New and Revised Draft Q&As on 
Biosimilar Development and the BPCI 
Act (Revision 3)  
 
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DRAFT GUIDANCE 
 
 
This guidance document is being distributed for comment purposes only.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 as 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 FDA-2011-
D-0611. 
 
For questions regarding this draft document, contact (CDER) Sandra Benton, 301-796-1042, 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) 
 
September 2021 
Biosimilars 
 
Revision 3 
 
   
New and Revised Draft Q&As on 
Biosimilar Development and the BPCI 
Act (Revision 3)   
 
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) 
 
 
 
September 2021 
Biosimilars 
 
Revision 3 
 
  Contains Nonbinding Recommendations 
DraftNot for Implementation 
TABLE OF CONTENTS 
 
 
 
INTRODUCTION......................................................................................................................... 1 
BACKGROUND ........................................................................................................................... 3 
QUESTIONS AND ANSWERS ................................................................................................... 4 
I.  BIOSIMILARITY OR INTERCHANGEABILITY ................................................................... 4 
Q.I.12.  How can an applicant demonstrate that its proposed injectable biosimilar product or 
proposed injectable interchangeable product has the same strength as the reference product? 4 
II.  PROVISIONS RELATED TO REQUIREMENTS TO SUBMIT A BLA FOR A 
BIOLOGICAL PRODUCT ............................................................................................................. 5 
III. EXCLUSIVITY .............................................................................................................................. 5 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  New and Revised Draft Q&As on Biosimilar Development and the 
2  BPCI Act (Revision 3)  
3  Guidance for Industry1 
4   
5   
6  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
7  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
8  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
9  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
10  for this guidance as listed on the title page. 
11   
12   
13   
14  INTRODUCTION 
15   
16  This guidance document provides answers to common questions from prospective applicants and 
17  other interested parties regarding the Biologics Price Competition and Innovation Act of 2009 
18  (BPCI Act).  The question and answer (Q&A) format is intended to inform prospective 
19  applicants and facilitate the development of proposed biosimilar products and proposed 
20  interchangeable products,2 as well as describe FDAs interpretation of certain statutory 
21  requirements added by the BPCI Act. 
22   
23  The BPCI Act created an abbreviated licensure pathway in section 351(k) of the Public Health 
24  Service Act (PHS Act) (42 U.S.C. 262(k)) for biological products shown to be biosimilar to, or 
25  interchangeable with, an FDA-licensed biological reference product (see sections 7001 through 
26  7003 of the Patient Protection and Affordable Care Act (Public Law 111148) (ACA)).  FDA 
27  believes that guidance for industry that provides answers to commonly asked questions regarding 
28  FDAs interpretation of the BPCI Act will enhance transparency and facilitate the development 
29  and approval of biosimilar and interchangeable products.  In addition, these Q&As respond to 
30  questions the Agency has received from prospective applicants regarding the submission of 
 
1 This draft guidance has been prepared by the Center for Drug Evaluation and Research (CDER) and the Center for 
Biologics Evaluation and Research (CBER) at the Food and Drug Administration (FDA or the Agency).  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.  You may submit comments on this 
guidance at any time.  Submit comments to Docket No. FDA-2011-D-0611 (available at 
https://www.regulations.gov/docket/FDA-2011-D-0611).  See the instructions in that docket for submitting 
comments. 
2 In this draft guidance, the following terms are used to describe biological products licensed under section 351(k) of 
the Public Health Service Act (PHS Act):  (1) biosimilar or biosimilar product refers to a product that FDA has 
determined to be biosimilar to the reference product (see section 351(i)(2) and (k)(2) of the PHS Act) and (2) 
interchangeable biosimilar 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).  The terms 
proposed biosimilar product and proposed interchangeable product are used to describe a product that is under 
development or is the subject of a pending 351(k) biologics license application.  Biosimilarity, interchangeability, 
and related issues are discussed in more detail in the BACKGROUND section of this guidance. 
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
31  biologics license applications (BLAs) for biosimilar and interchangeable products.  FDA may 
32  provide additional Q&As through draft guidance as appropriate. 
33   
34  This draft guidance document revises the draft guidance for industry New and Revised Draft 
35  Q&As on Biosimilar Development and the BPCI Act (Revision 2) (December 2018) and retains 
36  Q.I.12.  This draft guidance does not include new Q&As or make changes to currently issued 
37  draft or final Q&As.  Additional information about the Q&A format for this draft guidance 
38  document is provided in the Background section.   
39   
40  After FDA has considered any comments on a draft Q&A, the Q&A will be finalized by adding 
41  the Q&A, as a revision, to the final guidance document Questions and Answers on Biosimilar 
42  Development and the BPCI Act (September 2021), as appropriate.  This final guidance document 
43  is part of a series of guidance documents that FDA has developed to facilitate development of 
44  biosimilar and interchangeable products. 
45   
46  The final guidance documents issued to date address a broad range of issues, including: 
47    Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference 
48  Product (December 2016) 
49    Considerations in Demonstrating Interchangeability With a Reference Product (May 
50  2019) 
51    Labeling for Biosimilar Products (July 2018) 
52    Questions and Answers on Biosimilar Development and the BPCI Act (Revision 2) 
53  (September 2021) 
54    Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (April 
55  2015) 
56   
57  In addition, FDA has published draft guidance documents related to the BPCI Act, which, when 
58  finalized, will represent FDAs current thinking.  These draft guidance documents include: 
59    Biosimilarity and Interchangeability:  Additional Draft Q&As on Biosimilar 
60  Development and the BPCI Act (November 2020) 
61    Development of Therapeutic Protein Biosimilars:  Comparative Analytical Assessment 
62  and Other Quality-Related Considerations (May 2019) 
63    Formal Meetings Between the FDA and Sponsors or Applicants of BsUFA Products 
64  (June 2018) 
65    Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the 
66  PHS Act (August 2014) 
67   
68  The contents of this document do not have the force and effect of law and are not meant to bind 
69  the public in any way, unless specifically incorporated into a contract.  This document is 
70  intended only to provide clarity to the public regarding existing requirements under the law.  
71  FDA guidance documents, including this guidance, should be viewed only as recommendations, 
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
72  unless specific regulatory or statutory requirements are cited.  The use of the word should in 
73  Agency guidances means that something is suggested or recommended, but not required.   
74   
75   
76  BACKGROUND 
77   
78  The BPCI Act 
79   
80  The BPCI Act was enacted as part of the ACA on March 23, 2010.  The BPCI Act amended the 
81  PHS Act and other statutes to create an abbreviated licensure pathway for biological products 
82  shown to be biosimilar to, or interchangeable with, an FDA-licensed biological reference product 
83  (see sections 7001 through 7003 of the ACA).  Section 351(k) of the PHS Act, added by the 
84  BPCI Act, sets forth the requirements for the licensure of a proposed biosimilar or proposed 
85  interchangeable product. 
86   
87  Section 351(i) defines biosimilarity to mean that the biological product is highly similar to the 
88  reference product notwithstanding minor differences in clinically inactive components and that 
89  there are no clinically meaningful differences between the biological product and the reference 
90  product in terms of the safety, purity, and potency of the product (see section 351(i)(2) of the 
91  PHS Act). 
92   
93  A BLA submitted under section 351(k) (a 351(k) BLA) must contain, among other things, 
94  information demonstrating that the biological product is biosimilar to a reference product based 
95  upon data derived from analytical studies, animal studies, and a clinical study or studies (see 
96  section 351(k)(2)(A)(i)(I) of the PHS Act), unless FDA has determined that an element described 
97  in section 351(k)(2)(A)(i)(I) is unnecessary (see section 351(k)(2)(A)(ii) of the PHS Act).  To 
98  meet the standard for interchangeability, an applicant must provide sufficient information to 
99  demonstrate biosimilarity to the reference product and also to demonstrate that the biological 
100  product can be expected to produce the same clinical result as the reference product in any given 
101  patient, and if the biological product is administered more than once to an individual, the risk in 
102  terms of safety or diminished efficacy of alternating or switching between the use of the 
103  biological product and the reference product is not greater than the risk of using the reference 
104  product without such alternation or switch (see section 351(k)(4) of the PHS Act).  
105  Interchangeable products may be substituted for the reference product without the intervention of 
106  the prescribing health care provider (see section 351(i)(3) of the PHS Act). 
107   
108  Question-and-Answer Guidance Format 
109   
110  FDA has been using the format of Q&A guidance to describe the Agencys thinking on and 
111  update certain information and recommendations relevant to the development of biosimilar and 
112  interchangeable products.  This draft guidance includes only Q&As that are in draft form.  The 
113  guidance Questions and Answers on Biosimilar Development and the BPCI Act contains all 
114  Q&As that are final.  As FDA issues individual Q&As, they will first be incorporated into a draft 
115  Q&A guidance document.  After FDA has considered any comments on draft Q&As received 
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
116  during the relevant comment period and, as appropriate, incorporated suggested changes to the 
117  Q&As, individual Q&As will be finalized and moved to the final guidance document.   
118   
119  A Q&A that was previously in the final guidance document may be withdrawn and moved to a 
120  draft guidance document if FDA determines that the Q&A should be revised in some respect and 
121  reissued in a revised draft Q&A for comment.  A Q&A also may be withdrawn and removed 
122  from the Q&A guidance documents if, for instance, the issue addressed in the Q&A is addressed 
123  in another FDA guidance document.   
124   
125  FDA will provide the publication date of the current version of each Q&A, and information 
126  about whether the Q&A has been added to or modified in the relevant draft guidance document.  
127  FDA has maintained the original numbering of the guidance Q&As used in the December 2018 
128  final guidance document (Questions and Answers on Biosimilar Development and the BPCI Act), 
129  December 2018 draft guidance document (New and Revised Draft Q&As on Biosimilar 
130  Development and the BPCI Act (Revision 2)), and the November 2020 draft guidance document 
131  (Biosimilarity and Interchangeability:  Additional Draft Q&As on Biosimilar Development and 
132  the BPCI Act).  For ease of reference, a Q&A retains the same number when it moves from a 
133  draft guidance document to the final guidance document and, where appropriate, when a Q&A is 
134  withdrawn from the final guidance document and moved to a draft guidance document. 
135   
136  In this draft guidance document, several asterisks appear where Q&As have already been 
137  withdrawn or moved to the final guidance document.  
138   
139   
140  QUESTIONS AND ANSWERS 
141   
142  I.  BIOSIMILARITY OR INTERCHANGEABILITY 
143   
144  * * * * * 
145  Q.I.12.  How can an applicant demonstrate that its proposed injectable biosimilar 
146  product or proposed injectable interchangeable product has the same 
147  strength as the reference product?  
148  [Draft December 2018] 
149   
150  A.I.12.  Under section 351(k)(2)(A)(i)(IV) of the PHS Act, an applicant must demonstrate 
151  that the strength of the proposed biosimilar product or proposed interchangeable 
152  product is the same as that of the reference product.  Data and information 
153  generated as part of the analytical similarity assessment may inform the 
154  determination that a proposed biosimilar product or proposed interchangeable 
155  product has the same strength as its reference product.  As a scientific matter, 
156  there may be a need to take into account different factors and approaches in 
157  determining the strength of different biological products.  Sponsors should 
158  discuss their proposed approach with FDA and provide an adequate scientific 
159  basis for their approach to demonstrating same strength.  
160   
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
161    In general, a sponsor of a proposed biosimilar product or proposed 
162  interchangeable product with an injection dosage form (e.g., a solution) can 
163  demonstrate that its product has the same strength as the reference product by 
164  demonstrating that both products have the same total content of drug substance (in 
165  mass or units of activity) and the same concentration of drug substance (in mass 
166  or units of activity per unit volume).  In general, for a proposed biosimilar product 
167  or proposed interchangeable product that is a dry solid (e.g., a lyophilized 
168  powder) from which a constituted or reconstituted solution is prepared, a sponsor 
169  can demonstrate that the product has the same strength as the reference product by 
170  demonstrating that both products have the same total content of drug substance (in 
171  mass or units of activity). 
172   
173  Although not a part of demonstrating same strength, if the proposed biosimilar 
174  product or proposed interchangeable product is a dry solid (e.g., a lyophilized 
175  powder) from which a constituted or reconstituted solution is prepared, the 351(k) 
176  application generally should contain information that the concentration of the 
177  proposed biosimilar product or proposed interchangeable product, when 
178  constituted or reconstituted, is the same as that of the reference product, when 
179  constituted or reconstituted.  
180   
181  A sponsor should determine the content of drug substance for both the reference 
182  product and the proposed biosimilar product or proposed interchangeable product 
183  using the same method.  The strength of the proposed product generally should be 
184  expressed using the same units of measure as the reference product.   
185   
186  * * * * * 
187   
188   
189  II.  PROVISIONS RELATED TO REQUIREMENTS TO SUBMIT A BLA FOR A 
190  BIOLOGICAL PRODUCT 
191   
192  There are no draft Q&As for this section. 
193   
194   
195  III.  EXCLUSIVITY 
196   
197  There are no draft Q&As for this section. 
  5