more issues. We 
received comments from industry, individuals, and a trade organization.
    We describe and respond to the comments in section V.B below. We 
have numbered each comment topic to help distinguish between the issues 
raised in the comments. We have grouped similar comments together under 
the same number, and, in some cases, we have separated different issues 
discussed in the same comment for purposes of our responses. The number 
assigned to each comment topic is purely for organizational purposes 
and does not signify the comment's value or importance or the order in 
which comments were received.
    In addition, FDA has restructured the codified language to address 
comments and for ease of reading. The paragraph numbers in the codified 
text and preamble of this final rule differ from those used in the 
proposed rule. Where applicable in this preamble, we identify the 
paragraphs as numbered in the proposed, as well as final, codified 
language. Although the codified language has been restructured for ease 
of reading into a new Sec.  601.2(g), the separate paragraphs of this 
rule, applicable to certain deemed BLAs, to INDs for products that 
would be subject to licensure as a BLA, and to non-biological product 
constituent parts of combination products regulated under the PHS Act, 
each function independently to address specific circumstances and 
codify FDA's practices for those circumstances. In the event of a stay 
or invalidation of any paragraph of new Sec.  601.2(g), those 
paragraphs that remain in effect would continue to function sensibly 
\6\ to address their respective circumstances. For example, 
invalidation of Sec.  601.2(g), which is specific to certain deemed 
BLAs, would have no effect on the provisions applicable to applications 
outside the scope of that paragraph.
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    \6\ 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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B. Specific Comments and FDA Response

1. Final Sec.  601.2(g)(1) (Proposed Sec.  601.2(g))
    We proposed that an application for a biological product submitted 
to FDA for licensure under section 351 of the PHS Act, licensed under 
section 351 of the PHS Act, or, except as provided in proposed Sec.  
601.2(h), deemed to be licensed under section 351 of the PHS Act, may 
not incorporate by reference DS/DSI/DP information contained in a 
master file (see proposed Sec.  601.2(g)). We also proposed that 
amendments and supplements to these applications may not incorporate by 
reference such information contained in a master file.
    FDA received several comments addressing this aspect of the 
proposed rule, some of which agree with the need for the provision and 
with FDA's rationale, and some of which disagree. Some of the comments 
that disagree propose that FDA permit BLAs more generally to 
incorporate by reference information on DS/DSI/DP contained in master 
files or permit this on a case-by-case basis. A few comments suggest 
that BLAs should be permitted to incorporate certain kinds of DS/DSI/DP 
information by reference or that BLAs for certain products should be 
permitted to incorporate by reference DS/DSI/DP

[[Page 9746]]

information. For the reasons described below, we are not changing our 
approach in finalizing this proposal. However, because the final 
regulation also addresses combination products licensed in BLAs, final 
Sec.  601.2(g)(1) (as well as final Sec.  601.2(g)(3)) includes 
references to such applications. In addition, because Sec.  601.2(g)(1) 
applies to a BLA regardless of submission type (e.g., application for 
approval, licensed BLA, amendment, supplement), we have removed the 
reference to ``amendments'' and ``supplements.''
    (Comment 1) FDA received three comments disagreeing with FDA's 
proposed approach and suggesting that FDA instead permit BLAs more 
generally to incorporate by reference DS/DSI/DP information contained 
in master files on a case-by-case basis. One of these comments asserts 
that FDA's proposal is inconsistent with applying a risk-based approach 
to regulatory review of applications, and, in support of a case-by-case 
approach, specifically suggests that FDA permit BLAs to incorporate by 
reference this information when it does not increase risk to the 
patient.
    (Response 1) FDA disagrees that its proposal is inconsistent with 
applying a risk-based approach and declines to revise its proposal to 
permit incorporation by reference of DS/DSI/DP information contained in 
a master file on a case-by-case basis.
    FDA agrees that it is important to employ a science- and risk-based 
approach to its regulation of BLAs. Accordingly, FDA considers the 
establishment and function of a robust quality assurance program to be 
essential for evaluating, controlling, and mitigating product quality 
risks. The Agency has carefully considered the (generally) complex 
characteristics of most biological products and the risks to product 
quality inherent in the manufacture of these products. As stated in the 
preamble to the proposed rule, most biological products tend to have 
certain features (e.g., amino acid sequence, glycosylation, folding, 
cellular phenotype) essential to their intended effect and can be very 
sensitive to changes to the manufacturing process. In addition, 
biological products isolated from biological sources may be complex 
heterogeneous mixtures. As a result of such characteristics, the 
manufacture of most biological products carries increased potential 
risk to product quality. As a scientific matter, for biological 
products, the Agency considers it to be generally impractical for the 
applicant to confirm DS/DSI/DP quality characteristics without complete 
knowledge of, and control over, all aspects of the manufacturing 
process, including the manufacturing process for the DS/DSI/DP. Absent 
such knowledge and control, the applicant generally cannot operate a 
quality assurance program that independently identifies, assesses, and 
mitigates quality risks, which is critical to assuring the quality of a 
biological product.
    For biological products, FDA has found that the fragmentation of 
DS/DSI/DP information between a master file and a BLA results in a risk 
to quality that is very difficult to mitigate. Therefore, requiring DS/
DSI/DP information to be submitted as part of the BLA, rather than 
incorporated by reference to a master file, is consistent with FDA's 
scientific assessment of the risks associated with this category of 
products and the need for BLA applicants to have direct knowledge of 
and control over the entire manufacturing process.
    As we acknowledged in the preamble to the proposed rule, there may 
be some biological products for which referencing a DMF for DS/DSI/DP 
information presents somewhat less risk. However, FDA declines to adopt 
a case-by-case approach to BLAs incorporating by reference DS/DSI/DP 
information contained in master files. Given the complex 
characteristics of most biological products, the importance of the 
applicant's knowledge of and direct control over the manufacturing 
processes for biological products, and the advantages in administrative 
efficiency and predictability, the Agency is proceeding with an 
approach that draws a distinction between BLAs and NDAs with regard to 
the referencing of master files for DS/DSI/DP information, except for 
certain deemed BLAs (see section V.B.2).
    (Comment 2) One comment suggests that it would be unfair to 
prohibit sponsors of applications for ``biological products'' from 
incorporating by reference DS/DSI/DP information contained in master 
files while permitting sponsors of applications for ``drug products'' 
to do so because it would create unequal starting points and incentives 
for product development.
    (Response 2) FDA disagrees that it would be unfair to prohibit BLAs 
from incorporating by reference DS/DSI/DP information contained in 
master files while permitting applications under the FD&C Act to do so. 
FDA's longstanding practice of not permitting BLAs to incorporate by 
reference DS/DSI/DP information contained in master files is based on 
the differences in risk generally associated with products regulated 
under the PHS Act and products regulated under the FD&C Act, as 
described above and in the preamble to the proposed rule.
    With regard to a difference in starting points and incentives, 
nothing in this rule prohibits an IND for a product that would be 
subject to licensure under section 351 of the PHS Act from 
incorporating by reference DS/DSI/DP information contained in a master 
file, in the same way that an IND can for a product that would be 
subject to approval under the FD&C Act. Therefore, the starting points 
for INDs for products that would be regulated under the PHS Act and 
products that would be regulated under the FD&C Act are the same in 
this regard. Furthermore, it should be noted that at the BLA stage the 
inability to incorporate by reference DS/DSI/DP information contained 
in a master file does not remove BLA applicants' incentives or ability 
to proceed with product development. An applicant who does not intend 
to manufacture all aspects of the product for licensure may, as stated 
in the preamble to the proposed rule, consider other types of 
cooperative manufacturing arrangements, while still assuming 
responsibility for meeting the applicable product and establishment 
standards.\7\ These other arrangements would provide alternatives in 
cases where the incorporation by reference of a master file is not 
permitted.
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    \7\ See the guidance for industry ``Cooperative Manufacturing 
Arrangements for Licensed Biologics'' (Ref. 2).
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    (Comment 3) Two comments assert that BLAs should be permitted to 
incorporate by reference DS/DSI/DP information contained in master 
files because IND applications are permitted to do so.
    (Response 3) FDA disagrees with these comments. FDA requires an 
applicant to be able to submit DS/DSI/DP information directly to the 
BLA because, at the time a BLA is submitted, FDA expects the sponsor to 
have knowledge of and direct control over the manufacturing process.
    As described in the preamble to the proposed rule, INDs are 
permitted to incorporate by reference DS/DSI/DP information contained 
in master files for several reasons, including the following: exposure 
to the investigational product is limited to subjects enrolled in 
clinical trials, which are typically carried out in controlled 
settings; the sponsor and FDA can mitigate risk by closely monitoring 
patients in clinical trials to evaluate the safety of the 
investigational

[[Page 9747]]

product; and permitting INDs to incorporate by reference DS/DSI/DP 
information contained in master files may facilitate product 
development because a sponsor might otherwise choose not to make the 
significant investment to manufacture the DS/DSI/DP for the product at 
the early, investigational stage. None of these situations apply at the 
time of BLA submission.
    Because the rationale for permitting INDs to incorporate by 
reference DS/DSI/DP information contained in a master file does not 
apply at the BLA stage, FDA declines to change its approach and permit 
BLAs to incorporate such information by reference.
    (Comment 4) One comment contends that BLAs should be permitted to 
incorporate by reference DS/DSI/DP information contained in master 
files because, if there are concerns with the safety of a product 
during the BLA review process, FDA can issue a complete response letter 
or request mandatory postmarketing studies and postmarketing 
surveillance.
    (Response 4) Complete response letters are regulatory responses 
that convey deficiencies identified by FDA during the review and 
evaluation of an application. Postmarketing requirements, postmarketing 
commitments, and postmarketing surveillance are regulatory tools that 
can be used to assess and address potential product risks after the 
product is licensed. Complete response letters, postmarketing study 
commitments, and postmarketing surveillance are application-specific 
actions. For the reasons discussed above, FDA declines to take a case-
by-case (i.e., application-specific) approach to BLAs' incorporation by 
reference of DS/DSI/DP information contained in master files. 
Furthermore, complete response letters, postmarketing study 
commitments, and postmarketing surveillance are relevant only after the 
product has been developed and an application has been submitted to and 
reviewed and evaluated by the Agency. In contrast, given the importance 
of the applicant's knowledge of and direct control over the 
manufacturing processes for biological products, a clear rule that 
applies to all BLAs provides all applicants with administrative 
efficiency and predictability early in the development process about 
the Agency's expectations regarding the use of master files, allowing 
applicants to take these expectations into account in their product 
development plan and when preparing content to be submitted in the 
application.
    For the reasons discussed above, FDA declines to take a case-by-
case approach, and has concluded that the availability of complete 
response letters, postmarketing study commitments, and postmarketing 
surveillance does not provide a suitable alternative to FDA's approach, 
which is, among other things, intended to provide predictability 
regarding the use of master files for BLAs.
    (Comment 5) One comment proposes that FDA permit BLAs to 
incorporate by reference certain kinds of DS/DSI/DP information 
contained in a master file, advocating for the ability of BLAs to 
reference DS/DSI/DP information that is not ``highly product-
specific.'' As an example, the comment asserts that ``drug product 
information'' could be interpreted to encompass extensive aseptic 
processing information and, in certain circumstances, this information 
could be appropriately managed in a master file because elements of 
aseptic processing can cut across multiple products and very few 
elements of aseptic processing are drug product-specific. The comment 
also suggests that platform data to support viral clearance could be 
more appropriately captured once in a DMF instead of being repeated in 
multiple BLAs, thereby reducing burden on the Agency and sponsors.
    (Response 5) FDA declines to change its approach in order to permit 
BLAs to incorporate by reference certain DS/DSI/DP information 
contained in a master file as suggested by the comment.
    The comment uses, but does not explain what it means by, the term 
``highly product-specific information,'' other than providing examples 
of information that the comment considers not to be ``highly product-
specific,'' such as platform data to support viral clearance and 
aseptic processing information. It is unclear whether these examples 
would, in fact, be DS/DSI/DP information in the context of a particular 
BLA. FDA notes that an applicant may seek guidance from the relevant 
review division at the Agency if the applicant is unsure whether 
information in a master file constitutes DS/DSI/DP information in the 
context of a particular BLA.
    Accordingly, FDA declines to change this provision to treat DS/DSI/
DP information that is not ``highly product-specific'' different from 
any other kind of DS/DSI/DP information contained in master files.
    (Comment 6) One comment largely agrees with FDA's proposal and the 
rationale provided to support it but expresses concern about its 
application to purely synthetic drug substance intermediates, asserting 
that the considerations articulated in the proposed rule are 
appropriate only for biological products. The comment notes that a 
chemically synthesized polypeptide does not meet the definition of a 
biological product under section 7002(b) of the BPCI Act, which 
amended, in part, the definition of a ``biological product'' in the PHS 
Act to include a ``protein (except any chemically synthesized 
polypeptide).'' The comment requests clarity on the use of DMFs for 
drug substance intermediates for chemically synthesized polypeptides. 
The comment contends that some biological products may integrate drug 
substance intermediates that are chemically synthesized polypeptides. 
The comment asserts that the potential risks to quality are less 
significant in such cases because, according to the comment, these 
chemically synthesized polypeptides are not technically biological 
products. The comment contends that, under such circumstances, reliance 
on a DMF may be appropriate, and proposes that FDA allow reliance on a 
DMF for a drug substance intermediate that is purely synthetic.
    (Response 6) FDA notes that, after the comment period for the 
proposed rule closed, section 605 of the FCA Act further amended the 
definition of a ``biological product'' in section 351(i) of the PHS Act 
to remove the parenthetical exception for ``any chemically synthesized 
polypeptide'' from the statutory category of ``protein.'' Accordingly, 
the comment's assertion that BLAs should be permitted to reference a 
DMF for information about a drug substance intermediate that is a 
chemically synthesized polypeptide because a chemically synthesized 
polypeptide does not meet the definition of a biological product is no 
longer applicable.
    In addition, the inclusion of chemically synthesized polypeptides 
into the definition of a biological product does not change our overall 
concerns and approach with respect to biological products. Because 
chemically synthesized polypeptides can present many of the same issues 
and concerns as do other biological products, FDA's approach should be 
the same. When manufacturing processes for chemically synthesized 
polypeptides are appropriately designed, manufacturers can control the 
amino acid sequence and modifications to amino acids; however, the 
manufacturing of chemically synthesized polypeptides may still present 
risks to quality. As stated in the preamble to the proposed rule, most 
biological products tend to be

[[Page 9748]]

very sensitive to changes in their manufacturing process. For example, 
aspects of the manufacturing process (e.g., temperature) can affect the 
folding of polypeptides. Therefore, even for chemically synthesized 
polypeptides, it is important for the applicant to have knowledge of 
and control over all aspects of the manufacturing process and to 
implement a robust quality assurance program. For this reason, the 
final rule requires that information about chemically synthesized drug 
substance intermediates be submitted directly to the application, 
rather than be incorporated by reference to a master file.
    (Comment 7) One comment requests that BLAs for in vitro diagnostic 
(IVD) products, including those for licensed donor IVD screening tests, 
be excluded from the limitation on BLAs' incorporating by reference DS/
DSI/DP information contained in master files, asserting that the 
reasons for limiting the use of master files for this kind of 
information in BLAs for therapeutic products do not apply to BLAs for 
IVDs.
    (Response 7) FDA declines to exclude BLAs for IVD devices from the 
limitation on BLAs' use of master files for DS/DSI/DP information 
because such an exclusion is generally not necessary.
    IVD devices subject to a BLA are intended for use in screening 
donated human cells, tissues, and cellular and tissue-based products 
(HCT/Ps) and donated blood in order to ensure the compatibility between 
donors and recipients and the absence of infectious agents. These 
assays are performed on samples collected from the HCT/P or blood 
donor.
    Generally, the terms drug substance, drug substance intermediate, 
and drug product are not applicable to IVD devices. Therefore, the 
limitation in this rule on BLAs' use of master files for DS/DSI/DP 
information is not expected to affect BLAs for IVD devices. For this 
reason, the Agency considers it unnecessary to exclude BLAs for IVD 
devices from the scope of the rule's limitation on BLAs' use of master 
files for DS/DSI/DP information.
2. Final Sec.  601.2(g)(2) (Proposed Sec.  601.2(h))
    Final Sec.  601.2(g)(2) (proposed Sec.  601.2(h)) addresses 
applications that have been deemed to be BLAs pursuant to section 
7002(e)(4) of the BPCI Act, as amended by the FCA Act. This paragraph 
provides that a deemed BLA can continue to incorporate by reference DS/
DSI/DP information contained in a DMF if such information was 
referenced at the time the application was deemed to be a BLA. We 
received several comments on this provision, most of which agree with 
this provision and the rationale provided in the proposed rule. A few 
comments disagree and several request clarification regarding certain 
aspects of this paragraph. For the reasons given below, we decline to 
make the changes suggested by the comments and are, therefore, 
finalizing this requirement without substantive change.
    (Comment 8) One comment requests clarification regarding proposed 
Sec.  601.2(h). The comment requests that FDA explain whether all 
biological products approved in NDAs will be permitted to continue 
incorporating by reference DS/DSI/DP information contained in DMFs or 
whether it is only a specific subset of biological products, because 
the preamble to the proposed rule notes that it would allow ``certain'' 
biological products originally approved in an NDA under the FD&C Act to 
continue relying on a DMF for information on DS/DSI/DP after the NDA is 
deemed to be a license for the biological product.
    (Response 8) As explained in the preamble to the proposed rule and 
described in proposed Sec.  601.2(h), a deemed BLA that was relying on 
DS/DSI/DP information in a DMF at the time the application was deemed a 
BLA may continue to incorporate by reference that DS/DSI/DP information 
contained in that DMF. The reference in the preamble to the proposed 
rule to ``certain'' applications refers to deemed BLAs that 
incorporated by reference DS/DSI/DP information contained in a DMF at 
the time the application was deemed a BLA. These are the same 
applications specified in Sec.  601.2(g)(2) in this final rule.
    (Comment 9) One comment requests clarification regarding whether 
applications that reference DMF information may continue referencing 
the DMF if changes are made to the DMF.
    (Response 9) The preamble to the proposed rule explains that the 
rule is not intended to limit or restrict the changes that may be made 
to any master file, including a DMF containing DS/DSI/DP information. 
Changes made to such a DMF, including changes to previously referenced 
DS/DSI/DP information, do not restrict the ability of a deemed BLA to 
continue to incorporate by reference the DS/DSI/DP information in that 
DMF for the same purpose for which it was incorporated by reference at 
the time the application was deemed to be a BLA. For example, consider 
a former NDA that incorporated by reference information contained in a 
DMF regarding the manufacture of its drug substance and that, after the 
application was deemed to be a BLA, continues to incorporate by 
reference that drug substance information. If the DMF holder 
subsequently modifies drug substance manufacturing (for example, by 
making changes to the analytical methods or purification process for 
the drug substance), the deemed BLA may continue to incorporate by 
reference this modified drug substance information, provided that the 
BLA applicant informs the Agency of the change in the BLA in accordance 
with Sec.  601.12 (21 CFR 601.12). Alternatively, if the DMF holder 
adds information about manufacturing of drug product to the same DMF, 
FDA does not intend to permit the deemed BLA to incorporate by 
reference that new drug product information because it is not the type 
of information that was referenced by the former NDA at the time it was 
deemed to be a BLA.
    (Comment 10) One comment requests further information on the 
circumstances in which submission of a supplement to a BLA would not be 
sufficient and the submission of a new BLA would be required.
    (Response 10) FDA notes that a description of the kinds of changes 
that cannot be addressed through a supplement is outside the scope of 
this rule. The Agency has generally described its thinking on what 
constitutes a separate original application, amendment, or 
supplement.\8\
---------------------------------------------------------------------------

    \8\ For example, see the guidance for industry and FDA Staff 
``Bundling Multiple Devices or Multiple Indications in a Single 
Submission'' (Ref. 3).
---------------------------------------------------------------------------

    (Comment 11) One comment suggests that deemed BLAs are best 
described as ``expected to transition.''
    (Response 11) The applications described in Sec.  601.2(g)(2) in 
this final rule have already been deemed to be BLAs by operation of the 
statute (section 7002(e)(4) of the BPCI Act, as amended by section 607 
of the FCA Act). Therefore, referring to deemed BLAs as ``expected to 
transition'' would be inaccurate.
    (Comment 12) One comment suggests that FDA change proposed Sec.  
601.2(h) to state that any new BLAs will not be allowed to incorporate 
by reference DS/DSI/DP information contained in master files after 
March 23, 2020.
    (Response 12) The Agency declines to make the suggested change. 
Except as noted in final Sec.  601.2(g)(2) and (3), final Sec.  
601.2(g)(1) applies to all BLAs, whether new or existing. Therefore, 
the suggested change is not needed because,

[[Page 9749]]

under the final codified, a new BLA may not incorporate by reference 
DS/DSI/DP information contained in any master file.
    (Comment 13) One comment asserts that the BPCI Act was enacted to 
guarantee appropriate regulation of biological products to support 
public health and to ensure that only safe and effective products enter 
the market. The comment further maintains that the intent of the deemed 
BLA provision of section 7002(e)(4) of the BPCI Act is to ensure that 
scientific and technical complexities associated with the generally 
larger and typically more complex structure of biological products, as 
well as the processes by which such products are manufactured, are not 
overlooked. The comment asserts that it would therefore defeat the 
purpose of the BPCI Act to allow biological products initially approved 
in an NDA under the FD&C Act to continue to rely on a DMF for DS/DSI/DP 
information after the NDA is deemed to be a license for the biological 
product under the PHS Act. The comment recommends that deemed BLAs be 
regulated like other biological products with respect to use of master 
files.
    (Response 13) FDA agrees that, in general, scientific and technical 
complexities associated with the typically more complex structures of 
biological products, as well as the processes by which such products 
are manufactured, must not be overlooked (see section V.B.1). However, 
with respect to deemed BLAs that previously, as former NDAs, referenced 
a DMF for DS/DSI/DP information at the time of the transition, FDA 
considered the intent underlying the BPCI Act and, as elaborated in the 
proposed rule, took into account the following considerations that are 
specific to such deemed BLAs: (1) these applications have already been 
approved, and the applicants have marketed the product, in certain 
instances for decades, without overt safety concerns; (2) the deemed 
BLAs that incorporate by reference DS/DSI/DP information comprise only 
a small subset of all BLAs and reference a very small number of DMFs; 
and (3) many of these BLA applicants have accumulated knowledge about 
the products and have been able to implement appropriate control 
strategies based on this product knowledge. In addition, prohibiting 
these deemed BLAs from continuing to incorporate by reference DS/DSI/DP 
information in these DMFs might have the effect of halting or 
curtailing production of these products, resulting in drug shortages. 
FDA interprets the applicable statutory provisions such that the 
transition was not meant to interrupt access to these products. 
Therefore, on balance, FDA believes that public health is best served 
by allowing the small number of deemed BLAs to continue referencing DS/
DSI/DP information contained in DMFs on which they relied at the time 
of transition.
    (Comment 14) One comment acknowledges that the general concern 
about fragmentation of DS/DSI/DP information associated with the use of 
DMFs is lessened for deemed BLAs by the existence of generally 
longstanding relationships between the deemed-BLA applicants and the 
DMF holders because the applicants may have accumulated knowledge about 
the quality of the DS/DSI/DP supplied by the DMF holder over an 
extended period. The comment agrees that this accumulated knowledge 
allows a deemed BLA applicant to implement a more robust control 
strategy to mitigate the risk to product quality posed by the 
applicant's limited knowledge of the manufacturing process described in 
the DMF. The comment questions how this approach would change if the 
contents of the DMF change or the holder of the DMF changes.
    (Response 14) FDA does not consider that a change to the holder of 
the DMF or a change in previously referenced DS/DSI/DP information in 
the context of a DMF is inconsistent with the rationale for permitting 
deemed BLAs that previously referenced a master file for DS/DSI/DP 
information to continue referencing the DMF for the same type of 
information. The generally longstanding relationships between the 
deemed BLA applicant and the DMF holder, the knowledge accumulated by 
the deemed BLA applicant, and the knowledge accumulated by the DMF 
holder collectively provide some assurance about the quality of a 
product. When changes are made to a DMF, these assurances should 
continue to apply in most cases. In addition, the comparability studies 
required to demonstrate the safety, purity, and potency of post-change 
and pre-change material should provide further assurance of quality.
    When the DMF remains the same but the DMF holder changes, the 
deemed BLA applicant's product and process knowledge still remains; the 
deemed BLA applicant will also have designed and implemented a control 
strategy that is independent of the identity of the holder of the DMF. 
These measures collectively should provide continued assurance of 
quality under such circumstances. Therefore, it is appropriate to 
permit deemed BLAs to continue to incorporate by reference the same 
type of DS/DSI/DP information contained in a DMF after a change in the 
content of the DMF or the holder of the DMF.
    (Comment 15) One comment asserts that FDA's rationale for allowing 
deemed BLAs to continue incorporating by reference information on DS/
DSI/DP contained in DMFs is insufficient because it is based on a small 
subset of the deemed BLAs and a very small number of DMFs.
    (Response 15) This comment appears to misunderstand the set of 
deemed BLAs on which FDA's rationale is based. It is true that FDA's 
approach to deemed BLAs and their use of DMFs for DS/DSI/DP information 
applies to a small number of applications and DMFs. Deemed BLAs are a 
small subset of all BLAs, and deemed BLAs that reference a master file 
for DS/DSI/DP information are, in turn, a subset of all deemed BLAs. 
However, FDA's risk-based assessment of deemed BLAs' continued 
referencing of DMFs for DS/DSI/DP information is based on a 
consideration of the entire set of deemed BLAs that reference DMFs for 
such information, and it is only those deemed BLAs that will be able to 
continue referencing DS/DSI/DP information in a DMF. In other words, 
FDA considered the entire set of applications and DMFs that will be 
affected by final Sec.  601.2(g)(2).
    As elaborated in the preamble to the proposed rule, FDA considered 
the length of time these products have been marketed without being 
withdrawn or removed for reasons of safety or effectiveness; the 
acceptable quality of drug substances provided over decades through 
this incorporation by reference to DMFs; and the impact of disallowing 
use of DMFs for these deemed BLAs, which has the potential to curtail 
or halt production of some of these products, resulting in drug 
shortages with considerable negative impacts on public health. Based on 
these reasons, and the fact that there are a small number of deemed 
BLAs and a small number of master files referenced by these 
applications, the Agency has determined that it serves the public 
health best to permit these deemed BLAs to continue incorporating by 
reference the DS/DSI/DP information contained in this small set of 
master files.
    (Comment 16) One comment proposes that a biosimilar product that 
references a deemed BLA that incorporates by reference DS/DSI/DP 
information contained in a master file should also be permitted to 
incorporate by reference

[[Page 9750]]

the same information to assist in demonstrating biosimilarity.
    (Response 16) FDA recognizes that an applicant might submit a BLA 
for a biosimilar or interchangeable biosimilar product to a reference 
product that is approved in a deemed BLA and is permitted under the 
exception in final Sec.  601.2(g)(2) to continue incorporating by 
reference DS/DSI/DP information contained in a DMF. However, for the 
reasons outlined below, FDA declines to amend the proposed rule to also 
except such BLAs for biosimilar or interchangeable biosimilar products 
from final Sec.  601.2(g)(1).
    Consistent with FDA's longstanding practice for BLAs, and as 
codified in final Sec.  601.2(g)(1), a BLA may not reference a master 
file for DS/DSI/DP information because a BLA applicant needs to 
demonstrate knowledge of and direct control over the manufacture of the 
drug product, which includes manufacture of the drug substance and drug 
substance intermediate. For reasons discussed above, FDA believes that 
the public health is best served by allowing a small number of deemed 
BLAs--those that, in former approved applications under section 505 of 
the FD&C Act, relied on DMFs for DS/DSI/DP information--to continue 
referencing that information after being deemed a BLA. However, these 
reasons, such as avoiding disruptions in existing supply chains for 
products with deemed BLAs, do not apply to new BLAs, including BLAs for 
products that are biosimilar to or biosimilar and interchangeable with 
reference products in such deemed BLAs. We continue to consider that an 
approach which draws a clear distinction between deemed BLAs and other 
BLAs with regard to the referencing of master files for DS/DSI/DP 
information is the most appropriate.
    FDA notes that the lack of ability to reference a master file for 
DS/DSI/DP information should not preclude the development of a 
biosimilar or interchangeable biosimilar product to a reference product 
in a deemed BLA that is permitted to continue incorporating by 
reference DS/DSI/DP information from a DMF. For example, an application 
for licensure as a biosimilar typically will include data derived from 
comparative analytical studies between the proposed biosimilar and the 
reference product, which should be feasible even if the biosimilar or 
interchangeable biosimilar product application does not reference DS/
DSI/DP information that is incorporated by reference by the deemed BLA 
for the reference product. Moreover, data derived from comparative 
clinical studies, among other things, often will be included as part of 
a demonstration of biosimilarity. In general, a biosimilar applicant 
should be able to conduct such studies regardless of whether the 
biosimilar applicant can reference the same DMF for DS/DSI/DP 
information as the reference product.
    Furthermore, an applicant for a biosimilar or interchangeable 
biosimilar product that is not permitted to incorporate DS/DSI/DP 
information by reference to the DMF is not required to manufacture the 
DS/DSI/DP; as noted above and in the preamble to the proposed rule, 
alternatives are available, including the use of cooperative 
manufacturing arrangements that ensure that the licensee for the final 
product assumes responsibility for compliance with the applicable 
product and establishment standards.
    Overall, we do not believe that an applicant for a proposed 
biosimilar or interchangeable biosimilar product would face a barrier 
to generating the data necessary to demonstrate the biosimilarity or 
interchangeability of its proposed product to a reference product that 
incorporates by reference DS/DSI/DP information in a DMF, even if the 
biosimilar applicant is not permitted to incorporate by reference that 
same DS/DSI/DP information. Therefore, FDA declines to modify this 
provision as suggested.
    We note that the Agency has taken steps to help create a more 
competitive market for biological products, including encouraging the 
development of biosimilar products, and is working to implement 
additional measures to maximize clarity and efficiency in biosimilar 
development.\9\ The Agency invites prospective applicants who seek 
advice relating to the development and review of a biosimilar or 
interchangeable biosimilar product, including advice on the feasibility 
of licensure under section 351(k) of the PHS Act for a particular 
product, to contact the Agency. For Center for Drug Evaluation and 
Research (CDER)-regulated products, you may contact CDER-Biologics 
Biosimilars Inquiries at <a href="/cdn-cgi/l/email-protection#9dded9d8cfb0dff4f2f1f2faf4feeedff4f2eef4f0f4f1fcefeed4f3ece8f4eff4f8eeddfbf9fcb3f5f5eeb3faf2eb"><span class="__cf_email__" data-cfemail="7f3c3b3a2d523d1610131018161c0c3d16100c161216131e0d0c36110e0a160d161a0c3f191b1e5117170c51181009">[email protected]</span></a>; for Center for Biologics 
Evaluation and Research (CBER)-regulated products, you may contact CBER 
at <a href="/cdn-cgi/l/email-protection#a0c9cec4d5d3d4d2d98ec2c9cfcccfc7c9c3d3e0c6c4c18ec8c8d38ec7cfd6"><span class="__cf_email__" data-cfemail="a8c1c6ccdddbdcdad186cac1c7c4c7cfc1cbdbe8ceccc986c0c0db86cfc7de">[email protected]</span></a>.
---------------------------------------------------------------------------

    \9\ See ``Biosimilars Action Plan: Balancing Innovation and 
Competition,'' pgs. 5-7 (Ref. 4).
---------------------------------------------------------------------------

3. Final Sec.  601.2(g)(4) (Proposed Sec.  601.2(i))
    Final Sec.  601.2(g)(4) (proposed Sec.  601.2(i)) codifies the 
Agency's practice of permitting BLAs to incorporate by reference 
information other than DS/DSI/DP information contained in master files, 
including in DMFs. Comments that address this proposed provision did 
not object to FDA's overall approach or the underlying rationale, and 
some focused on operational aspects of the provision. Therefore, we are 
finalizing Sec.  601.2(g)(4) without substantive changes. Because this 
provision applies to a BLA regardless of submission type, we have 
removed the reference to amendments and supplements.
    (Comment 17) Three comments request clarification or codification 
of the type of data and information that constitutes information other 
than DS/DSI/DP information that is contained in master files and can be 
leveraged by BLAs.
    (Response 17) In the preamble to the proposed rule, we provided 
examples of the kinds of information that are not DS/DSI/DP 
information, including excipients, stabilizers, penetrants, container 
closure, and other materials. However, we decline to codify in this 
rule an exhaustive list of the specific types of information that are 
not DS/DSI/DP information and that can be included in a master file and 
incorporated by reference by a BLA. A potential applicant may seek 
additional guidance from the relevant review division if the applicant 
is unsure whether it is appropriate to incorporate by reference a 
particular type of information contained in a master file.
    (Comment 18) One comment requests that FDA codify the tests and 
analyses that should be performed by the applicant when data or 
information is being incorporated by reference by the BLA.
    (Response 18) FDA declines to codify the tests and analyses that 
the applicant should perform because these depend on, among other 
things, the nature of the data and information contained in the master 
file and incorporated by reference.
    (Comment 19) One comment requests that FDA clarify whether proposed 
Sec.  601.2(i) applies to master files held by contract manufacturing 
organizations (CMOs). The comment reasons that sponsors developing 
biological products frequently incorporate into BLAs information other 
than DS/DSI/DP (e.g., for a fill or incorporation of a device, such as 
an autoinjector) by referencing a master file held by a CMO.
    (Response 19) FDA clarifies that this final rule applies to all 
master files containing information that is being considered for 
incorporation by reference by a BLA, regardless of the ownership of the 
master file. Therefore, BLAs may incorporate by reference information 
(other than DS/DSI/DP

[[Page 9751]]

information) that is contained in master files held by CMOs.
    (Comment 20) One comment requests that FDA update the proposed rule 
to explicitly state that Type V DMFs can be used for certain non-
product-specific equipment and facility information, including 
sterilization validation information, to support multiple NDAs/BLAs.
    (Response 20) Final Sec.  601.2(g)(4) codifies that BLAs may 
incorporate by reference information other than DS/DSI/DP information 
contained in master files. Information in Type V DMFs, like information 
in all master files, may be incorporated by reference by multiple 
applications, provided that the information is not DS/DSI/DP 
information. We do not consider it necessary to explicitly reference 
Type V DMFs in the codified language.
    (Comment 21) One comment requests that FDA qualify proposed Sec.  
601.2(i) by adding that nothing in proposed Sec.  601.2(g) limits or 
alters a license holder's ability to modify a product under Sec.  
601.12, nor is it intended to expand or reduce the changes allowed to a 
deemed BLA that incorporates by reference information contained in 
master files.
    (Response 21) FDA declines to change proposed Sec.  601.2(i) (final 
Sec.  601.2(g)(4)) as the comment requests. As stated in the preamble 
to the proposed rule, this codification of current practice is not 
intended to alter an applicant's existing ability to modify a product 
under Sec.  601.12. We further stated in the preamble to the proposed 
rule that the proposed rule is also not intended to expand or reduce 
the changes allowed to a deemed BLA that incorporates by reference 
information contained in master files.
4. Combination Products Approved in BLAs
    The Agency recognized in the preamble for the proposed rule that 
there are combination products approved in BLAs. Although the proposed 
rule did not focus on combination products in BLAs, in the preamble, we 
stated our position that the rationale for the treatment of BLAs for 
biological products also applies to the biological product constituent 
part(s) of combination products licensed under the PHS Act (i.e., BLAs 
should not be permitted to incorporate by reference DS/DSI/DP 
information contained in master files for a biological product 
constituent part of a combination product for the same reasons that 
BLAs for biological products should not be permitted to do so).\10\ 
Additionally, the Agency specifically requested comments on whether 
BLAs should be permitted to incorporate by reference DS/DSI/DP 
information for any non-biological product constituent part of a 
combination product.
---------------------------------------------------------------------------

    \10\ The Agency intends to continue to take a consistent 
approach to biological product constituent parts of combination 
product applications subject to regulation under other (non-BLA) 
marketing applications (i.e., non-BLA marketing applications for 
combination products should not be permitted to incorporate by 
reference DS/DSI/DP information contained in master files for 
biological product constituent parts).
---------------------------------------------------------------------------

    We received several comments disagreeing with our position that, 
since BLAs for biological products cannot incorporate by reference DS/
DSI/DP information contained in a master file, then BLAs should also 
not be permitted to incorporate by reference such information for a 
biological product constituent part of a combination product. We also 
received comments both in support and not in support of permitting BLAs 
to incorporate by reference DS/DSI/DP information for the non-
biological product constituent part(s) of a combination product. We did 
not receive any comments discussing whether BLAs should be able to 
reference master files for information other than DS/DSI/DP information 
for either the biological or non-biological product constituent parts 
of a combination product.
    Based on our consideration of the comments regarding BLAs' 
incorporation by reference of information contained in master files for 
constituent parts of combination products, we are addressing 
combination products approved as BLAs under section 351 of the PHS Act 
in the final rule.
    a. BLAs referencing a master file for DS/DSI/DP information for a 
biological product constituent part of a combination product: final 
Sec.  601.2(g)(1) (proposed Sec.  601.2(g)). We received several 
comments disagreeing with our position that BLAs will not be permitted 
to incorporate by reference DS/DSI/DP information contained in a master 
file for a biological product constituent part of a combination 
product.
    (Comment 22) The comments disagreeing with FDA's proposal regarding 
biological product constituent parts of a combination product refer to 
the reasons that the commenters disagree with the Agency's rationale 
for not permitting BLAs generally to reference master files for DS/DSI/
DP information but do not provide a reason for their disagreement that 
is specific to a biological product constituent part of a combination 
product.
    (Response 22) The comments do not provide any reason why a BLA 
should be permitted to reference a master file for DS/DSI/DP 
information for a biological product constituent part of a combination 
product. Instead, the comments refer to the arguments they provide for 
why BLAs more generally should be permitted to incorporate by reference 
DS/DSI/DP information. In section V.B.1 of this preamble, we explain 
why we disagree with that position. None of the comments suggest that 
there is anything unique about a biological product constituent part of 
a combination product that warrants not extending the approach for BLAs 
to a biological product constituent part of a combination product in a 
BLA. Accordingly, we have modified final Sec.  601.2(g)(1) to state 
that, except as provided, a BLA may not incorporate by reference DS/
DSI/DP information contained in a master file, including for a 
biological product constituent part of a combination product.
    b. BLAs referencing a master file for information other than DS/
DSI/DP information for a constituent part of a combination product: 
final Sec.  601.2(g)(4) (proposed Sec.  601.2(i)). With regard to the 
referencing of a master file for information other than DS/DSI/DP 
information, we did not receive any comments objecting to BLAs' 
referencing this information for either a biological product 
constituent part or a non-biological product constituent part of a 
combination product. Therefore, FDA has decided that these BLAs, like 
all other BLAs, may incorporate by reference information other than DS/
DSI/DP information contained in master files (see section V.B.3). 
Accordingly, final Sec.  601.2(g)(4) covers the incorporation by 
reference of information contained in master files that is not DS/DSI/
DP information by all BLAs, regardless of whether such information is 
incorporated by reference for the product or for a constituent part of 
a combination product.
    c. BLAs referencing a master file for DS/DSI/DP information for a 
non-biological product constituent part of a combination product: final 
Sec.  601.2(g)(3) (new). As discussed above, in the preamble of the 
proposed rule, the Agency specifically requested comments on whether 
applications for combination products submitted in BLAs should be 
permitted to incorporate by reference DS/DSI/DP information for any 
non-biological product constituent part of a combination product. FDA 
received numerous comments on this topic. Most

[[Page 9752]]

of the comments support permitting BLAs to reference master files for 
DS/DSI/DP information with respect to the non-biological product 
constituent part(s) of a combination product, while a few comments are 
against such an approach. The comments we received helped inform our 
decision to clarify in this final rule that a BLA may incorporate by 
reference DS/DSI/DP information contained in any master file for any 
non-biological product constituent part of a combination product.
    (Comment 23) Several comments support codifying in the final rule 
that BLAs are permitted to incorporate by reference DS/DSI/DP 
information contained in master files for the non-biological product 
constituent parts of combination products, but the comments do not 
provide a rationale. Another comment reasons that DMFs for drug 
products have been relied on for decades and enabling continued 
referencing of DS/DSI/DP information for the non-biological product 
constituent part(s) of a combination product in a BLA will allow 
further development of ``superior treatments.'' An additional comment 
suggests that permitting BLAs to reference a master file for DS/DSI/DP 
information for the non-biological product constituent part(s) of a 
combination product would enable biological product and small molecule 
manufacturers to collaborate more efficiently. Finally, one comment 
analogizes that, because a BLA would be permitted to incorporate any 
information from the device master file system for a medical device 
constituent part of a combination product, BLAs should also be able to 
reference DMFs for DS/DSI/DP information for drug constituent parts.
    (Response 23) We agree that BLAs should be permitted to reference 
master files for DS/DSI/DP information with respect to the non-
biological product constituent part(s) of combination products. As we 
explained in the preamble to the proposed rule, historically, the 
Agency has, as a scientific matter, expected applicants to submit 
information about DS/DSI/DP directly to the BLA for a biological 
product, rather than have the BLA incorporate it by reference to a 
master file. However, as a scientific matter, a similar expectation 
would not apply to applications for non-biological products regulated 
under the FD&C Act, which are permitted to incorporate by reference DS/
DSI/DP information contained in a master file.
    Much of the rationale for why a BLA is not permitted to reference a 
master file for DS/DSI/DP information does not apply in the case of a 
non-biological product constituent part of a combination product in a 
BLA. As we explained in the preamble to the proposed rule, the risk 
associated with the manufacture of biological products is generally 
significantly higher than that associated with the manufacture of 
products regulated under NDAs, which are often less complex.\11\ This 
is because most biological products tend to have certain features 
(e.g., amino acid sequence, glycosylation, folding, cellular phenotype) 
essential to their intended effect and can be very sensitive to changes 
to their manufacturing process, which makes them less amenable to 
characterization than small molecule chemical entities. While these 
considerations apply to biological product constituent parts of 
combination products, they generally do not apply to non-biological 
product constituent parts, which are often relatively simple, 
homogenous, and fully characterizable by extensive analytical testing. 
As such, the need for direct knowledge and control in the manufacturing 
of a non-biological product constituent part is generally mitigated by 
the ability to define the non-biological constituent part through 
analytical testing, and the risk associated with such manufacturing is 
generally lower than that associated with the manufacture of the 
biological product constituent part.
---------------------------------------------------------------------------

    \11\ As addressed in the preamble to the proposed rule, the 
Agency recognizes that, in limited circumstances, this may not 
always be the case.
---------------------------------------------------------------------------

    As two comments suggest, such an approach is consistent with how a 
non-biological product constituent part of a combination product, such 
as a drug constituent part, would be treated if it were a standalone 
product regulated under the FD&C Act. Additionally, we agree with the 
comment that permitting such referencing of information for non-
biological product constituent part(s) could foster innovation by 
enabling more efficient collaboration between the manufacturer of the 
non-biological product constituent part and the manufacturer of the 
final product submitted in a BLA.
    Accordingly, final Sec.  601.2(g)(3) permits BLAs to incorporate by 
reference DS/DSI/DP information contained in a master file for the non-
biological product constituent part(s) of a combination product.
    (Comment 24) One comment does not support allowing BLAs to 
incorporate by reference DS/DSI/DP information for the non-biological 
product constituent part(s) of a combination product. The comment 
contends that the lack of knowledge and control over a drug constituent 
part for which a master file is referenced for DS/DSI/DP information 
introduces risk when that drug constituent part is combined with a 
biological product constituent part.
    (Response 24) We understand that permitting a BLA to reference a 
master file for DS/DSI/DP information for a non-biological product 
constituent part, such as a drug constituent part, that is then 
combined with a biological product constituent part may introduce 
additional risk for the final combination product. However, the Agency 
considers it generally practical for the BLA applicant to confirm the 
DS/DSI/DP quality characteristics of the non-biological product 
constituent part through testing. This feasibility of testing and 
characterizing the non-biological product constituent part generally 
enables the BLA applicant to implement a robust control strategy for 
the final combination product that can mitigate the risks to quality 
arising from the applicant's lack of access to the DS/DSI/DP 
information for the non-biological product constituent part. 
Furthermore, the applicant would still be expected at the time of 
review of the BLA to have sufficient control strategies for the entire 
combination product, including an appropriate control strategy to 
mitigate the risk of the applicant not having access to the 
manufacturing information for the non-biological product constituent 
part.
    (Comment 25) Another comment is concerned with non-biological 
product constituent parts categorically being permitted to reference a 
master file for DS/DSI/DP information because special controls may be 
necessary for drug constituent parts that are cytotoxic in nature, such 
as in the case of an antibody-drug conjugate combination product 
licensed in a BLA.
    (Response 25) FDA acknowledges that the manufacture of cytotoxic 
drugs requires special expertise and controls to address the risks 
associated with the toxic nature of the drug, such as the 
implementation of special air-handling systems to reduce the risk of 
exposure to the cytotoxic drug by manufacturing personnel. We point 
out, however, that such controls to address toxicity-related risks 
differ from the controls that are discussed elsewhere throughout this 
rulemaking, which address the risks associated with the generally 
complex manufacturing of biological products. Permitting a BLA to 
incorporate by reference DS/DSI/DP information contained in a master 
file for a cytotoxic drug constituent part of a combination product 
does not increase the toxicity-related risks associated with either the

[[Page 9753]]

manufacture of the cytotoxic drug constituent part or the manufacture 
of the combination product that contains the cytotoxic drug constituent 
part. Furthermore, the toxicity-related risks associated with the 
manufacture of a cytotoxic drug constituent part of a combination 
product licensed in a BLA are unlikely to differ significantly from the 
toxicity-related risks associated with the manufacture of cytotoxic 
drug products that are not constituent parts of combination products 
licensed in BLAs. Therefore, FDA declines to treat cytotoxic drug 
constituent parts differently from other non-biological product 
constituent parts and will permit BLAs to incorporate by reference DS/
DSI/DP information contained in master files for cytotoxic drug 
constituent parts of combination products.
    (Comment 26) One comment expresses concern that the BLA applicant 
would have a greater burden to establish a quality assurance program to 
mitigate the risk if the BLA incorporates by reference DS/DSI/DP 
information contained in a master file for the non-biological product 
constituent part of a combination product and this would be costlier 
and more complex than if the BLA is not permitted to rely on a master 
file for such information for the non-biological product constituent 
part.
    (Response 26) To the extent that there is concern that an applicant 
would find it costlier and more complex to establish a quality 
assurance program to mitigate the risk associated with the use of a 
master file for DS/DSI/DP information for the non-biological product 
constituent part of a combination product than it would be to directly 
include such information in the BLA, we point out that FDA is not 
mandating the use of master files under such circumstances.
5. Final Sec.  601.2(g)(5) (Proposed Sec.  601.2(j))
    FDA proposed in Sec.  601.2(j) of the proposed rule that INDs for 
products that would be subject to licensure under the PHS Act not be 
restricted from incorporating by reference any information, including 
DS/DSI/DP information, contained in a master file, including a DMF 
submitted under Sec.  314.420 (21 CFR 314.420). Several comments 
support the proposed approach. However, a few comments disagree and 
recommend that, as is the case for BLAs, an IND for a product that 
would be subject to licensure under the PHS Act not be permitted to 
incorporate by reference DS/DSI/DP information.
    (Comment 27) One comment disagrees with FDA's proposed approach of 
permitting INDs for products that would be subject to licensure under 
the PHS Act to incorporate by reference DS/DSI/DP information contained 
in a master file. The comment contends that the approach is 
unreasonable because, while exposure to the biological product is 
limited during the IND stage, the IND should still ensure that clinical 
trial subjects are not exposed to what the comment considers 
unreasonable harm should the IND incorporate by reference DS/DSI/DP 
information contained in a master file.
    (Response 27) FDA agrees that it is important to ensure that 
clinical trial subjects are not exposed to an unreasonable risk of harm 
but disagrees with the comment's assessment of FDA's approach.
    During early preclinical development for a new product, the primary 
goal of FDA and sponsors is to ensure that the product is reasonably 
safe for initial use in humans and to determine whether the test 
product exhibits pharmacological activity that justifies commercial 
development. When a product is identified as a viable candidate for 
further development, the sponsor then focuses on collecting the data 
and information necessary to establish that the product will not expose 
humans to unreasonable risks when used in limited, early-stage clinical 
studies.
    Clinical trials permit the assessment of the safety and efficacy of 
investigational products from early drug development through the 
approval process and beyond. To ensure that clinical trial subjects are 
not exposed to unreasonable risk of harm, FDA has issued numerous 
regulations governing human subject protection and the conduct of 
clinical trials, including regulations regarding informed consent (part 
50 (21 CFR part 50)) and institutional review boards, which also 
participate in the oversight of clinical trials (21 CFR part 56).
    All subjects in clinical trials under an IND receive appropriate 
informed consent that discusses the known benefits and risks. With 
limited exceptions, investigators must obtain the informed consent of 
subjects (or their legally authorized representatives) in clinical 
trials under IND (Sec.  50.20). In seeking informed consent, certain 
information is provided to subjects, including a description of 
reasonably foreseeable risks and a description of benefits that may 
reasonably be expected (Sec.  50.25).
    Furthermore, safety monitoring is not static and continues to apply 
as product development progresses. IND regulations in part 312 (21 CFR 
part 312) set forth safeguards that are designed to ensure such safety. 
Sponsors are expected to continue to ensure the safety of subjects and, 
as new safety information is identified, to take appropriate steps, 
which may include incorporating additional safety monitoring and 
updating the informed consent form. FDA has authority to place an 
investigation on clinical hold (Sec.  312.42) if it finds that human 
subjects are or would be exposed to an unreasonable and significant 
risk of illness or injury. IND regulations at Sec.  312.56 state that a 
sponsor who determines that its investigational drug presents an 
unreasonable and significant risk to subjects must discontinue those 
investigations that present the risk.
    As explained above and in the preamble to the proposed rule, 
exposure to the investigational product is limited at the IND stage 
because the product is only administered to subjects enrolled in 
clinical trials, which are typically carried out in controlled 
settings. The controlled nature of a clinical trial allows for close 
safety monitoring of these subjects, rapid identification of any safety 
issues that may arise, and implementation of corresponding mitigation 
strategies.
    For these reasons, FDA considers that the existing safeguards 
available in the IND process are sufficient to ensure that subjects 
participating in clinical trials, including those for products that 
would ultimately be regulated under BLAs and for which the INDs 
incorporate by reference DS/DS/DP information contained in master 
files, are not exposed to unreasonable risk of harm.
    (Comment 28) Another comment expresses concern that the sponsor of 
an IND for a product that would be subject to licensure under the PHS 
Act that incorporates DS/DSI/DP information by reference to a master 
file may not be able to develop the necessary knowledge and control 
over the manufacturing process when product development reaches the BLA 
stage. Therefore, the comment suggests setting a deadline during the 
development stage by which time the sponsor needs to demonstrate 
knowledge and control over the manufacturing process and can no longer 
incorporate by reference DS/DSI/DP information from a master file.
    (Response 28) FDA notes that a deadline to develop the requisite 
knowledge and direct control is not necessary because the submission of 
the BLA effectively serves as a deadline. As

[[Page 9754]]

noted in the preamble to the proposed rule, it has been FDA's practice 
to permit INDs for products that would be subject to licensure under 
the PHS Act to incorporate by reference DS/DSI/DP information contained 
in a master file. By later stages of development, however, FDA requires 
the sponsors to have knowledge of and direct control over the 
manufacturing process, and to be able to submit DS/DSI/DP information 
directly to the BLA. A sponsor can plan its product development to 
ensure that, at the time the BLA is submitted, the sponsor is able to 
meet these requirements.
    (Comment 29) Several comments agree with the Agency's proposed 
approach with respect to INDs for products that would be subject to 
licensure under the PHS Act and the referencing of master files for 
information including DS/DSI/DP information. One comment suggests that 
allowing the referencing of DS/DSI/DP information at the IND stage 
could promote product development and proposes that this benefit be 
explicitly included in the corresponding codified section. Another 
comment advises that permitting INDs for products that would be subject 
to licensure under the PHS Act to reference master files for DS/DSI/DP 
information ensures that previous knowledge is leveraged.
    (Response 29) We agree that not limiting the ability of INDs for 
products that would be subject to licensure under the PHS Act to 
reference a master file for DS/DSI/DP information may facilitate 
product development. As we explained in the preamble of the proposed 
rule, and as discussed above, without this option a sponsor might not 
choose to make the significant investment to manufacture the necessary 
DS/DSI/DP for a product at this early stage of development. However, we 
do not think it is necessary to add an explicit reference to the 
benefit of promoting product development to the codified language.
6. Other Issues Raised by Commenters
    (Comment 30) One comment suggests that it would be helpful if the 
Agency defined the term ``drug substance intermediate,'' especially in 
reference to combination products.
    (Response 30) FDA is not defining the term ``drug substance 
intermediate'' in this rule because such a definition would have 
implications beyond the scope of this rule. FDA will consider whether 
to provide a definition in rulemaking that has a broader scope since 
the term is used throughout the BLA regulations.\12\
---------------------------------------------------------------------------

    \12\ FDA notes that an applicant may seek guidance from the 
relevant review division at the Agency if the applicant is unsure 
whether information in a master file constitutes DS/DSI/DP 
information in the context of a particular BLA.
---------------------------------------------------------------------------

    (Comment 31) One comment requests that FDA outline any plans for 
publication of guidances that more clearly articulate the Agency's 
current thinking on specific kinds of master files (e.g., those 
containing information on autoinjectors, on fillers, or those owned by 
CMOs) that may be referenced in BLAs, to enable appropriate referencing 
of relevant master files, thereby promoting improved compliance and 
reducing the risk of delays in application reviews.
    (Response 31) FDA will take this suggestion under consideration 
with respect to the development of future guidances. FDA annually 
publishes nonbinding lists of new and revised draft guidance documents 
that it plans to publish in the upcoming calendar year. In addition, a 
potential applicant may also seek additional guidance from the relevant 
review division if the applicant is unsure whether it is appropriate to 
incorporate by reference a particular type of information contained in 
a master file.
    (Comment 32) One comment encourages FDA to undertake modifications 
to internal processes and training of staff and revise the DMF guidance 
to implement this rule. Specifically, the comment requests that FDA: 
(1) update its internal training procedures and relevant procedural 
documents to ensure that Agency reviewers consistently implement and 
apply proposed Sec.  601.2(i) during application assessment; (2) update 
the DMF guidance to improve the format and layout of a DMF to avoid 
duplicating the content of DMFs across multiple applications and 
supplements; (3) explore potential technological solutions to permit 
cross-linking between BLAs and DMFs; and (4) incorporate the feedback 
provided in this comment into the revised draft guidance ``Drug Master 
Files'' (Ref. 5).
    (Response 32) FDA agrees that consistency in the implementation of 
final Sec.  601.2(g)(4) (proposed Sec.  601.2(i)) is important. As with 
any regulation, FDA will work to ensure correct and consistent 
implementation of this rule.
    Regarding the DMF guidance, we note that the revised draft guidance 
was issued on October 21, 2019, and reflects additional information to 
assist sponsors in improving the format of DMFs. Comments to guidance 
documents may be submitted at any time.
    Regarding technological solutions to permit cross-referencing 
between BLAs and DMFs, FDA believes that its recent efforts in the area 
of electronic submissions of DMFs may address some of the 
concerns.<SUP>13 14</SUP>
---------------------------------------------------------------------------

    \13\ See the revised draft guidance for industry ``Drug Master 
Files'' (Ref. 5).
    \14\ See the guidance for industry ``Providing Regulatory 
Submissions in Electronic Format--Certain Human Pharmaceutical 
Product Applications and Related Submissions Using the eCTD 
Specifications'' (Ref. 6) for relevant discussion of FDA's current 
thinking on electronic submissions.
---------------------------------------------------------------------------

    (Comment 33) One comment requests that there should also be 
provisions established that would notify applicants referencing a DMF 
when that DMF has been altered (without disclosing proprietary 
information). The comment notes that such notification would be 
beneficial to regulators and applicants who would be aware of any 
changes made by the DMF holder that may improve quality or safety of 
the final product.
    (Response 33) The purpose of this rule is to clarify when BLAs and 
INDs for products subject to licensure under the PHS Act can use master 
files. The operation of a DMF, which is addressed under Sec.  314.420, 
falls outside the scope of this rule; accordingly, FDA declines to 
address this issue in this rule.
    (Comment 34) One comment observes that, if a DMF were reviewed 
prior to submission of an NDA or abbreviated new drug application 
(ANDA), it would allow companies, especially less established ones, to 
avoid any issues with referencing an incomplete DMF for their NDA or 
ANDA filing. Additionally, the comment suggests that FDA should 
consider eliminating assessment fees to encourage smaller biotech and 
pharmaceutical companies to develop biosimilars.
    (Response 34) FDA declines to make changes to this final rule that 
would address these suggestions because the process for incorporating 
by reference information contained in master files, the timing of such 
referencing, and the fees related to assessment of DMFs are outside the 
scope of this rule.
    (Comment 35) One comment notes, without suggesting any changes, 
that in the description of the proposed rule for proposed paragraph 
Sec.  601.2(h), FDA should include information on the impact of the 
transition of an NDA to a BLA on exclusivity of the product.
    (Response 35) Exclusivity considerations are outside the scope of 
this rule. We note that FDA has issued guidance that, in part, 
addresses FDA's

[[Page 9755]]

current thinking about its interpretation of section 7002(e) of the 
BPCI Act and exclusivity.\15\
---------------------------------------------------------------------------

    \15\ See the guidance for industry ``Interpretation of the 
`Deemed to be a License' Provision of the Biologics Price 
Competition and Innovation Act of 2009'' (Ref.1).
---------------------------------------------------------------------------

    (Comment 36) One comment requests that FDA approve stem cells as an 
alternative to surgery that can be covered by insurance; another 
comment relates to ``pandemic flu'' and acquired immunity.
    (Response 36) These topics are outside the scope of this rule.

VI. Effective/Compliance Date

    This final rule is effective 30 days after the date of publication 
in the Federal Register.

VII. Economic Analysis of Impacts

    We have examined the impacts of the final rule under Executive 
Order 12866, Executive Order 13563, Executive Order 14094, the 
Regulatory Flexibility Act (5 U.S.C. 601-612), the Congressional Review 
Act/Small Business Regulatory Enforcement Fairness Act (5 U.S.C. 801, 
Pub. L. 104-121), 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 final rule is not a 
significant regulatory action under Executive Order 12866 Section 
3(f)(1).
    Because this rule is not likely to result in an annual effect on 
the economy of $100 million or more or meets other criteria specified 
in the Congressional Review Act/Small Business Regulatory Enforcement 
Fairness Act, OIRA has determined that this rule does not fall within 
the scope of 5 U.S.C. 804(2).
    The Regulatory Flexibility Act requires us to analyze regulatory 
options that would minimize any significant impact of a rule on small 
entities. Because this rule does not impose new regulatory burden on 
small entities, other than administrative costs of reading and 
understanding the rule, we certify that the final 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 estimates of 
anticipated impacts, before issuing ``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 current threshold after adjustment for inflation is $177 
million, using the most current (2022) Implicit Price Deflator for the 
Gross Domestic Product. This final rule will not result in an 
expenditure in any year that meets or exceeds this amount.
    Allowing deemed BLAs for biological products to continue 
referencing DMFs for DS/DSI/DP information will generate net cost-
saving benefits for the private and government sectors. Furthermore, 
the final rule will provide certainty, promote continuity, and help 
avoid potential disruptions in the supply of certain biological 
products that were approved in applications under section 505 of the 
FD&C Act and deemed, pursuant to section 7004(e) of the BPCI Act, to be 
licenses for the biological products under section 351 of the PHS Act.
    By allowing certain BLAs to continue referencing a DMF for DS/DSI/
DP information, FDA avoids imposing a potential new regulatory burden. 
Affected entities will incur minimal costs to read and understand the 
rule. FDA estimates that over 10 years at a discount rate of 7 percent, 
the final rule will generate annualized net cost savings ranging from 
$0.40 million to $5.19 million with a primary estimate of $2.80 
million; at a discount rate of 3 percent, the final rule will generate 
annualized net cost savings ranging from $0.37 million to $5.17 million 
with a primary estimate of $2.77 million. Table 1 summarizes our 
estimate of the annualized costs and the annualized cost-saving 
benefits of the final rule.

                                    Table 1--Summary of Benefits, Costs, and Distributional Effects of the Final Rule
                                                               [Millions in 2022 dollars]
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                      Units
                                                                                   ------------------------------------------
                Category                     Primary    Low estimate      High                                     Period                Notes
                                            estimate                    estimate    Year dollars    Discount       covered
                                                                                                    rate  (%)      (years)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
    Annualized Monetized $millions/year.         $2.81         $0.41         $5.20          2022             7            10  Cost savings.
                                                 $2.78         $0.38         $5.18          2022             3            10  Cost savings.
Costs:
    Annualized Quantified...............  ............  ............  ............  ............             7  ............  ..........................
                                                                                                             3
    Qualitative.........................  ............  ............  ............  ............  ............  ............  ..........................
    Annualized Monetized $millions/year.         $0.01         $0.01         $0.01          2022             7            10  ..........................
                                                 $0.01         $0.01         $0.01          2022             3            10  ..........................
    Annualized Quantified...............  ............  ............  ............  ............             7  ............  ..........................
                                                                                                             3
    Qualitative.........................  ............  ............  ............  ............  ............  ............  ..........................
Transfers:
    Federal Annualized Monetized          ............  ............  ............  ............             7  ............  ..........................
     $millions/year.                                                                                         3
--------------------------------------------------------------------------------------------------------------------------------------------------------
    From/To.............................  From:
                                          To:                                       ............
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 9756]]

 
    Other Annualized Monetized $millions/ ............  ............  ............  ............             7  ............  ..........................
     year.                                                                                                   3
--------------------------------------------------------------------------------------------------------------------------------------------------------
    From/To.............................  From:
                                          To:                                       ............
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects:
--------------------------------------------------------------------------------------------------------------------------------------------------------
    State, Local, or Tribal Government:
     None.
    Small Business: None................
    Wages: None.........................
    Growth: None........................
--------------------------------------------------------------------------------------------------------------------------------------------------------

    We have developed a comprehensive Economic Analysis of Impacts that 
assesses the impacts of the final rule. The full analysis of economic 
impacts is available in the docket for this final rule (Ref. 7) and at 
https://www.fda.gov/about-fda/economics-staff/regulatory-impact-analyses-ria.

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

    This final rule contains no collection of information. Therefore, 
clearance by the Office of Management and Budget under the Paperwork 
Reduction Act of 1995 is not required.

X. Federalism

    We have analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. We have determined that the 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 rule in accordance with the principles set 
forth in Executive Order 13175. We have determined that the rule does 
not contain policies that have substantial direct effects 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. Accordingly, we 
conclude that the rule does not contain policies that have tribal 
implications as defined in the Executive Order and, consequently, a 
tribal summary impact statement is not required.

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/. Although FDA 
verified the website addresses in this document, please note that 
websites are subject to change over time.

    1. FDA, Guidance for Industry, ``Interpretation of the `Deemed 
to be a License' Provision of the Biologics Price Competition and 
Innovation Act of 2009,'' December 2018. Available at https://www.fda.gov/media/119272/download. Accessed May 12, 2023.
    2. FDA, Guidance for Industry, ``Cooperative Manufacturing 
Arrangements for Licensed Biologics,'' November 2008. Available at 
https://www.fda.gov/media/70712/download. Accessed May 12, 2023.
    3. FDA, Guidance for Industry and FDA Staff, ``Bundling Multiple 
Devices or Multiple Indications in a Single Submission,'' June 2007. 
Available at https://www.fda.gov/media/73500/download. Accessed May 
12, 2023.
    4. FDA, ``Biosimilars Action Plan: Balancing Innovation and 
Competition,'' July 2018. Available at https://www.fda.gov/media/114574/download. Accessed May 12, 2023.
    5. FDA, Draft Guidance for Industry, ``Drug Master Files 
(Rev.1),'' October 2019. Available at https://www.fda.gov/media/131861/download. Accessed May 12, 2023.
    6. FDA, Guidance for Industry, ``Providing Regulatory 
Submissions in Electronic Format--Certain Human Pharmaceutical 
Product Applications and Related Submissions Using the eCTD 
Specifications (Rev. 7),'' February 2020. Available at https://www.fda.gov/media/135373/download. Accessed May 12, 2023.
    7. Final Regulatory Impact Analysis, ``Biologics License 
Applications and Master Files.''

List of Subjects in 21 CFR Part 601

    Administrative practice and procedure, Biologics, Confidential 
business information.

    Therefore, under the Public Health Service Act and under authority 
delegated to the Commissioner of Food and Drugs, 21 CFR part 601 is 
amended as follows:

PART 601--LICENSING

0
1. The authority citation for part 601 is revised to read as follows:

    Authority: 15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353, 
355, 356b, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 
216, 241, 262, 263, 264; sec 122, Pub. L. 105-115, 111 Stat. 2322 
(21 U.S.C. 355 note), sec 7002(e), Pub. L. 111-148, 124 Stat. 817, 
as amended by sec. 607, Division N, Pub. L. 116-94, 133 Stat. 3127.

0
2. In Sec.  601.2, add paragraph (g) to read as follows:


Sec.  601.2  Applications for biologics licenses; procedures for 
filing.

* * * * *
    (g) Master files--(1) Biologics license applications under section 
351 of the Public Health Service Act not permitted to incorporate by 
reference drug substance, drug substance intermediate, or drug product 
information contained in a master file. Except as provided in 
paragraphs (g)(2) and (3) of this section, a biologics license 
application under section 351 of the Public Health Service Act may not 
incorporate by reference drug substance, drug substance

[[Page 9757]]

intermediate, or drug product information contained in a master file, 
including a drug master file submitted under Sec.  314.420 of this 
chapter, for the product, including for a biological product 
constituent part of a combination product.
    (2) Former approved applications deemed to be licenses for 
biological products pursuant to section 7002(e)(4) of the Biologics 
Price Competition and Innovation Act of 2009. An application for a 
biological product that:
    (i) Is a former approved application under section 505 of the 
Federal Food, Drug, and Cosmetic Act that, pursuant to section 
7002(e)(4) of the Biologics Price Competition and Innovation Act of 
2009, has been deemed to be a license for the biological product under 
section 351 of the Public Health Service Act; and
    (ii) At the time it was so deemed, incorporated by reference drug 
substance, drug substance intermediate, and/or drug product information 
contained in a drug master file submitted under Sec.  314.420 of this 
chapter, may continue to incorporate by reference the information 
contained in that drug master file. Amendments and supplements to such 
applications may also continue to incorporate by reference the 
information contained in that drug master file.
    (3) Non-biological product constituent parts of combination 
products regulated under biologics license applications under section 
351 of the Public Health Service Act. A biologics license application 
under section 351 of the Public Health Service Act may incorporate by 
reference drug substance, drug substance intermediate, and/or drug 
product information contained in a master file, including a drug master 
file submitted under Sec.  314.420 of this chapter, for any non-
biological product constituent part of a combination product.
    (4) Biologics license applications under section 351 of the Public 
Health Service Act permitted to incorporate by reference information 
contained in a master file that is not drug substance, drug substance 
intermediate, or drug product information. Nothing in paragraph (g)(1) 
of this section limits or restricts a biologics license application 
under section 351 of the Public Health Service Act from incorporating 
by reference information contained in any master file, including a drug 
master file submitted under Sec.  314.420 of this chapter, that is not 
drug substance, drug substance intermediate, or drug product 
information.
    (5) Investigational new drug applications. Nothing in paragraph 
(g)(1) of this section limits or restricts an investigational new drug 
application for a product that would be subject to licensure under 
section 351 of the Public Health Service Act from incorporating by 
reference any information, including drug substance, drug substance 
intermediate, and drug product information, contained in a master file, 
including a drug master file submitted under Sec.  314.420 of this 
chapter.

    Dated: January 30, 2024.
Robert M. Califf,
Commissioner of Food and Drugs.
[FR Doc. 2024-02741 Filed 2-9-24; 8:45 am]
BILLING CODE 4164-01-P


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