Postapproval Manufacturing Changes to

Biosimilar and Interchangeable

Biosimilar Products
Questions and Answers
Guidance for Industry
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.

Comments and suggestions regarding this draft document should be submitted within 60 days of
publication in the Federal Register of the notice announcing the availability of the draft
guidance. Submit electronic comments to https://www.regulations.gov. Submit written
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630
Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the
docket number listed in the notice of availability that publishes in the Federal Register.

For questions regarding this draft document, contact (CDER) Nidhi Pamidimukkala 301-796-
3397 or Nidhi.Pamidimukkala@fda.hhs.gov, or (CBER) Office of Communication, Outreach
and Development, 800-835-4709 or 240-402-8010.

U.S. Department of Health and Human Services

Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)

July 2024
Biosimilars
Postapproval Manufacturing Changes to
Biosimilar and Interchangeable
Biosimilar Products
Questions and Answers
Guidance for Industry
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: druginfo@fda.hhs.gov
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
and/or
Office of Communication, Outreach and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 71, Room 3128
Silver Spring, MD 20993-0002
Phone: 800-835-4709 or 240-402-8010
Email: ocod@fda.hhs.gov
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances

U.S. Department of Health and Human Services

Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)

July 2024
Biosimilars
 Contains Nonbinding Recommendations
Draft — Not for Implementation
TABLE OF CONTENTS

I. INTRODUCTION............................................................................................................. 4
II. BACKGROUND ............................................................................................................... 5
A. Section 351 of the PHS Act ............................................................................................................ 5
B. Q&A Guidance Format ................................................................................................................. 6
III. QUESTIONS AND ANSWERS ....................................................................................... 6
A. Recommendations for Reporting Categories .............................................................................. 6
B. Recommendations for Product Quality Data .............................................................................. 9
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1 Postapproval Manufacturing Changes to Biosimilar and

2 Interchangeable Biosimilar Products
3 Questions and Answers
4 Guidance for Industry 1 0F

5
6
7 This draft guidance, when finalized, will represent the current thinking of the Food and Drug
8 Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not
9 binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the
10 applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible
11 for this guidance as listed on the title page.
12
13
14
15
16 I. INTRODUCTION
17
18 This guidance provides answers to commonly asked questions from applicants and other
19 interested parties (collectively referred to as applicants throughout this guidance) regarding
20 postapproval manufacturing changes (referred to as manufacturing changes throughout this
21 guidance) made to licensed biosimilars and licensed interchangeable biosimilars. 2 This 1F

22 question-and-answer (Q&A) guidance is intended to inform prospective and current applicants of

23 the nature and type of information that applicants should provide in support of manufacturing
24 changes to licensed biosimilars and licensed interchangeable biosimilars in different reporting
25 categories.
26
27 Under § 601.12 (21 CFR 601.12), applicants must inform FDA about each change in the product,
28 production process, quality controls, equipment, facilities, or responsible personnel, established
29 in the approved biologics license application (BLA). Before distributing a product made using a
30 change, an applicant must assess the effects of the change and demonstrate through appropriate
31 validation and/or other clinical and/or nonclinical laboratory studies the lack of adverse effect of
32 the change on the identity, strength, quality, purity, or potency of the product (i.e., product

1
This guidance has been prepared by the Office of Pharmaceutical Quality in the Center for Drug Evaluation and
Research in consultation with the Center for Biologics Evaluation and Research at the Food and Drug
Administration.
2
In this guidance, the following terms are used to describe biological products licensed under section 351(k) of the
Public Health Service Act (PHS Act) (42 U.S.C. 262(k)): (1) biosimilar or biosimilar product refers to a product
that FDA has determined to be biosimilar to an FDA-licensed biological reference product (see section 351(i)(2) (42
U.S.C. 262(i)(2)) and (k)(2) of the PHS Act); and (2) interchangeable biosimilar, interchangeable biosimilar
product, or interchangeable product refers to a biosimilar product that FDA has also determined to be
interchangeable with the reference product (see section 351(i)(3) and (k)(4) of the PHS Act).

4
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33 quality) as these factors may relate to the safety or effectiveness of the product. 3,4 In addition,
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34 applicants are required to inform FDA about each change in the labeling established in the
35 approved BLA.5
36
37 This guidance applies to manufacturing changes made to products licensed under section 351(k)
38 of the Public Health Service Act (PHS Act) (42 U.S.C. 262(k)) determined to be biosimilar to or
39 interchangeable with an FDA-licensed biological reference product.6
40
41 In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
42 Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
43 as recommendations, unless specific regulatory or statutory requirements are cited. The use of
44 the word should in Agency guidances means that something is suggested or recommended, but
45 not required.
46
47
48 II. BACKGROUND
49
50 A. Section 351 of the PHS Act
51
52 Section 351 of the PHS Act provides an abbreviated licensure pathway for biological products
53 shown to be biosimilar to or interchangeable with an FDA-licensed biological reference product.
54 Section 351(k) of the PHS Act sets forth the requirements for licensure of such biosimilar
55 products and interchangeable biosimilar products.
56
57 Section 351(i)(2) of the PHS Act defines biosimilarity to mean “that the biological product is
58 highly similar to the reference product notwithstanding minor differences in clinically inactive
59 components” and that “there are no clinically meaningful differences between the biological
60 product and the reference product in terms of the safety, purity, and potency of the product.” To
61 meet the standard for interchangeability, the applicant must: (1) demonstrate biosimilarity to the
62 reference product; (2) demonstrate that the biological product “can be expected to produce the
63 same clinical result as the reference product in any given patient”; and (3) if the biological
64 product “is administered more than once to an individual, the risk in terms of safety or
65 diminished efficacy of alternating or switching between the use of the biological product and the
66 reference product is not greater than the risk of using the reference product without such
67 alternation or switch.”7 Interchangeable products may be substituted for the reference product at

3
See § 601.12(a) through (d). In this guidance, product quality refers to the identity, strength, quality, purity, and
potency of a product as these factors may relate to the safety or effectiveness of the product.
4
Manufacturers of biosimilars and interchangeable biosimilars must also comply with other statutory and regulatory
requirements, including the current good manufacturing practice requirements described in section 501(a)(2)(B) of
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 351(a)(2)(B)) and regulations in 21 CFR parts 4, 210, 211,
600 through 680, and 820, as applicable to the specific product.
5
See § 601.12(a) and (f).
6
Reference product means the single biological product licensed under section 351(a) of the PHS Act against which
a biological product is evaluated in a 351(k) application (section 351(i)(4) of the PHS Act).
7
See section 351(k)(4) of the PHS Act.

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68 the pharmacy level without the intervention of the prescribing health care provider, subject to
69 State law.8
70
71 B. Q&A Guidance Format
72
73 FDA has been using the Q&A guidance format to describe FDA’s thinking and to update certain
74 information and recommendations relevant to the development of biosimilar and interchangeable
75 biosimilar products. This guidance discusses recommendations regarding manufacturing
76 changes to licensed biosimilar and licensed interchangeable biosimilar products. 9 5F

77
78 FDA is publishing this guidance to fulfill the commitment made as part of the negotiations
79 relating to reauthorization of the Biosimilar User Fee Act (BsUFA). 10 FDA is committed to a
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80 focused effort to further advance the development of safe and effective biosimilar and
81 interchangeable biosimilar products through the development of foundational guidances for these
82 products. 11
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83
84
85 III. QUESTIONS AND ANSWERS
86
87 Q1. What is the nature and type of information, for different reporting categories, that
88 FDA recommends to support postapproval manufacturing changes to licensed
89 biosimilar and licensed interchangeable biosimilar products?
90
91 A. Recommendations for Reporting Categories
92
93 Similar to manufacturing changes to biological products licensed under section 351(a) of the
94 PHS Act, applicants must report manufacturing changes to a biosimilar or an interchangeable
95 biosimilar licensed under section 351(k) of the PHS Act according to the requirements in
96 § 601.12. Applicants must evaluate the potential impact of the proposed changes on the identity,
97 strength, quality, purity, or potency of the product as they may relate to the safety and
98 effectiveness of a licensed biosimilar or a licensed interchangeable biosimilar and report

8
See section 351(i)(3) of the PHS Act.
9
Postapproval manufacturing changes to biosimilars is the subject of Q&A I.20 in the guidance for industry
Questions and Answers on Biosimilar Development and the BPCI Act (September 2021). FDA intends to withdraw
Q&A I.20 from that guidance when this guidance becomes final. We update guidances periodically. For the most
recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents.
10
The Biosimilar User Fee Act of 2012 (BsUFA I) added sections 744G and 744H to the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 379j–51 and 379j–52), authorizing FDA to collect user fees for a 5-year period from
persons who develop biosimilar and interchangeable biosimilar products. BsUFA was reauthorized for a 5-year
period for a third time on September 30, 2022 (Biosimilar User Fee Amendments of 2022 (BsUFA III)), Title IV–
Fees Relating to Biosimilar Biological Products, Public Law 112-144) for fiscal years 2023 through 2027.
11
See Section II.D.2.d. of Biosimilar Biological Product Reauthorization Performance Goals and Procedures Fiscal
Years 2023 Through 2027 (BsUFA III commitment letter) available at
https://www.fda.gov/media/152279/download.

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99 manufacturing changes to FDA using the appropriate reporting category, as described in
100 § 601.12. 12 8F

101
102 For recommendations regarding postapproval reporting categories for commonly reported
103 manufacturing changes for specified biological products13 (a category that includes currently
104 licensed biosimilar or interchangeable biosimilar products), applicants should refer to the
105 guidances for industry Changes to an Approved Application for Specified Biotechnology and
106 Specified Synthetic Biological Products (July 1997) and CMC Postapproval Manufacturing
107 Changes for Specified Biological Products To Be Documented in Annual Reports (December
108 2021). Applicants can also refer to the International Council for Harmonisation (ICH) guidance
109 for industry Q12 Technical and Regulatory Considerations for Pharmaceutical Product
110 Lifecycle Management (May 2021)14 for a framework to facilitate the management of
111 postapproval manufacturing changes for drug substances and drug products, including biological
112 products. Additionally, as applicable, applicants can consider the recommendations in the
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113 guidance for industry Chemistry, Manufacturing, and Controls Changes to an Approved
114 Application: Certain Biological Products (June 2021). 15 10F

115
116 As described in § 601.12, the reporting categories for manufacturing changes to an approved
117 application are provided below:
118
119 • Prior Approval Supplement (PAS): An applicant must submit a PAS for major
120 changes and must obtain approval of the PAS from FDA before distribution of the
121 product manufactured using the change(s). 16 A major change is one that has a substantial
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122 potential to have an adverse effect on the identity, strength, quality, purity, or potency of
123 the product as these factors may relate to the safety or effectiveness of the product.
124 Applicants can submit a comparability protocol in a PAS to propose specified types of
12

125 postapproval chemistry, manufacturing, and controls (CMC) change(s), which, if

126 approved, may justify a reduced reporting category for the particular change because the
127 use of the protocol for that type of change reduces the potential risk of an adverse
128 effect. 17 13F

129

12
See § 601.12(a)(1), (2), and (b) through (e).
13
Specified biological products are biological products, as defined in 21 CFR 600.3(h), that fall under one of the
categories specified in § 601.2(a) (21 CFR 601.2(a)).
14
See also the draft guidance for industry ICH Q12: Implementation Considerations for FDA-Regulated Products
(May 2021). When final, this guidance will represent the FDA’s current thinking on this topic.
15
Products licensed under a 351(k) application (i.e., licensed biosimilars and licensed interchangeable biosimilars)
are outside the scope of the guidance for industry Chemistry, Manufacturing and Controls Changes to an Approved
Application: Certain Biological Products (June 2021). However, the scientific principles regarding reporting
categories and recommendations described in that guidance might also help inform which reporting categories are
appropriate for manufacturing changes to licensed biosimilars and licensed interchangeable biosimilars.
16
See § 601.12(b).
17
See § 601.12(e). In this guidance, comparability protocol is synonymous with postapproval change management
protocol in the ICH guidance for industry Q12 Technical and Regulatory Considerations for Pharmaceutical
Product Lifecycle Management (May 2021). For recommendations pertaining to the submission of comparability
protocols for postapproval CMC changes, see the guidance for industry Comparability Protocols for Postapproval
Changes to the Chemistry, Manufacturing, and Controls Information in an NDA, ANDA, or BLA (October 2022).

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130 • Changes Being Effected in 30 Days (CBE-30)/Changes Being Effected (CBE-0)

131 Supplements: An applicant must request approval for moderate changes that require a
132 CBE-30 supplement to FDA, and the supplement must be received by FDA at least 30
133 days before distribution of the product made using the change. 18 A moderate change is
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134 one that has a moderate potential to have an adverse effect on the identity, strength,
135 quality, purity, or potency of the product as these factors may relate to the safety or
136 effectiveness of the product. If FDA informs the applicant within 30 days after receipt of
137 the supplement that the change requires approval prior to distribution or any of the
138 information required to be included in the supplement is missing, the applicant must not
139 distribute the product made using the change until FDA determines that compliance with
140 § 601.12 is achieved.19 In certain circumstances, FDA may determine that, based on
141 FDA’s experience with a particular type of change, the supplement for such a change is
142 usually complete and provides the proper information, and there are particular assurances
143 that the proposed change has been appropriately submitted, such as when the change has
144 been validated in accordance with a previously approved comparability protocol. In
145 these circumstances, FDA may determine that the product made using the change may be
146 distributed at the time of receipt of the supplement (CBE-0 supplement) by FDA.20,21
147
148 • Annual Report: An applicant must document minor changes in an annual report. 22 A 16F

149 minor change is one that has a minimal potential to have an adverse effect on the identity,
150 strength, quality, purity, or potency of the product as these factors may relate to the safety
151 or effectiveness of the product.
152
153 When reporting a manufacturing change to a licensed biosimilar or a licensed interchangeable
154 biosimilar to FDA, the applicant should clearly identify the reporting category under which the
155 change is being reported. If the manufacturing change requires a supplement submission (i.e.,
156 PAS, CBE-30, or CBE-0), the applicant should specify the supplement as a CMC supplement
157 and identify the reporting category in the submission. Additionally, the cover letter must include
158 a complete list of all the changes contained in the supplement. 23 For manufacturing changes that
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18
See § 601.12(c).
19
See § 601.12(c)(4).
20
See § 601.12(c)(5). Changes that, in FDA’s experience, have been submitted properly with the appropriate
information and could be implemented under § 601.12(c)(5) at the time of receipt of the supplement by FDA
without a previously approved comparability protocol are described in the guidances for industry Changes to an
Approved Application for Specified Biotechnology and Specified Synthetic Biological Products (July 1997) and
Chemistry, Manufacturing, and Controls Changes to an Approved Application: Certain Biological Products (June
2021), as applicable.
21
Where the applicant has an approved comparability protocol under § 601.12(e) for the use of a CBE-0 supplement
and presents evidence in the CBE-0 supplement that the change has been validated in accordance with the approved
protocol, the product made using the change may be distributed immediately upon receipt of the supplement by
FDA.
22
See § 601.12(d).
23
See § 601.12(a)(5).

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159 impact labeling, the applicant should include the corresponding labeling changes with the CMC
160 supplement. 24 19F

161
162 B. Recommendations for Product Quality Data
163
164 An applicant who intends to make a manufacturing change to a licensed biosimilar or a licensed
165 interchangeable biosimilar should follow the principles outlined in the ICH guidance for industry
166 Q5E Comparability of Biotechnological/Biological Products Subject to Changes in Their
167 Manufacturing Process (June 2005). When changes are made to the manufacturing process, the
168 applicant should evaluate the comparability of the biosimilar or interchangeable biosimilar
169 product before and after the manufacturing change (comparability exercise). The extent of data
170 and information necessary to establish comparability should be commensurate with the type of
171 manufacturing change and its overall potential to adversely affect the quality, safety, and
172 efficacy of the product. The design of the comparability exercise, including the quality
173 attributes25 to be compared and analytical methods to be used, should address the risks of the
174 manufacturing change(s) and should provide sufficient data and information to demonstrate the
175 comparability of the biosimilar or interchangeable biosimilar product premanufacturing and
176 postmanufacturing change. In addition to comparability data, other product quality data and
177 information, such as process validation data, should be included in the supplement, as
178 applicable. 2620F

179
180 Data and information submitted in support of manufacturing changes should demonstrate that
181 quality attributes remain comparable among prechange and postchange products and should
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182 demonstrate that consistency in the quality, safety, and efficacy of the postchange product is
183 predictable. The postchange biosimilar or interchangeable biosimilar product should be
184 evaluated at the process step most appropriate to detect a change in the quality attributes. This
185 may entail evaluating the product at multiple stages of manufacture. For instance, in some cases,
186 it might be appropriate to compare prechange and postchange data on intermediates most
187 affected by the manufacturing change in addition to the drug substance and the drug product to
188 support the determination of comparability.
189
24
See § 601.12(a) and (f) for the requirements pertaining to reporting labeling changes to FDA. If applicants have
questions about the reporting classification recommendations for submissions that include both manufacturing and
labeling changes, FDA advises applicants to consult with the appropriate FDA review division. For
recommendations on labeling for biosimilars and interchangeable biosimilars, see the draft guidance for industry
Labeling for Biosimilar and Interchangeable Biosimilar Products (September 2023). When final, this guidance will
represent the FDA’s current thinking on this topic. For recommendations on classification categories A through F
for certain supplement submissions, as established in BsUFA III, see the draft guidance for industry Classification
Categories for Certain Supplements Under BsUFA III (August 2023). When final, this guidance will represent the
FDA’s current thinking on this topic.
25
The ICH guidance for industry Q5E Comparability of Biotechnological/Biological Products Subject to Changes
in Their Manufacturing Process (June 2005) defines quality attribute as “[a] molecular or product characteristic that
is selected for its ability to help indicate the quality of the product. Collectively, the quality attributes define
identity, purity, potency, and stability of the product, and safety with respect to adventitious agents. . . .” (See page
13 of ICH Q5E.)
26
For general principles and approaches that FDA considers appropriate elements of process validation for the
manufacture of drugs, including biological products, see the guidance for industry Process Validation: General
Principles and Practices (January 2011).

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190 The goal of the comparability exercise is to ensure that manufacturing process changes do not
191 lead to an adverse impact on the quality, safety, and efficacy of the licensed biosimilar or the
192 licensed interchangeable biosimilar. The comparability exercise should include a side-by-side
193 analytical comparison of a sufficient number of lots of prechange and postchange material,
194 including stability data, as appropriate. As described in ICH Q5E, for certain manufacturing
195 process changes, even slight modifications of the production and procedures might cause
196 changes in the stability of the postchange product, and appropriate studies should be considered
197 to confirm that suitable storage conditions and controls are selected. Comparative stability
198 studies conducted under relevant storage conditions (e.g., accelerated testing, stress testing)
199 among prechange and postchange materials can detect subtle differences that may not be readily
200 detectable by characterization studies and may, therefore, provide greater insight into differences
201 between the prechange and the postchange product. These comparative stability studies are
202 especially important when the proposed manufacturing changes can alter protein structure or
203 purity and impurity profiles. 27 The selection of the conditions for the stability studies should be
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204 justified based on relevance to the product and risks associated with the manufacturing change.
205 A comparison of analytical data from the postchange material to the historical analytical data
206 (i.e., prechange material) may be sufficient to support a manufacturing change if the quality
207 attributes of the prechange and the postchange material are comparable. The historical analytical
208 data should include results from biosimilar or interchangeable biosimilar lots used in the
209 comparative analytical assessment (CAA), 28 biosimilar or interchangeable biosimilar lots used in
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210 the clinical development of the biosimilar or the interchangeable biosimilar, lots used to support
211 process consistency, and commercial materials manufactured after approval, as applicable. 24F

212 When a subset of all available historical data is selected for the comparison, a scientific
213 justification should be provided. If an analytical assay has changed since licensure of the
214 biosimilar or the interchangeable biosimilar, adequate assay bridging data on assay performance
215 should be provided.
216
217 Q2. What reference materials should applicants include in the comparability exercise?
218
219 In general, an applicant should include a well-qualified, in-house reference material in the 28F

220 comparability exercise to evaluate whether a postchange biosimilar or interchangeable biosimilar

221 remains comparable to the prechange product. The in-house reference material serves as an
222 important calibration point for the evaluation(s) conducted in a comparability exercise.29
223
224 If applicants submit sufficient data to enable an informed prediction that no adverse impact on
225 the quality, safety, or efficacy of the postchange product is expected, FDA may consider the data

27
See page 8 of ICH Q5E. For further information, see the guidances for industry Q5C Quality of Biotechnological
Products: Stability Testing of Biotechnological/Biological Products (July 1996) and Q1A(R2) Stability Testing of
New Drug Substances and Products (November 2003).
28
For recommendations on the design and evaluation of comparative analytical studies, see the draft guidance for
industry Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality-
Related Considerations (May 2019). When final, this guidance will represent the FDA’s current thinking on this
topic.
29
In this guidance, in-house reference material refers to the appropriately characterized material prepared in-house
by the manufacturer from a representative lot(s) for the purpose of biological assay and physicochemical testing of
subsequent lots. For further information on in-house reference materials, see the ICH guidance for industry Q6B
Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products (August 1999).

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226 adequate to support the change without the inclusion of reference materials beyond the in-house
227 reference material in the comparability exercise. However, demonstration of comparability to
228 support manufacturing change(s) should provide adequate assurance that a postchange product
229 remains biosimilar to or interchangeable with the reference product. When differences in the
230 quality attributes are observed between the prechange and the postchange material, comparison
231 to the data from the reference product submitted to support licensure should be considered to
232 help assess the potential impact and acceptability of these differences.
233
234 Q3. How should proposals to introduce a licensed biosimilar and/or licensed
235 interchangeable biosimilar product into a multiproduct manufacturing area or a
236 multiproduct contract manufacturing facility be reported?
237
238 An applicant proposing to introduce its licensed biosimilar or licensed interchangeable biosimilar
239 into a multiproduct manufacturing area or a multiproduct contract manufacturing facility 30 25F

240 should refer to the guidances for industry Changes to an Approved Application for Specified
241 Biotechnology and Specified Synthetic Biological Products (July 1997), CMC Postapproval
242 Manufacturing Changes for Specified Biological Products To Be Documented in Annual Reports
243 (December 2021), and Chemistry, Manufacturing, and Controls Changes to an Approved
244 Application: Certain Biological Products (June 2021), as applicable, for recommendations on
245 the appropriate postapproval reporting category to report such changes. The reporting category
246 should be determined based on risks associated with product introduction(s) to the quality
247 attributes of the licensed biosimilar or the licensed interchangeable biosimilar.
248
249 Risks associated with introducing a licensed biosimilar or a licensed interchangeable biosimilar
250 into a multiproduct manufacturing area or a multiproduct contract manufacturing facility depend
251 on the type of product being introduced and the potential addition of further control measures to
252 ensure that the product meets its intended quality characteristics, including purity. Identity
253 testing is one tool used to detect and control such risks. 31 26F

254
255 The introduction of a licensed biosimilar or a licensed interchangeable biosimilar into a
256 multiproduct manufacturing area or a multiproduct contract manufacturing facility — where the
257 reference product is manufactured and/or another applicant’s biosimilar or interchangeable
258 biosimilar product(s) referencing the same reference product is manufactured — poses risks such
259 as cross-contamination or product mix-ups. In these cases, a respective single identity test for
260 each product might not always be able to distinguish the different products. Therefore, in

30
As recognized in 21 CFR 200.10(b) and § 211.22(a) (21 CFR 211.22(a)), FDA is aware that some drug
manufacturing activities may be performed at contract facilities. When a drug manufacturer uses a contract facility,
the drug manufacturer’s quality control unit is responsible for approving or rejecting drug products manufactured,
processed, packed, or held under contract by another company (§ 211.22(a)). Additionally, FDA’s biological
product regulations define manufacturer in 21 CFR 600.3(t) to include an applicant for a licensed product where the
applicant assumes responsibility for compliance with the applicable product and facility standards. See 21 CFR
210.3(b)(15) for the definition of quality control unit, § 211.22 for the requirements and responsibilities of the
quality control unit, and 21 CFR 600.10 through 600.15 for establishment standards for biological product facilities.
For further information, see also the guidances for industry Cooperative Manufacturing Arrangements for Licensed
Biologics (November 2008) and Contract Manufacturing Arrangements for Drugs: Quality Agreements (November
2016).
31
See § 610.14 (21 CFR 610.14).

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261 addition to identity tests for each product, current good manufacturing practice requirements,
262 including applicable manufacturing and procedural controls (e.g., separate manufacturing areas,
263 control of personnel, process, and material flow, and control of materials, as applicable) to
264 prevent cross-contamination or mix-ups, must be followed. 32 Such manufacturing and
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265 procedural controls should be described in sufficient detail to enable FDA to evaluate whether
266 the proposed controls are adequate to address such risks.
267
268 Q4. What is the nature and type of CMC information that FDA recommends to support
269 the approval of a supplement for a dosage form or a strength that has not previously
270 been licensed under the 351(k) BLA?
271
272 When submitting a supplement to a BLA submitted under section 351(k) of the PHS Act (a
273 351(k) BLA) that proposes a new dosage form or a new strength (i.e., a dosage form or strength
274 not previously licensed in the 351(k) BLA), applicants must include information demonstrating,
275 among other things, that the dosage form and the strength of the proposed biosimilar or the
276 proposed interchangeable biosimilar product “are the same as those of the reference
277 product.” 33, 34 In addition, to support approval of a supplement to a 351(k) BLA proposing a
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278 new dosage form or a new strength, the supplement must include information demonstrating that
279 the proposed biosimilar or the proposed interchangeable biosimilar is “highly similar to the
280 reference product notwithstanding minor differences in clinically inactive components” and
281 “there are no clinically meaningful differences between the biological product and the reference
282 product in terms of the safety, purity, and potency of the product.” 35 Further, to support approval
31 F

283 of a supplement for a new dosage form or a new strength as an interchangeable biosimilar
284 product, information submitted in the supplement needs to be sufficient to show that the
285 proposed product meets the interchangeability standards described in section 351(k)(4) of the
286 PHS Act.36 The proposal of a new dosage form or a new strength that has not previously been
287 licensed under the 351(k) BLA is generally considered a major change; therefore, the appropriate
288 reporting category for these changes would generally be a PAS.
289
290 A supplement proposing a new dosage form or a new strength generally should include the
291 following CMC-related information: (1) adequate comparability data between a licensed
292 biosimilar or interchangeable biosimilar (i.e., prechange product) and the proposed biosimilar or
293 interchangeable biosimilar with the new dosage form or strength (i.e., postchange product), (2)
294 CAA data, and (3) manufacturing data (e.g., process validation) to support the proposed
295 postchange product. The extent of the comparability data and the CAA data should be justified
296 based on a risk assessment of the differences between the prechange product and the postchange
297 product. In some cases, additional data (such as pharmacokinetic studies) should be submitted to

32
See, e.g., 21 CFR 211.42, 211.80, 211.100 and §§ 601.2(d) and 610.14.
33
See section 351(k)(2)(A)(i)(IV) of the PHS Act.
34
As noted in Q&A I.21 of the guidance for industry Questions and Answers on Biosimilar Development and the
BPCI Act, “an applicant may not seek approval, in a 351(k) application or a supplement to an approved 351(k)
application, for a route of administration, a dosage form, or a strength that is different from that of the reference
product.”
35
See section 351(k)(3) and (i)(2) of the PHS Act.
36
See section 351(k)(3) and (i)(3) of the PHS Act.

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 Contains Nonbinding Recommendations
Draft — Not for Implementation
298 support approval of the supplement for the proposed dosage form or strength.37 It may be
299 considered reasonable for the design of the CAA studies used to support the proposed dosage
300 form or strength to leverage the CAA data previously submitted in the 351(k), without additional
301 CAA studies comparing the proposed new dosage form or strength to its reference product.
302 However, applicants should assess whether additional CAA studies with the new dosage form or
303 the new strength are appropriate to address the potential impact of the differences in the dosage
304 form or strength on product quality. Applicants should also consider how the proposed product
305 would be used (e.g., whether the dosage form or strength is indication- and/or population-
306 specific for the reference product).
307
308 Consider the following illustrative examples to help applicants determine when leveraging the
309 CAA data previously submitted in the 351(k) BLA may be appropriate. The provided examples
310 presume that the same drug substance is used to manufacture the prechange and postchange
311 products.
312
313 • The applicant submits a supplement proposing a new strength that has the same route of
314 administration, dosage form, and excipients, and the same patient population and
315 indication as a biosimilar or an interchangeable biosimilar product licensed under the
316 351(k) BLA. In this case, leveraging the CAA previously submitted in the 351(k) BLA
317 along with a risk-based comparability exercise between the prechange strength(s) and the
318 proposed postchange strength may be reasonable.
319
320 • The applicant submits a supplement proposing a new dosage form and a new strength
321 intended for a different patient population or indication than the biosimilar or
322 interchangeable biosimilar product(s) licensed under the 351(k) BLA. In this case,
323 although the CAA data previously submitted in the 351(k) BLA may be leveraged, the
324 applicant should also include a risk-based targeted CAA between the proposed product
325 with the new dosage form and strength and its reference product and include a risk-based
326 comparability exercise between the prechange and postchange products.
327
328 In both cases, in addition to the comparability exercise and potentially new CAA data, the
329 applicant should include all relevant manufacturing information for the proposed strength or
330 dosage form in the supplement, including process validation data. As with other changes
331 requiring CMC data, the extent of product quality data and information that should be submitted
332 would be dependent on the proposed change.
333
334 Various additional scenarios are possible, and the data and information appropriate to support
335 each unique scenario may be different. FDA recommends that applicants discuss 38 with the 32F

336 appropriate FDA review division the adequacy of the analytical and manufacturing data that
337 should be provided to support approval of a supplement for a dosage form or a strength that has
338 not previously been licensed under the 351(k) BLA before submitting the supplement.

37
This guidance does not address the circumstances under which such additional data should be submitted or
provide recommendations on the nature and type of information (other than CMC information) that should be
submitted in those circumstances.
38
See the draft guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants of BsUFA
Products (August 2023). When final, this guidance will represent the FDA’s current thinking on this topic.

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