Federal Register / Vol. 89, No. 29 / Monday, February 12, 2024 / Rules and Regulations 9743 

PART 39—AIRWORTHINESS 

DIRECTIVES 

■ 1. The authority citation for part 39 

continues to read as follows: 

Authority: 49 U.S.C. 106(g), 40113, 44701. 

§ 39.13 [Amended] 

■ 2. The FAA amends § 39.13 by adding 

the following new airworthiness 

directive: 

2024–03–04 The Boeing Company: 

Amendment 39–22673; Docket No. 

FAA–2024–0224; Project Identifier AD– 

2024–00055–T. 

(a) Effective Date 

This airworthiness directive (AD) is 

effective February 12, 2024. 

(b) Affected ADs 

None. 

(c) Applicability 

This AD applies to The Boeing Company 

Model 737–8, 737–8200, and 737–9 

airplanes, certificated in any category, with 

an original airworthiness certificate or 

original export certificate of airworthiness 

issued on or before December 20, 2023. 

(d) Subject 

Air Transport Association (ATA) of 

America Code 27, Flight controls. 

(e) Unsafe Condition 

This AD was prompted by a report of a 

missing washer and nut and consequent 

migrated bolt discovered by an operator 

during scheduled maintenance. The FAA is 

issuing this AD to address improper torque 

of the aft rudder quadrant output rod 

fasteners, which may cause a disconnect 

between the aft rudder quadrant and the 

output rod, which would result in loss of 

rudder control via the rudder pedals to 

counter an engine-out scenario during 

takeoff/climb out or to counter a high 

crosswind during landing. The unsafe 

condition, if not addressed, could result in 

loss of continued safe flight and landing. 

(f) Compliance 

Comply with this AD within the 

compliance times specified, unless already 

done. 

(g) Inspection 

Within 30 days after the effective date of 

this AD, perform a one-time detailed visual 

inspection or remote video inspection of the 

aft rudder quadrant for missing bolts, nuts, 

and washers; a gap between the bolt/nut/ 

washer and quadrant; and insufficient thread 

protrusion. 

Note 1 to paragraph (g): Guidance for 

accomplishing the actions required by 

paragraph (g) of this AD can be found in 

Boeing Multi Operator Message MOM– 

MOM–23–0993–01B, dated December 27, 

2023. 

(h) On-Condition Actions 

If any discrepancy is found during the 

inspection required by paragraph (g) of this 

AD, do the actions specified in paragraphs 

(h)(1) through (3) of this AD before further 

flight. 

(1) Do a detailed inspection of the bolt, 

washer, and nut for damage and, before 

further flight, replace any missing or 

damaged bolts, washers, and nuts. 

(2) Install each bolt, washer, and nut with 

a torque of 65 in-lb. 

(3) Perform a rudder travel test to ensure 

that the rudder is operating correctly. If the 

test fails, before further flight, do applicable 

corrective actions and repeat until the test is 

passed. 

Note 2 to paragraph (h) of this AD: 

Guidance for accomplishing the actions 

required by paragraph (h) of this AD can be 

found in Boeing Multi Operator Message 

MOM–MOM–23–0993–01B, dated December 

27, 2023. 

(i) Credit for Previous Actions 

This paragraph provides credit for the 

actions specified in paragraphs (g) and (h) of 

this AD, if those actions were performed 

before the effective date of this AD using 

Boeing Multi Operator Message MOM– 

MOM–23–0993–01B, dated December 27, 

2023. 

(j) Alternative Methods of Compliance 

(AMOCs) 

(1) The Manager, AIR–520, Continued 

Operational Safety Branch, FAA, has the 

authority to approve AMOCs for this AD, if 

requested using the procedures found in 14 

CFR 39.19. In accordance with 14 CFR 39.19, 

send your request to your principal inspector 

or responsible Flight Standards Office, as 

appropriate. If sending information directly 

to the manager of the certification office, 

send it to the attention of the person 

identified in paragraph (k)(1) of this AD. 

Information may be emailed to: 9-ANMSeattle-ACO-AMOC-Requests@faa.gov. 

(2) Before using any approved AMOC, 

notify your appropriate principal inspector, 

or lacking a principal inspector, the manager 

of the responsible Flight Standards Office. 

(3) An AMOC that provides an acceptable 

level of safety may be used for any repair, 

modification, or alteration required by this 

AD if it is approved by The Boeing Company 

Organization Designation Authorization 

(ODA) that has been authorized by the 

Manager, AIR–520, Continued Operational 

Safety Branch, FAA, to make those findings. 

To be approved, the repair method, 

modification deviation, or alteration 

deviation must meet the certification basis of 

the airplane, and the approval must 

specifically refer to this AD. 

(k) Related Information 

(1) For more information about this AD, 

contact Anthony Caldejon, Aviation Safety 

Engineer, FAA, 2200 South 216th St., Des 

Moines, WA 98198; phone: 206–231–3534; 

email: Anthony.V.Caldejon@faa.gov. 

(2) For service information identified in 

this AD that is not incorporated by reference, 

contact Boeing Commercial Airplanes, 

Attention: Contractual & Data Services 

(C&DS), 2600 Westminster Blvd., MC 110– 

SK57, Seal Beach, CA 90740–5600; telephone 

562–797–1717; website myboeingfleet.com. 

(l) Material Incorporated by Reference 

None. 

Issued on February 2, 2024. 

Caitlin Locke, 

Director, Compliance & Airworthiness 

Division, Aircraft Certification Service. 

[FR Doc. 2024–02930 Filed 2–8–24; 2:00 pm] 

BILLING CODE 4910–13–P 

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. 

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. 


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9744 Federal Register / Vol. 89, No. 29 / Monday, February 12, 2024 / Rules and Regulations 

1FDA 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. 

2 ‘‘Biologics License Applications and Master 

Files,’’ 84 FR 30968 (June 28, 2019). 

3See 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). 

4Section 607 of Division N of the FCA Act, 2020 

(Pub. L. 116–94, 133 Stat 3127), amended section 

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, natalia.comella@fda.hhs.gov; 

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. 

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 

Abbreviation/ 

acronym What it means 

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. 

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 


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Federal Register / Vol. 89, No. 29 / Monday, February 12, 2024 / Rules and Regulations 9745 

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). 

5For 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-complianceregulatory-information/guidances-drugs. 

6See, 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). 

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

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 antibodydrug 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 § 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 nonbiological 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 § 601.2(g), those 

paragraphs that remain in effect would 

continue to function sensibly 6 to 

address their respective circumstances. 

For example, invalidation of § 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. 

B. Specific Comments and FDA 

Response 

1. Final § 601.2(g)(1) (Proposed 

§ 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 § 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 § 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-bycase 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 


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9746 Federal Register / Vol. 89, No. 29 / Monday, February 12, 2024 / Rules and Regulations 

7See the guidance for industry ‘‘Cooperative 

Manufacturing Arrangements for Licensed 

Biologics’’ (Ref. 2). 

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 § 601.2(g)(1) (as 

well as final § 601.2(g)(3)) includes 

references to such applications. In 

addition, because § 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. 

(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 


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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., applicationspecific) 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 productspecific. 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 productspecific’’ 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 


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8For example, see the guidance for industry and 

FDA Staff ‘‘Bundling Multiple Devices or Multiple 

Indications in a Single Submission’’ (Ref. 3). 

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 § 601.2(g)(2) (Proposed 

§ 601.2(h)) 

Final § 601.2(g)(2) (proposed 

§ 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 

§ 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 § 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 § 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 § 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

(Comment 11) One comment suggests 

that deemed BLAs are best described as 

‘‘expected to transition.’’ 

(Response 11) The applications 

described in § 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 § 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 § 601.2(g)(2) and (3), final 

§ 601.2(g)(1) applies to all BLAs, 

whether new or existing. Therefore, the 

suggested change is not needed because, 


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Federal Register / Vol. 89, No. 29 / Monday, February 12, 2024 / Rules and Regulations 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 riskbased 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 § 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 


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9See ‘‘Biosimilars Action Plan: Balancing 

Innovation and Competition,’’ pgs. 5–7 (Ref. 4). 

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 

§ 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 § 601.2(g)(1). 

Consistent with FDA’s longstanding 

practice for BLAs, and as codified in 

final § 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 

CDER-BiologicsBiosimilarsInquiries@

fda.hhs.gov; for Center for Biologics 

Evaluation and Research (CBER)- 

regulated products, you may contact 

CBER at industry.biologics@fda.hhs.gov. 

3. Final § 601.2(g)(4) (Proposed 

§ 601.2(i)) 

Final § 601.2(g)(4) (proposed 

§ 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 § 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 

§ 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 


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10The Agency intends to continue to take a 

consistent approach to biological product 

constituent parts of combination product 

applications subject to regulation under other (nonBLA) 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). 

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 § 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 § 601.2(i) by 

adding that nothing in proposed 

§ 601.2(g) limits or alters a license 

holder’s ability to modify a product 

under § 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 § 601.2(i) (final § 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 

§ 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. 

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 § 601.2(g)(1) 

(proposed § 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 

§ 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 § 601.2(g)(4) 

(proposed § 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 § 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 nonbiological product constituent part of a 

combination product: final § 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 


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11As addressed in the preamble to the proposed 

rule, the Agency recognizes that, in limited 

circumstances, this may not always be the case. 

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 nonbiological 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. 

As two comments suggest, such an 

approach is consistent with how a nonbiological 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 nonbiological 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 § 601.2(g)(3) 

permits BLAs to incorporate by 

reference DS/DSI/DP information 

contained in a master file for the nonbiological 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 nonbiological product constituent part 

through testing. This feasibility of 

testing and characterizing the nonbiological 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 nonbiological 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 nonbiological 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 toxicityrelated risks associated with either the 


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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 § 601.2(g)(5) (Proposed 

§ 601.2(j)) 

FDA proposed in § 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 

§ 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 (§ 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 (§ 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 

(§ 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 

§ 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 


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12FDA 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. 

13See the revised draft guidance for industry 

‘‘Drug Master Files’’ (Ref. 5). 

14See 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. 

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

(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 § 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 § 601.2(g)(4) (proposed § 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.13 14

(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 § 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 § 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 


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15See 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). 

current thinking about its interpretation 

of section 7002(e) of the BPCI Act and 

exclusivity.15

(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] 

Category Primary 

estimate Low estimate High estimate 

Units 

Notes 

Year dollars 

Discount 

rate 

(%) 

Period 

covered 

(years) 

Benefits: 

Annualized Monetized $millions/year .................. $2.81 

$2.78 

$0.41 

$0.38 

$5.20 

$5.18 

2022 

2022 

7 

3 

10 

10 

Cost savings. 

Cost savings. 

Costs: 

Annualized Quantified ......................................... ...................... ...................... ...................... ...................... 7 

3 

......................

Qualitative ............................................................ ...................... ...................... ...................... ...................... ...................... ......................

Annualized Monetized $millions/year .................. $0.01 

$0.01 

$0.01 

$0.01 

$0.01 

$0.01 

2022 

2022 

7 

3 

10 

10 

Annualized Quantified ......................................... ...................... ...................... ...................... ...................... 7 

3 

......................

Qualitative ............................................................ ...................... ...................... ...................... ...................... ...................... ......................

Transfers: 

Federal Annualized Monetized $millions/year .... ...................... ...................... ...................... ...................... 7 

3 

......................

From/To ............................................................... From: To: 


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9756 Federal Register / Vol. 89, No. 29 / Monday, February 12, 2024 / Rules and Regulations 

TABLE 1—SUMMARY OF BENEFITS, COSTS, AND DISTRIBUTIONAL EFFECTS OF THE FINAL RULE—Continued 

[Millions in 2022 dollars] 

Category Primary 

estimate Low estimate High estimate 

Units 

Notes 

Year dollars 

Discount 

rate 

(%) 

Period 

covered 

(years) 

Other Annualized Monetized $millions/year ........ ...................... ...................... ...................... ...................... 7 

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/regulatoryimpact-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 

■ 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. 

■ 2. In § 601.2, add paragraph (g) to read 

as follows: 

§ 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 


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Federal Register / Vol. 89, No. 29 / Monday, February 12, 2024 / Rules and Regulations 9757 

1The HHH Act was enacted as both Title II of the 

Omnibus Indian Advancement Act (Pub. L. 106– 

568, 114 Stat. 2868, approved December 27, 2000) 

and Subtitle B of Title V of the American 

Homeownership and Economic Opportunity Act of 

2000 (Pub. L. 106–569, 114 Stat. 2944, approved 

December 27, 2000). 

2Section 513 of the HHH Act adds sections 801 

through 824 of NAHASDA’s Title VIII, which 

authorize this NHHBG program. 25 U.S.C. 4221 et 

seq. Although NAHASDA may be referenced 

throughout this rule, NHHBG serves Native 

Hawaiians specifically. 

3 67 FR 40773; see Native American Housing 

Assistance and Self-Determination Act of 1996 

[hereinafter NAHASDA] sections 810–811, 25 

U.S.C. 4229–30. There are also differences between 

the statutory authorities governing the IHBG and 

NHHBG programs. In 2008, the Native American 

Housing Assistance and Self-Determination 

Reauthorization Act of 2008 (Pub. L. 110–411) 

(NAHASDA Reauthorization Act), made several 

changes to, inter alia, statutory requirements 

governing HUD’s IHBG program, and implemented 

statutory changes to NAHASDA made by several 

Continued 

intermediate, or drug product 

information contained in a master file, 

including a drug master file submitted 

under § 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 § 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 § 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 § 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 § 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 

DEPARTMENT OF HOUSING AND 

URBAN DEVELOPMENT 

24 CFR Part 1006 

[Docket No. FR–6273–F–02] 

RIN 2577–AD13 

Implementing Rental Housing 

Assistance for the Native Hawaiian 

Housing Block Grant Program 

AGENCY: Office of the Assistant 

Secretary for Public and Indian 

Housing, HUD. 

ACTION: Final rule. 

SUMMARY: This rule amends HUD’s 

regulations covering rental housing 

assistance for the Native Hawaiian 

Housing Block Grant (NHHBG) program, 

consistent with the Native American 

Housing Assistance and SelfDetermination Act of 1996 (NAHASDA). 

The amendments clarify and improve 

consistency with NAHASDA’s statutory 

requirements and HUD’s Indian 

Housing Block Grant (IHBG) program 

regulations. This rule would also help to 

make affordable housing opportunities, 

in the form of NHHBG-assisted rental 

housing, more available to eligible 

Native Hawaiian families. 

DATES: Effective March 13, 2024. 

FOR FURTHER INFORMATION CONTACT: 

Claudine Allen, Lead Native Hawaiian 

Program Specialist, Office of Native 

American Programs, HUD Honolulu 

Field Office, 1003 Bishop Street, Suite 

2100, Honolulu, HI 96813; telephone 

number 808–457–4674 (this is not a tollfree number). HUD welcomes and is 

prepared to receive calls from 

individuals who are deaf or hard of 

hearing, as well as from individuals 

with speech and communication 

disabilities. To learn more about how to 

make an accessible telephone call, 

please visit https://www.fcc.gov/ 

consumers/guides/telecommunicationsrelay-service-trs. 

SUPPLEMENTARY INFORMATION: 

I. Background 

Statutory Authority for the Native 

Hawaiian Housing Block Grant program 

Section 513 of the Hawaiian 

Homelands Homeownership Act of 2000 

(HHH Act),1 Public Law 106–569, 

amended the Native American Housing 

Assistance and Self-Determination Act 

of 1996 (25 U.S.C. 4101 et seq.) 

(NAHASDA) by adding to it a new 

‘‘Title VIII—Housing Assistance for 

Native Hawaiians.’’ Title VIII of 

NAHASDA established the Native 

Hawaiian Housing Block Grant 

(NHHBG) program to provide block 

grant assistance for affordable housing 

for eligible Native Hawaiians, including 

rental assistance.2

The NHHBG program must primarily 

benefit low-income Native Hawaiian 

families who are eligible to reside on the 

Hawaiian Home Lands. 25 U.S.C. 

4222(a); 25 U.S.C. 4228(a)(2)(A). These 

families experience more significant 

housing challenges compared to Native 

Hawaiian households overall, including 

other Hawaii residents and Native 

Hawaiians already residing on the 

Hawaiian Home Lands. 

Interim Rule 

On June 13, 2002, HUD published an 

interim rule (‘‘interim rule’’) adding 

new regulations at 24 CFR part 1006 to 

implement the NHHBG program. 67 FR 

40773. HUD modeled the NHHBG 

regulations after the Indian Housing 

Block Grant (IHBG) regulations 

implemented at 24 CFR part 1000 

because NAHASDA authorizes and 

applies overlapping requirements to 

both programs.3


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