The Deemed To Be a 
License Provision of 
the BPCI Act 
Questions and Answers  
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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) 
 
March 2020 
Procedural 
   
  The Deemed To Be a 
License Provision of 
the BPCI Act 
Questions and Answers 
Guidance for Industry 
 
 
Additional copies are available from: 
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Center for Drug Evaluation and Research 
Food and Drug Administration 
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Email: druginfo@fda.hhs.gov 
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and/or 
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 Food and Drug Administration 
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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) 
 
March 2020 
Procedural  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
I.  INTRODUCTION ...................................................................................................... 1 
II.  BACKGROUND ........................................................................................................ 2 
A.  BPCI Act...................................................................................................................... 2 
B.  Transition Period for Certain Biological Products ........................................................... 3 
III.  QUESTIONS AND ANSWERS ................................................................................. 4 
A.  Identification of Products Subject to the Transition Provision .......................................... 4 
B.  Applications for Biological Products Submitted Under Section 505 of the FD&C Act on or 
Before the Transition Date .................................................................................................... 7 
C.  Statutory and Regulatory Requirements for BLAs .........................................................12 
D.  Transition of Biological Products from the Orange Book to the Purple Book ....................22 
E.  Designation of Proper Name .........................................................................................22 
IV.  COMPLIANCE POLICY FOR REQUIREMENTS RELATED TO LABELING.. 23 
 
  Contains Nonbinding Recommendations 
 
The Deemed To Be a License Provision of the BPCI Act 
Questions and Answers 
Guidance for Industry1 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the 
title page.   
 
 
 
I.  INTRODUCTION 
 
This guidance is intended to provide answers to common questions about FDAs implementation 
of the transition  provision  of the Biologics  Price Competition  and Innovation  Act of 2009 
(BPCI Act) under which an application  for a biological  product approved under section 505 of 
the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355) as of March 23, 2020, 
will be deemed to be a license for the biological  product under section 351 of the Public Health 
Service Act (PHS Act) (42 U.S.C. 262) on March 23, 2020 (the transition date).2  This guidance 
also describes FDAs compliance policy  for the labeling  of biological  products that are the 
subject of deemed biologics  license applications  (BLAs).  This guidance is intended to facilitate 
planning  for the transition date and provide further clarity regarding the Agencys 
implementation  of this statutory provision.    
 
Although the majority  of therapeutic biological  products have been licensed under section 351 of 
the PHS Act, some protein products historically  have been approved under section 505 of the 
FD&C Act.  On March 23, 2010, the BPCI Act was enacted as part of the Patient Protection and 
Affordable Care Act (Public Law 111-148).  The BPCI Act clarified the statutory authority under 
which certain protein products will be regulated by amending the definition  of a biological 
product in section 351(i) of the PHS Act to include a protein (except any chemically 
synthesized polypeptide),  and describing procedures for submission  of a marketing application 
for certain biological  products.  Section 605 of the Further Consolidated  Appropriations  Act, 
2020, further amended the definition  of a biological  product in section 351(i) of the PHS Act 
                                              
1 This guidance has been prepared by the Center for Drug Evaluation and Research (CDER) in cooperation with the 
Center for Biologics Evaluation and Research (CBER) at FDA. 
2 Section 607 of the Further Consolidated Appropriations Act, 2020 (Public Law 116-94), amended section 
7002(e)(4) of the BPCI Act to provide that FDA will continue to review an application for a biological product 
under section 505 of the FD&C Act after March 23, 2020, so long as that application was submitted under section 
505 of the FD&C Act, is filed not later than March 23, 2019, and is not approved as of March 23, 2020.  If such an 
application is approved under section 505 of the FD&C Act before October 1, 2022, it will be deemed to be a license 
for the biological product under section 351 of the PHS Act upon approval (see section 7002(e)(4)(B)(iii) and (vi) of 
the BPCI Act). 
 
  1  Contains Nonbinding Recommendations 
 
to remove the parenthetical (except any chemically  synthesized polypeptide)  from the statutory 
category of protein.3    
 
The BPCI Act requires that a marketing application  for a biological  product (that previously 
could have been submitted under section 505 of the FD&C Act) must be submitted under section 
351 of the PHS Act; this requirement is subject to certain exceptions during a 10-year transition 
period ending on March 23, 2020 (see section 7002(e)(1)-(3) and (e)(5) of the BPCI Act).  On 
March 23, 2020 (i.e., the transition date), an approved application  for a biological  product under 
section 505 of the FD&C Act shall be deemed to be a license for the biological  product under 
section 351 of the PHS Act (see section 7002(e)(4)(A) of the BPCI Act; see also section 
7002(e)(4)(B) of the BPCI Act).4   
 
In general, FDAs guidance documents do not establish legally  enforceable responsibilities.   
Instead, guidances describe the Agencys current thinking  on a topic and should be viewed only 
as recommendations,  unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidances means that something  is suggested or recommended, but 
not required.  
 
 
II.  BACKGROUND 
 
A.  BPCI Act 
 
The BPCI Act amended the PHS Act and other statutes to create an abbreviated licensure 
pathway in section 351(k) of the PHS Act for biological  products shown to be biosimilar  to, or 
interchangeable with, an FDA-licensed biological  reference product (see sections 7001 through 
7003 of the BPCI Act).  The objectives of the BPCI Act are conceptually similar to those of the 
Drug Price Competition  and Patent Term Restoration Act of 1984 (Public Law 98-417) 
(commonly  referred to as the Hatch-Waxman Amendments), which established abbreviated 
pathways for the approval of drug products under section 505(b)(2) and 505(j) of the FD&C Act.  
An abbreviated licensure pathway for biological  products can present challenges given the 
scientific and technical complexities  that may be associated with the generally larger, and 
typically  more complex, structure of biological  products, as well as the processes by which such 
products are manufactured.  Most biological  products are produced in a living  system, such as a 
microorganism  or plant or animal cells, whereas small molecule drugs are typically 
manufactured through chemical synthesis. 
 
Section 351(k) of the PHS Act, added by the BPCI Act, sets forth, among other things, the 
requirements for an application  for a proposed biosimilar  product and an application  or a 
                                              
3 As amended by the BPCI Act and the Further Consolidated Appropriations Act, 2020, a biological product is 
defined, in relevant part, as a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or 
derivative, allergenic product, protein, or analogous product . . . applicable to the prevention, treatment, or cure of a 
disease or condition of human beings (see section 351(i) of the PHS Act).  
 
4 Section 607 of the Further Consolidated Appropriations Act, 2020, redesignated section 7002(e)(4) of the BPCI 
Act as section 7002(e)(4)(A) and added the title In General to the new subparagraph.  Conforming revisions have 
been made throughout this guidance to refer to the new subparagraph. 
  2  Contains Nonbinding Recommendations 
 
supplement for a proposed interchangeable product.  Section 351(i) defines biosimilarity  to 
mean that the biological  product is highly  similar  to the reference product notwithstanding 
minor differences in clinically  inactive components and that there are no clinically  meaningful 
differences between the biological  product and the reference product in terms of the safety, 
purity, and potency of the product (section 351(i)(2) of the PHS Act).  A 351(k) application 
must contain, among other things, information  demonstrating  that the biological  product is 
biosimilar  to a reference product based upon data derived from analytical studies, animal studies, 
and a clinical  study or studies, unless FDA determines, in its discretion,  that certain studies are 
unnecessary in a 351(k) application  (see section 351(k)(2) of the PHS Act).  To meet the 
standard for interchangeability,  an applicant must provide sufficient information  to 
demonstrate biosimilarity,  and also to demonstrate that the biological  product can be expected to 
produce the same clinical  result as the reference product in any given patient and, if the 
biological  product is administered more than once to an individual,  the risk in terms of safety or 
diminished  efficacy of alternating or switching between the use of the biological  product and the 
reference product is not greater than the risk of using the reference product without such 
alternation or switch (see section 351(k)(4) of the PHS Act).  Interchangeable products may be 
substituted for the reference product without the intervention  of the prescribing  health care 
provider (see section 351(i)(3) of the PHS Act). 
 
B.  Transition Period for Certain Biological Products 
 
Section 7002(e) of the BPCI Act provides that a marketing application  for a biological  product 
(that previously  could have been submitted under section 505 of the FD&C Act) must be 
submitted under section 351 of the PHS Act, subject to the following  exception during the 
transition period described below. 
 
An application  for a biological  product may be submitted under section 505 of the FD&C Act 
not later than March 23, 2020, if the biological  product is in a product class5 for which a 
biological  product in such product class was approved under section 505 of the FD&C Act not 
later than March 23, 2010. 
 
However, an application  for a biological  product may not be submitted under section 505 of the 
FD&C Act if there is another biological  product approved under section 351(a) of the PHS Act 
that could be a reference product6 if such application  were submitted under section 351(k) of 
the PHS Act. 
 
                                              
5 FDA has interpreted the statutory term product class for purposes of determining whether an application for a 
biological product may be submitted under section 505 of the FD&C Act during the transition period (see FDAs 
guidance for industry Questions and Answers on Biosimilar Development and the BPCI Act (December 2018) 
(Biosimilars Q&A Guidance), at Q. II.2).  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/regulatory-
information/search-fda-guidance-documents.  
6 The term reference product means the single biological product licensed under section 351(a) of the PHS Act 
against which a biological product is evaluated in an application submitted under section 351(k) (see section 
351(i)(4) of the PHS Act).
 
  3  Contains Nonbinding Recommendations 
 
An approved application  for a biological  product under section 505 of the FD&C Act shall be 
deemed to be a license for a biological  product under section 351 of the PHS Act (a deemed 
BLA) on March 23, 2020 (see section 7002(e)(4)(A) of the BPCI Act; see also section 
7002(e)(4)(B) of the BPCI Act).  For additional  information  about FDAs interpretation of this 
transition  provision,  please refer to FDAs guidance for industry Interpretation of the 
Deemed to be a License Provision of the Biologics Price Competition and Innovation Act of 
2009 (December 2018) (Transition Policy Final Guidance). 
 
 
III.  QUESTIONS AND ANSWERS  
 
A.  Identification of Products Subject to the Transition Provision 
 
Q1.  What products are affected by the transition provision?  How will the holder of an 
approved new drug application (NDA) for a biological product know if it will be 
affected by the transition provision? 
 
The deemed to be a license provision  in section 7002(e)(4)(A) of the BPCI Act (also known as 
the transition provision)  will apply on March 23, 2020, to each approved application  for a 
biological  product under section 505 of the FD&C Act.7  The BPCI Act and Further 
Consolidated  Appropriations  Act, 2020, amended the definition  of a biological  product in 
section 351(i) of the PHS Act to include a protein.   
 
FDA has previously  stated its interpretation  of the statutory term protein in the amended 
statutory definition  of biological  product.8   As explained in FDAs final rule entitled 
 
Definition  of the Term Biological  Product (Biological  Product Definition  Final Rule), FDA 
interprets the term protein to mean any alpha amino acid polymer with a specific defined 
sequence that is greater than 40 amino acids in size.  When two or more amino acid chains in an 
amino acid polymer are associated with each other in a manner that occurs in nature, the size of 
                                              
7 General references in this guidance to applications submitted or approved under section 505 of the FD&C Act 
also may include ANDAs, to the extent applicable.  An ANDA generally must contain information to demonstrate, 
among other things, that the proposed generic drug has the same active ingredient(s), conditions of use, dosage form, 
route of administration, strength, and (with certain permissible differences) labeling as the reference listed drug 
(section 505(j)(2)(A) of the FD&C Act).  Given the complexity of protein molecules and limitations of current 
analytical methods, it may be difficult for manufacturers of proposed protein products to demonstrate that the active 
ingredient in their proposed product is the same as the active ingredient in an already approved product, and thus 
ANDAs are not a focus of this guidance.  There are no currently marketed biological products that were approved 
through the ANDA pathway. 
 
8 See, e.g., 80 FR 24259, April 30, 2015 (announcing the availability of a guidance for industry entitled 
Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation 
Act of 2009, available at www.regulations.gov (Docket No. FDA-2011-D-0611)).  FDA also described its 
interpretation of the term chemically synthesized polypeptide in the statutory definition of biological product as 
amended by the BPCI Act in this guidance and in a proposed rule entitled Definition of the Term Biological 
Product (83 FR 63817, December 12, 2018).  However, this interpretation is no longer necessary to our 
interpretation of the statutory term biological product, given that the parenthetical exception for any chemically 
synthesized polypeptide subsequently was removed from the category of protein (see section 605 of the Further 
Consolidated Appropriations Act, 2020).
 
 
  4  Contains Nonbinding Recommendations 
 
the amino acid polymer for purposes of this interpretation will be based on the total number of 
amino acids in those chains, and will not be limited  to the number of amino acids in a contiguous 
sequence.9  FDA interprets the statutory definition  of biological  product such that any amino 
acid polymer composed of 40 or fewer amino acids (i.e., a peptide) is outside the scope of the 
term protein.  A peptide is not a biological  product and will continue to be regulated as a 
drug under the FD&C Act unless the peptide otherwise meets the statutory definition  of a 
biological  product (e.g., a peptide vaccine) (see Q. II.1 in FDAs draft guidance for industry 
New and Revised Draft Q&As on Biosimilar Development and the BPCI Act (Revision 2) 
(December 2018) (Biosimilars  Q&A Draft Guidance)).  Moreover, a drug product that contains a 
protein only as an inactive ingredient  (e.g., a drug product formulated with human serum 
albumin  as an inactive ingredient)  is not considered to be a protein for purposes of the 
statutory definition  of biological  product and the transition provision  of the BPCI Act. 
 
The prescription or over-the-counter status of a biological  product with an approved application 
under section 505 of the FD&C Act will not change when the approved application  is deemed to 
be a license for the biological  product under section 351 of the PHS Act on March 23, 2020. 
 
Examples of biological  products approved under the FD&C Act are listed in the Appendix to the 
Transition Policy Final Guidance.  To enhance transparency and facilitate planning  for the 
transition date, FDA is posting on the FDA website (https://www.fda.gov/drugs/guidance-
compliance-regulatory-information/deemed-be-license-provision-bpci-act)  a preliminary  list of 
approved applications  for biological  products under the FD&C Act (as of December 31, 2019) 
that will be affected by the transition  provision,  and FDA intends to periodically  update the list 
before the transition  date (see Q3 below).  Shortly after the transition  date, FDA intends to post a 
final list of approved applications  under the FD&C Act that have been deemed to be licenses 
under the PHS Act. 
 
Q2.  Does the holder of an approved NDA for a biological product on FDAs list need to 
take any affirmative steps for its NDA to be deemed a BLA?   
 
FDA interprets the transition  provision  to mean that the holder of an approved application  for a 
biological  product does not need to take any affirmative steps for its NDA to be deemed a BLA.  
Specifically,  FDA interprets section 7002(e)(4)(A) of the BPCI Act to mean that an approved 
application  under the FD&C Act for a biological  product will be deemed to be a license for the 
biological  product on the transition  date by operation of the statute.10    
 
 
                                              
9 In the Federal Register of February 21, 2020, FDA issued a final rule that amends its regulation that defines 
biological product to incorporate changes made by the BPCI Act and the Further Consolidated Appropriations 
Act, 2020, and to provide its interpretation of the statutory term protein (85 FR 10057).  This rule is effective on 
March 23, 2020. 
 
10 Similarly, FDA interprets section 7002(e)(4)(B)(iii) of the BPCI Act to mean that upon approval under the FD&C 
Act of any application described in section 7002(e)(4)(B)(i) of the BPCI Act, the approved application for the 
biological product would be deemed to be a license for the biological product by operation of the statute.  For 
purposes of this guidance, we focus on the transition of approved NDAs to deemed BLAs pursuant to section 
7002(e)(4)(A) of the BPCI Act. 
  5  Contains Nonbinding Recommendations 
 
The statute is silent regarding the process for accomplishing  the transition of approved NDAs to 
deemed BLAs.  FDA intends to send a letter to such application  holders on March 23, 2020, 
advising  that the approved NDA was deemed to be a BLA at 12:00 am Eastern Daylight Time 
(EDT) on March 23, 2020, and no longer exists as an NDA.  (If the NDA is approved on March 
23, 2020, the approved NDA will be deemed to be a BLA immediately  after approval.)  In the 
letter, FDA also will notify the application  holder that it has been issued a license that authorizes 
the application  holder to manufacture the biological  product within the meaning of section 351 of 
the PHS Act and to introduce the biological  product or deliver the biological  product for 
introduction  into interstate commerce (see Q6 below).  The letter also will remind application 
holders that they will need to ensure that the listing  information  for the biological  product is 
updated in FDAs electronic Drug Registration and Listing System (eDRLS) between March 23, 
2020, and June 30, 2020, to reflect a change in the prefix of the application  number (from 
NDA to BLA) (see 21 CFR 207.57(b)).  FDA notes that the deeming of an approved NDA 
to be a BLA and the corresponding  update of the eDRLS listing  information  for the biological 
product to change the prefix for the application  number will not result in the need for a new 
National Drug Code (NDC) number with a new product code.  Accordingly,  in the absence of 
other changes made by the application  holder that would require a new NDC number, biological 
products approved under the FD&C Act will retain their current NDC number after the NDA is 
deemed to be a BLA.  This will provide consistency for manufacturers and for the databases and 
pharmacy systems that track drug and biological  products. 
 
To enhance transparency and facilitate planning  for the transition date, FDA is posting on the 
FDA website a preliminary  list of approved applications  for biological  products under the FD&C 
Act (as of December 31, 2019) that will be affected by the transition provision,  and FDA intends 
to periodically  update the list before the transition date (see Q1 above).  Biological  products 
approved in NDAs that are deemed to be BLAs will be removed from FDAs Approved Drug 
Products With Therapeutic Equivalence Evaluations (the Orange Book) on March 23, 2020, and 
will be listed in FDAs Lists of Licensed Biological Products with Reference Product Exclusivity 
and Biosimilarity or Interchangeability Evaluations (the Purple Book) and the CDER 
Therapeutic Biologics Products list on or shortly after the March 23, 2020, transition  date. 
 
Q3.  Who should an application holder contact if it believes that its approved NDA 
should or should not be included on FDAs preliminary list of approved applications 
for biological products that will be affected by the transition provision?  
 
If an application  holder or other person reviews, on FDAs website, the preliminary  list of 
approved applications  for biological  products under the FD&C Act that will be affected by the 
transition provision  and believes that an approved NDA should be added to the list or should not 
be included on the list, the application  holder or other person should submit a comment to the 
public docket established for this guidance and the preliminary  list.  For information  on 
submission  of comments to the public  docket, please refer to the Federal Register (FR) Notice of 
Availability  of this guidance.  
 
  6  Contains Nonbinding Recommendations 
 
Q4.  How will FDA notify the sponsor of a proposed biological product who seeks to 
obtain approval under section 505 of the FD&C Act that the planned application 
would need to be approved under the FD&C Act on or before March 23, 2020?  
 
FDA provided notice to sponsors of proposed biological  products intended for submission  in an 
application  under section 505 of the FD&C Act that they will be affected by the transition 
provision  through the Biosimilars  Q&A Guidance, as well as through FDAs draft guidance for 
industry Implementation of the Deemed to be a License Provision of the Biologics Price 
Competition and Innovation Act of 2009 (March 2016) (Transition  Policy Draft Guidance) and 
the Biosimilars  Q&A Draft Guidance.  In the Biosimilars  Q&A Guidance, FDA initially  stated 
its interpretation of the statutory term protein in the amended definition  of biological  product 
(see Q1 above and Biological  Product Definition  Final Rule).  In the Transition  Policy Final 
Guidance, FDA provides recommendations  to sponsors of proposed protein products intended 
for submission  in an application  that may not receive final approval under section 505 of the 
FD&C Act on or before March 23, 2020, to facilitate alignment of product development plans 
with FDAs interpretation  of section 7002(e) of the BPCI Act.11  FDA recommends that sponsors 
of development programs for proposed protein products evaluate whether a planned submission 
under section 505 of the FD&C Act would allow adequate time for approval of the application 
prior to March 23, 2020, considering,  among other things, whether the submission  may require a 
second cycle of review and, for certain types of applications,  whether unexpired patents or 
exclusivity  may delay final approval.  If a sponsor is unsure whether its proposed product may 
receive approval under the FD&C Act by March 23, 2020, the sponsor should consider 
submitting  a BLA under section 351(a) or 351(k) of the PHS Act instead.  For additional 
information,  please see the Transition Policy Final Guidance. 
 
B.  Applications for Biological Products Submitted Under Section 505 of the 
FD&C Act on or Before the Transition Date 
 
Q5.  When will the holder of an approved NDA for a biological product receive the 
application number that will be used for its deemed BLA?   
 
FDA intends to assign the same application  number used for the approved NDA to the deemed 
BLA on the March 23, 2020, transition  date.  As a hypothetical  example, NDA 012345 would be 
deemed to be BLA 012345 on the transition date.  This approach is intended to minimize  burden 
on holders of approved applications  for biological  products under the FD&C Act who are 
preparing submissions  to their applications  around the transition date and to facilitate the 
administrative  conversion of any pending supplements to such applications  (see the Transition 
Policy Final Guidance for additional  information  regarding such supplements).  The use of a 
predictable application  numbering  system for deemed BLAs is also expected to facilitate 
preparation and submission  of a 351(k) BLA for a proposed biosimilar  or interchangeable 
                                              
11 After FDA issued the Transition Policy Final Guidance, the Further Consolidated Appropriations Act, 2020 was 
enacted.  Section 607 of this Act amended section 7002(e)(4) of the BPCI Act to provide that FDA will continue to 
review an application for a biological product under section 505 of the FD&C Act after March 23, 2020, so long as 
that application was submitted under section 505 of the FD&C Act, is filed not later than March 23, 2019, and is not 
approved as of March 23, 2020.  If such an application is approved under section 505 of the FD&C Act before 
October 1, 2022, it will be deemed to be a license for the biological product under section 351 of the PHS Act upon 
approval (see section 7002(e)(4)(B)(iii) and (vi) of the BPCI Act). 
  7  Contains Nonbinding Recommendations 
 
product that references a product licensed in a deemed 351(a) BLA as a reference product.  The 
FDA letter that notifies the application  holder that its approved NDA is deemed to be a BLA on 
the transition date will include the products BLA number. 
 
Q6.  When will the holder of an approved NDA for a biological product receive the 
license number that will apply to its deemed BLA(s)?  
 
The FDA letter that notifies the application  holder that its approved NDA is deemed to be an 
approved BLA will include the U.S. license number assigned to the application  holder.  Each 
establishment that is listed in the approved NDA as currently involved  in the manufacture of the 
biological  product on the transition  date will be considered a licensed establishment  on that date 
(see section 7002(e)(4)(A) of the BPCI Act; see also section 7002(e)(4)(B)(iii)  of the BPCI Act).  
FDA does not intend to conduct pre-license inspections  of manufacturers of the transitioning 
biological  products because FDA interprets section 7002(e)(4)(A) of the BPCI Act to mean that 
an approved application  under the FD&C Act for the biological  product will  be deemed to be a 
license on the transition date by operation of the statute.12  Moreover, the establishments will 
have been inspected in connection with the previously  approved NDAs under the FD&C Act (see 
Q16 below for information  on establishment inspections related to certain supplements to a 
deemed 351(a) BLA). 
 
FDA issues only one U.S. license number per BLA holder, regardless of the number of licensed 
biological  products manufactured by that BLA holder under separate BLAs.  Accordingly,  if an 
NDA holder is also a BLA holder and has been assigned a U.S. license number for another 
biological  product, the NDA holder will  not be issued a different U.S. license number when its 
approved NDA for a biological  product is deemed to be a BLA on the transition  date. 
 
Section 351(a)(1)(B)(ii) of the PHS Act requires that each package of a biological  product is 
plainly  marked with, among other things,  the applicable license number of the manufacturer of 
the biological  product in order for the biological  product to be introduced or delivered for 
introduction  into interstate commerce.  To minimize  possible disruption  in the distribution  of 
biological  products in the United States and to minimize  burden on holders of deemed BLAs, 
FDA intends to adopt a compliance policy for the labeling  of biological  products that are the 
subject of deemed BLAs (see Q14 and section IV below for additional  information  on the 
compliance policy for labeling  of biological  products in deemed BLAs). 
 
Q7.  Will an approved NDA for a biological product be deemed to be a 351(a) BLA or a 
351(k) BLA? 
 
FDA interprets the transition  provision,  along with the applicable  provisions  of the FD&C Act 
and the PHS Act, to mean that an approved NDA, including  an application  submitted through the 
pathway described by section 505(b)(2) of the FD&C Act (505(b)(2) application),  will be 
deemed to be a 351(a) BLA on the transition date. 
 
Section 7002(e) of the BPCI Act is directed primarily  to the submission  of an application  for a 
biological  product during the transition  period ending on March 23, 2020, and does not explicitly 
                                              
12 See also footnote 10 in the response to Q2. 
  8  Contains Nonbinding Recommendations 
 
state whether an approved NDA will be deemed to be a 351(a) BLA or a 351(k) BLA.  The 
Agencys interpretation  that an approved NDA submitted under section 505(b)(1) of the FD&C 
Act will be deemed to be a 351(a) BLA is based on the shared requirement that both types of 
applications  contain full reports of investigations  of safety and effectiveness (or, for a 351(a) 
BLA, safety, purity, and potency).  We expect that the measures FDA has taken to minimize 
differences in the review and approval of products in marketing applications  submitted under 
section 351(a) of the PHS Act and section 505(b)(1) of the FD&C Act will facilitate 
implementation  of the statutory provision  under which an approved NDA will be deemed to be a 
BLA. 
 
The Agencys interpretation  that an approved 505(b)(2) application  will be deemed to be a 
351(a) BLA reflects the shared requirement that both types of applications  contain full reports of 
investigations  of safety and effectiveness (or, for a 351(a) BLA, safety, purity, and potency).13  
This approach also reflects the Agencys view that it is more appropriate to regulate a biological 
product approved through the 505(b)(2) pathway that may be intended to differ in certain 
respects (e.g., different strength, dosage form, or route of administration  or approved conditions 
of use) from a previously  approved product under the statutory and regulatory framework for 
351(a) BLAs, as such differences are not permitted under the statutory framework for 351(k) 
BLAs.  Moreover, FDAs approval of a 505(b)(2) application  reflects the Agencys evaluation of 
the data against a different statutory standard than a determination  of biosimilarity  or 
interchangeability  under section 351(k) of the PHS Act. 
 
Q8.  Will an approved NDA for a biological product that has been discontinued from 
marketing be deemed to be a BLA?   
 
Section 7002(e)(4) states that an approved application  for a biological  product under section 
505 of the [FD&C Act] will be deemed to be a BLA on the transition date.  Accordingly,  FDA 
interprets the statute to mean that an approved NDA for a biological  product that has been 
discontinued  from marketing,  but for which FDA has not withdrawn approval of the application, 
will be deemed to be a BLA on the transition date.  The holder of an NDA for a discontinued 
product must comply with applicable statutory and regulatory requirements for its application 
before the transition  date, and after its application  is deemed to be a BLA.  These requirements 
include,  for example, postmarketing  reporting of adverse drug experiences and, if appropriate, 
the submission  of proposed revisions to product labeling.   If the holder of a deemed BLA for a 
biological  product that has been discontinued  from marketing seeks to reintroduce the product to 
the market, the BLA holder should consult with the relevant FDA review division  before 
submitting  a supplement to the deemed BLA, to discuss any data and information  that may be 
needed. 
 
                                              
13 A 505(b)(2) application is an NDA that contains full reports of investigations of safety and effectiveness, where at 
least some of the information required for approval comes from studies not conducted by or for the applicant and for 
which the applicant has not obtained a right of reference or use (e.g., FDAs finding of safety and/or effectiveness 
for a listed drug or published literature).   
  9  Contains Nonbinding Recommendations 
 
Q9.  How will the transition on March 23, 2020, affect the annual program fee for an 
approved NDA for a biological product?  
 
Under section 736(a)(2) of the FD&C Act, a person named as the applicant in a human drug 
application  (which refers to an NDA or a 351(a) BLA, subject to applicable statutory exceptions) 
is assessed an annual prescription drug program fee.  A prescription  drug program fee is assessed 
each fiscal year for each prescription  drug product identified  in a human drug application 
approved as of October 1 of the fiscal year, with certain exceptions described by statute.  For 
more information  about the prescription  drug program fee, consult the FDA guidance for 
industry Assessing User Fees Under the Prescription Drug User Fee Amendments of 2017 (May 
2018). 
 
In general, sponsors of biological  products for which annual prescription drug program fees are 
assessed prior to the transition,  and that are deemed to be licensed under section 351(a) of the 
PHS Act on the transition date, will continue to be assessed prescription drug program fees for 
such products after the transition,  subject to applicable statutory requirements and exceptions.  
 
Q10.  If an applicant withdraws an NDA that is tentatively approved on or before the 
transition date, or otherwise pending with FDA, and submits an application for the 
same product under section 351(a) of the PHS Act, will an additional PDUFA 
application fee be assessed? 
 
An applicant (or the applicants licensee, assignee, or successor) will not be charged a 
Prescription Drug User Fee Act (PDUFA) application  fee for the submission  of an application 
under section 351(a) of the PHS Act if all of the following  circumstances are satisfied (see 
section 736(a)(1)(C) of the FD&C Act): 
 
  The applicant previously  submitted an NDA for the same product and paid the associated 
PDUFA application  fee for the NDA. 
 
  The NDA was accepted for filing.   (Note that an NDA for a biological  product will not be 
accepted for filing  after the transition date.) 
 
  The NDA was not approved14 or was withdrawn (without a waiver). 
 
For questions regarding user fees, please contact the User Fee Staff at 
CDERCollections@fda.hhs.gov  or 301-796-7900. 
 
                                              
14 An NDA that is tentatively approved is not an approved NDA (see 21 CFR 314.105(a)). 
  10  Contains Nonbinding Recommendations 
 
Q11.  If the applicant withdraws an NDA that is tentatively approved on or before the 
transition date, or otherwise pending with FDA, and submits an application for the 
same product under section 351(k) of the PHS Act, will a BsUFA application fee be 
assessed?   
 
An application  for licensure of a biological  product under section 351(k) of the PHS Act meets 
the definition  of a biosimilar  biological  product application  in section 744G(4) of the FD&C 
Act, with certain exceptions.  Under section 744H(a)(2) of the FD&C Act, a biosimilar 
biological  product application  fee is assessed to the applicant at the time of submission  of a 
biosimilar  biological  product application,  unless an exception applies under section 
744H(a)(2)(D).  Certain applicants may be eligible  for a small business waiver of the biosimilar 
biological  product application  fee under section 744H(d)(1) of the FD&C Act.  If an applicant 
withdraws an NDA that is tentatively approved or pending on or before the transition  date and 
later submits a biosimilar  biological  product application  under section 351(k) of the PHS Act, the 
applicant would be assessed a biosimilar  biological  product application  fee for the 351(k) 
application,  unless a small business waiver has been granted or the applicant previously 
submitted a biosimilar  biological  product application  for the same product and meets the other 
criteria for the exception described in section 744H(a)(2)(D) of the FD&C Act.  For more 
information  about the biosimilar  biological  product application  fee, consult the FDA guidance 
for industry Assessing User Fees Under the Biosimilar User Fee Amendments of 2017 (June 
2018).  
 
Q12.  Will approved NDAs that are deemed to be BLAs remain within the same review 
office/division in CDER?  Will pending NDAs that are withdrawn and submitted as 
BLAs be reviewed within the same CDER review office/division?  
 
In general, approved NDAs that are deemed to be BLAs will remain within the same review 
office/division  within CDERs Office of New Drugs (OND) after the transition  date, subject to 
any reassignments related to any reorganization  of CDERs OND.  Similarly,  pending NDAs that 
are withdrawn and submitted as BLAs will be reviewed within the same OND review 
office/division.    
 
With respect to the product quality assessment, review responsibilities  within CDERs Office of 
Pharmaceutical Quality (OPQ) for products composed of amino acid polymers are in the process 
of being assigned or reassigned based on certain characteristics of the molecule,  rather than the 
regulatory pathway, with the expectation that the reassignments will be completed by the 
transition date.  Accordingly,  on the transition date, we generally expect to maintain the assigned 
OPQ review offices for approved NDAs that are deemed BLAs, as well as pending NDAs that 
are withdrawn and submitted as BLAs.   
   
  11  Contains Nonbinding Recommendations 
 
C.  Statutory and Regulatory Requirements for BLAs 
 
Q13.  Will the holder of a deemed 351(a) BLA be subject to requirements under the PHS 
Act and FDA regulations for BLAs that are different from requirements for NDAs? 
If so, when will the requirements apply to deemed BLAs?  
 
The holder of a deemed 351(a) BLA will be subject to applicable  requirements under the PHS 
Act and FDA regulations and, as provided in section 351(j) of the PHS Act, also will be subject 
to requirements under the FD&C Act that apply to BLAs.  In general, FDA anticipates that a 
holder of an NDA for a biological  product that is being deemed a 351(a) BLA will experience 
minimal  disruption  due to differences in requirements under the FD&C Act and PHS Act.  FDA 
has taken measures to minimize  differences in the review and approval of products required to 
have licensed BLAs under section 351(a) of the PHS Act and products required to have approved 
NDAs under section 505(b)(1) of the FD&C Act (see section 123(f) of the Food and Drug 
Administration  Modernization  Act of 1997 (FDAMA) (Public Law 105-115)).  However, there 
are certain statutory and regulatory requirements for biological  products regulated under the PHS 
Act that differ from requirements for drug products regulated under the FD&C Act.  FDA is 
committed to working with application  holders to minimize  any potential burden.   
 
Labeling requirements for deemed BLAs, including  certain differences between the requirements 
in the PHS Act and FD&C Act, are further described in Q14 below.  The Agencys compliance 
policy for the labeling  of biological  products that are the subject of deemed BLAs is described in 
section IV below. 
 
Biological  products that are deemed to be licensed under section 351 of the PHS Act on March 
23, 2020, will be subject to chemistry, manufacturing,  and controls (CMC) requirements 
applicable to products regulated under the PHS Act beginning  on March 23, 2020.15  Holders of 
deemed BLAs should be aware that there are certain CMC-related requirements that differ 
between the PHS Act and FD&C Act.  However, as further described in Q15 below, the burden 
related to these statutory and regulatory differences is expected to be minor.   
 
Q14.  Will the holder of a deemed BLA need to update the product labeling to conform to 
labeling requirements for BLAs? 
 
The holder of a deemed BLA will be required to revise the product labeling  (e.g., container 
labels, carton labeling,  and prescribing information)  so that biological  products introduced or 
delivered for introduction  into interstate commerce on or after March 23, 2020, conform to 
labeling  requirements for biological  products regulated under section 351 of the PHS Act.  
However, FDA acknowledges that holders of deemed BLAs may need time to revise their 
labeling  to conform to such requirements and may not be able to make these revisions until 
receiving the information  provided in the letter sent from FDA on the transition date.  
Accordingly,  based on our understanding  that holders of deemed BLAs may need time to 
                                              
15 Similarly, any biological product that is deemed to be licensed under section 351 of the PHS Act after March 23, 
2020, pursuant to section 7002(e)(4)(B)(iii) of the BPCI Act will be subject to CMC requirements applicable to 
products regulated under the PHS Act beginning on the date on which the approved NDA for the biological product 
is deemed to be a BLA for the biological product. 
  12  Contains Nonbinding Recommendations 
 
conform their products labeling  to BLA labeling  requirements, FDA generally does not intend 
to object to the labeling  of biological  products marketed under a deemed BLA with labeling  that 
does not conform to certain labeling  requirements until March 23, 2025, provided that the 
labeling  at issue complies with all other applicable labeling  requirements (see section IV below 
for information  about the Agencys compliance policy).  FDA recommends, in order to facilitate 
the implementation  of the proposed revisions within that timeframe, that the holder of the 
deemed BLA submit a prior approval supplement (PAS) with proposed revised product labeling 
between March 23, 2020 (when the approved application  under section 505 of the FD&C Act for 
the biological  product is deemed to be a BLA), and March 23, 2022.16  
 
Most labeling  requirements for container labels, carton labeling,  and prescribing  information  are 
the same for biological  products currently regulated under the FD&C Act as they are for 
biological  products regulated under the PHS Act.  However, there are certain labeling 
requirements under the PHS Act and regulations  for BLAs that differ from requirements under 
the FD&C Act and regulations  for NDAs.   
 
The PHS Act requires that each package of a biological  product is plainly  marked with, among 
other things, the proper name of the biological  product contained in the package and the 
name, address, and applicable license number of the manufacturer of the biological  product in 
order for the biological  product to be introduced or delivered for introduction  into interstate 
commerce (see section 351(a)(1)(B) of the PHS Act; 21 CFR 610.61, 610.63, 610.64 and 
201.1(m)).  The package means the immediate  carton, receptacle, or wrapper, including  all 
labeling  matter therein and thereon, and the contents of the one or more enclosed containers.  If 
no package, as defined in the preceding sentence, is used, the container shall be deemed to be the 
package (21 CFR 600.3(cc)).  The manufacturer of a biological  product regulated under the 
PHS Act that needs to be identified  on each package is the BLA holder (see 21 CFR 
600.3(t)(definition  of manufacturer); see also 21 CFR 610.63 (labeling  requirements for divided 
manufacturing responsibility)).17    
 
The holder of the deemed BLA will need to revise product labeling  to ensure that the biological 
products are labeled with the proper name of the biological  product,  the name and address of the 
manufacturer (if the required information  on the manufacturer is not already provided),  and the 
license number, and that the labeling  otherwise conforms to the labeling  requirements for 
biological  products regulated under section 351 of the PHS Act (see section IV below for 
information  about the Agencys compliance policy).  The FDA letter that notifies the application 
holder that its approved NDA is deemed to be a BLA on the transition  date will provide the U.S. 
                                              
16 Depending on the circumstances, submission of a PAS may be required to make the BLA-specific labeling 
revisions for certain deemed BLAs (see 21 CFR 601.12(f)(1)).  However, to facilitate efficient and appropriate 
revisions to container labels, carton labeling, and prescribing information, FDA recommends submitting a PAS even 
when doing so would not be required. 
 
17 This definition differs in certain respects from the use of the term manufacturer in the context of a drug product 
regulated under the FD&C Act (see, e.g., 21 CFR 201.1(b)).  The name and address of the distributor of a biological 
product may appear on the labeling provided that the name, address, and license number of the manufacturer also 
appears on the label and the name of the distributor is qualified by one of the phrases listed in 21 CFR 610.64 (e.g., 
Manufactured by [BLA holder] for [Distributor]).  FDA notes that a BLA holder is not required to list a contract 
manufacturer on the labeling because contract facilities are considered to be under the control of the BLA holder. 
  13  Contains Nonbinding Recommendations 
 
license number assigned to the application  holder.  The license authorizes the application  holder 
to manufacture the biological  product within the meaning of section 351 of the PHS Act and to 
introduce the biological  product or deliver the biological  product for introduction  into interstate 
commerce.  FDA will  designate the proper name of the biological  product in the license (see 21 
CFR 600.3(k) and Q21 below). 
 
There are additional  requirements for the container labels and carton labeling  for a biological 
product regulated under section 351 of the PHS Act (see 21 CFR 610.60 and 21 CFR 610.61; see 
also 21 CFR 610.62 for requirements applicable to biological  products that do not fall within the 
specified categories of biological  products described in 21 CFR 601.2 (non-specified  biological 
products)).  In the table below, we provide an overview of key changes18 from NDA labeling 
requirements for container labels and carton labeling  that will apply to biological  products in 
deemed BLAs. 
 
                                              
18 Additional labeling requirements not summarized in this chart are described in the text that follows. 
  14  Contains Nonbinding Recommendations 
 
Table. Selected Requirements for Container Labels and Carton Labeling for Biological 
Products 
Labeling  Change From NDA Labeling Requirements 
Information  That Will Apply to Biological Products in Deemed BLAs 
  New Required Information 
Proper Name  Container labels and carton labeling must include the proper name of the biological 
product designated by FDA in the license (see 21 CFR 610.60(a)(1) and 610.61(a)).   
 
For non-specified biological products (e.g., pancrelipase, urofollitropin), the regulations 
provide more specific requirements for the position and prominence of the proper name, 
and the legibility of information on the package and container label (see 21 CFR 610.62). 
Manufacturer  The name and address of the manufacturer (i.e., the BLA holder) must appear on 
Name, Address,  container labels and carton labeling in the format specified by the regulations (see 21 
and License  CFR 610.60(a)(2) and 610.61(b); see 21 CFR 600.3(t) for the definition of manufacturer 
Number  and 21 CFR 610.63 for labeling requirements for divided manufacturing responsibility).   
 
  For containers capable of bearing only a partial label, only the proper name, the lot 
number or other lot identification, and the name of the manufacturer is required (see 
21 CFR 610.60(c)); we also recommend including the strength and expiration date.   
 
  The name and address of the distributor of the biological product may appear in 
addition to the name and address of the manufacturer.  The qualifying phrases used 
for a distributor are the same for drug and biological products (compare 21 CFR 
201.1(h)(5) with 21 CFR 610.64). 
 
Container labels and carton labeling must also include the license number of the 
manufacturer of the biological product (see 21 CFR 610.60(a)(2) and 610.61(b)).   
  Required Information That May Currently Appear in Approved  Labeling 
Preservative  Carton labeling must include the name of the preservative used (which already appears in 
the statement of ingredients on the carton of biological products approved under the 
FD&C Act) and its concentration (see 21 CFR 610.61(e)).  
 
If no preservative is used and the absence of a preservative is a safety factor, the words 
no preservative must appear on the carton labeling (see 21 CFR 610.61(e)). 
Potency Statement  Carton labeling must include the minimum potency of product expressed in terms of 
official standard of potency (compare 21 CFR 610.61(r) with 21 CFR 201.51(a)). 
 
If potency is a factor and no U.S. standard of potency has been prescribed, the words No 
U.S. standard of potency must appear on the carton labeling (see 21 CFR 610.61(r)). 
Source of the  Carton labeling must include the source of the product when a factor in safe 
Product When a  administration, such as products made from sources that may be allergenic (see 21 CFR 
Factor in Safe  610.61(p)).  
Administration 
 
Certain requirements for container labels and carton labeling  (see, e.g., 21 CFR 610.60(a)(5) and 
(c), and 21 CFR 610.61(j))  can be addressed by including  a statement that refers to the 
prescribing information  and by including  the required information  in the prescribing information 
(see, e.g., 21 CFR 610.61(l),  (n), and (q)). 
 
There also are certain differences in the content of prescribing information  for biological 
products regulated under the PHS Act.  The key differences for the prescribing  information  for a 
biological  product regulated under the PHS Act are that the labeling  must include the proper 
name of the biological  product, including  any appropriate descriptors (see 21 CFR 201.57(a)(2)), 
and the manufacturer name, address, and license number (see 21 CFR 610.60(a)(2) and 
610.61(b)).  Conforming  revisions also would need to be made to FDA-approved patient 
  15  Contains Nonbinding Recommendations 
 
labeling.   In addition,  for biological  products that are required to meet the content and format 
requirements of the Physician Labeling  Rule (PLR) as described in 21 CFR 201.56(d) and 
201.57, the year used for the Initial  U.S. Approval included  in the Highlights  of Prescribing 
Information (Highlights)  differs for a biological  product under the FD&C Act (i.e., the year of 
initial  U.S. approval of the new molecular entity) and the PHS Act (i.e., the year of initial  U.S. 
approval of the new biological  product).  Accordingly,  the Initial U.S. Approval in the Highlights 
may need to be revised to reflect the year in which the first NDA for the biological  product(s) 
described in the labeling  was initially  approved.   
 
The date of initial  approval of the NDA (and not the date on which the NDA is deemed to be a 
BLA) and the date(s) of approval of efficacy supplement(s) will continue to govern the 
applicability  of the labeling  content and format requirements described by 21 CFR 201.56(d) and 
201.57.  For NDAs that are not required to have labeling  in PLR format, application  holders may 
consider voluntarily  converting the labeling  to PLR format because the PLR format represents a 
more useful and modern approach for communicating  information  on the safe and effective use 
of products and makes prescribing information  more accessible for use with electronic 
prescribing tools and other electronic information  resources.  
 
The holder of a deemed BLA for a biological  product should submit all proposed revisions to 
product labeling  necessary to conform to labeling  requirements for biological  products regulated 
under section 351 of the PHS Act (i.e., container labels, carton labeling,  prescribing  information, 
and patient labeling)  together in the same PAS.  To facilitate identification  of the type of 
submission  for the Agency, the applicant should mark clearly on the cover letter, Deemed BLA 
Labeling Revisions.   
 
Q15.  Are there different requirements related to CMC that will apply to a biological 
product in a deemed 351(a) BLA?  
 
Certain CMC requirements and recommendations  applicable to biological  products regulated 
under the PHS Act may differ in some respects from CMC requirements and recommendations 
applicable to biological  products regulated under the FD&C Act.  However, FDA expects that in 
many instances the practical implications  of such differences on holders of deemed BLAs will be 
minimal  because the CMC requirements under both the PHS Act and the FD&C Act address 
many of the same types of CMC considerations for ensuring quality biological  products.  For 
example, FDA anticipates that most biological  products subject to the transition provision,  upon 
being deemed BLAs, will meet the related general BLA requirements (e.g., potency, sterility, 
purity, and identity) under the PHS Act based on the products having been previously  approved 
under the FD&C Act.   
 
The holders of deemed BLAs may be required to report or provide different information  than is 
required for biological  products under the FD&C Act.  In the sections below, we highlight  such 
requirements, namely lot release, biological  product distribution  reports, notification  of 
manufacturing problems involving  distributed  products, and establishment standards for non-
specified biological  products.   
 
  16  Contains Nonbinding Recommendations 
 
Additionally,  as with all biological  products, FDA may recommend changes to the control 
strategy throughout  the product life cycle to modernize control strategies, to address product-
specific issues, and to help ensure that biological  products remain safe, pure, and potent for their 
approved conditions  of use.  Furthermore, as with all biological  products, these changes may be 
recommended as a result of postapproval or surveillance inspections,  which are independent of a 
submission  and generally expected to be similar for a biological  product whether approved in an 
NDA prior to the transition date or licensed in a BLA.  For inspections related to CMC 
supplements see Q16 below. 
 
FDA is committed to working with application  holders to minimize  any potential burden, and 
encourages application  holders with any CMC-related questions to contact OPQ/Office of 
Program and Regulatory Operations (OPRO) at CDER-OPQ-Inquiries@fda.hhs.gov.   
 
1.  Lot Release 
 
FDA may require that a BLA holder submit samples and CMC data for each lot of product for 
FDA review and release (see 21 CFR 610.2).  However, FDA generally does not anticipate that 
lot release requirements will apply for biological  products approved in NDAs that are deemed to 
be BLAs.   
 
In 1995, FDA announced the elimination  of lot-by-lot  release for licensed well-characterized 
therapeutic recombinant DNA-derived and monoclonal  antibody  biotechnology  products (see the 
1995 Federal Register notice Interim Definition  and Elimination  of Lot-by-Lot Release For 
Well-Characterized Therapeutic Recombinant DNA-Derived and Monoclonal  Antibody 
Biotechnology  Products; Notice, (60 FR 63048, December 8, 1995)).  FDA subsequently 
amended 21 CFR 601.2 to specify, instead of the term well characterized biotechnology 
product, the categories of products to which lot-by-lot  release would not be necessary (see 
Elimination  of Establishment  License Application  for Specified Biotechnology  and Specified 
Synthetic Biological  Products, 61 FR 24227, May 14, 1996).  Most of the biological  products 
subject to the transition provision  will meet the description of products for which lot-by-lot 
release is not required.  Furthermore, for biological  products that do not fall into the categories 
specified in 21 CFR 601.2, FDA generally does not anticipate that lot-by-lot  release will be 
needed.  As stated in the December 1995 Federal Register notice:  
 
[O]nce a company has demonstrated its ability to consistently produce acceptable lots, 
and has procedures in place that will prevent the release of lots that do not meet release 
specifications, it is not necessary for FDA to verify that each manufactured lot is 
acceptable for release.19 
 
FDA generally considers application  holders for biological  products subject to the transition 
provision  as having demonstrated the ability  to consistently produce acceptable lots and as 
having procedures in place that will prevent the release of lots that do not meet release 
specifications based on product history.  
 
                                              
19 See 60 FR 63048, December 8, 1995. 
  17  Contains Nonbinding Recommendations 
 
2.  Product Distribution Reports 
 
FDA anticipates that all biological  product application  holders will have adequate records of the 
product distributed to the market.  Although the frequency and content of distribution  reporting 
required for products regulated under the FD&C Act and PHS Act differ, FDA expects these 
differences will present minimal  burden to holders of deemed BLAs. 
 
Application  holders of biological  products affected by the transition provision  should be aware 
that 21 CFR 600.81, which covers product distribution  reporting for licensed BLAs, requires 
submission  of more granular distribution  data than is required for approved NDAs under 21 CFR 
314.81.  However, FDA anticipates that affected application  holders will generally already have 
the distribution  information  specified in 21 CFR 600.81.  Additionally,  21 CFR 600.81 requires 
reporting every 6 months, in contrast to annual reporting.  However, holders of deemed BLAs 
may request at any time, including  within the first 6 months of being deemed a BLA, a waiver to 
provide product distribution  reports annually  (e.g., to align with the timing  of the holders 
Annual Report) rather than every 6 months (21 CFR 600.90).  The requirements for a waiver 
request are described in 21 CFR 600.90. 
 
3.  Notification of Manufacturing Problems Involving Distributed Products 
 
Regardless of whether a biological  product has been approved under the FD&C Act or licensed 
under the PHS Act, application  holders are required to report certain events that have the 
potential to affect the safety, purity, or potency of a distributed  product.  Under the FD&C Act, 
reporting of such events is through a field alert report (FAR) (see 21 CFR 314.81(b)(1)), while 
under the PHS Act, reporting is through a biological  product deviation  report (BPDR) (see 21 
CFR 600.14).  FDA expects the change in reporting between FAR and BPDR will present 
minimal  burden to holders of deemed BLAs.   
 
In particular, we note that under 21 CFR 600.14, application  holders for biological  products 
approved under the FD&C Act will be required, once the product is deemed to be licensed under 
a BLA, to report on events with the potential to affect the safety, purity, or potency of a 
distributed  product by submission  of BPDRs to CDER.  Additionally,  the BPDR is to be 
submitted as soon as possible but within 45 calendar days of acquiring  information  reasonably 
suggesting that a reportable event has occurred (rather than within 3 calendar days as is required 
in the case of a FAR).  Finally,  for any initial  FAR submitted by the holder of an approved NDA 
for a biological  product before March 23, 2020, the corresponding  follow-up report is to be 
submitted as a BPDR if submitted on or after March 23, 2020. 
 
4.  Establishment Standards for Non-Specified Biological Products 
 
Biological  products that do not fall within the specified categories of biological  products 
described in 21 CFR 601.2 (non-specified  biological  products) are subject to certain additional 
CMC-related requirements under the PHS Act when seeking marketing approval in a BLA or 
BLA supplement (see establishment standards described in 21 CFR 600.10, 600.11, 600.12 and 
600.13).  These requirements differ in some respects from establishment standards under the 
FD&C Act; however, FDA expects the practical implications  for transition  biological  products to 
  18  Contains Nonbinding Recommendations 
 
be minimal.   As a preliminary  matter, we note that an approved NDA for a biological  product 
will be deemed to be a license (i.e., an approved BLA) for the biological  product by operation of 
the BPCI Act.  Accordingly,  certain premarket approval requirements may not be applicable 
unless the application  holder seeks approval of a supplement to the deemed BLA and the 
requirement applies to the supplement (see Q16 below).  Moreover, as provided in 21 CFR 
601.2, the additional  requirements described above are not applicable to the specified 
categories of biological  products described in that section of the regulations,  and many 
transition biological  products will fall within those identified  categories of biological  products, 
for which such additional  requirements would not be applicable. 
 
Q16.  What is required for CMC changes submitted in a PAS or changes being effected 
supplements submitted to deemed 351(a) BLAs? 
 
FDA requires applicants or application  holders of biological  productswhether approved under 
the FD&C Act or licensed under the PHS Actto notify FDA about each change in the 
conditions  established in an approved application.   The types of reporting categories for 
biological  products generally are the same for an NDA (see 21 CFR 314.70) and for a BLA (see 
21 CFR 601.12), and in both cases, the applicant or application  holder is expected to demonstrate 
that the postchange product continues to be of acceptable quality as it may relate to the safety or 
effectiveness of the product.  Overall, the nature and type of data required to support such a 
demonstration  has historically  been similar for biological  products approved under the FD&C 
Act or licensed under the PHS Act. 
 
However, there are limited  differences with respect to the type, timing,  and evaluation  of certain 
data in submissions,  and verification  of these data during the review cycle and inspection  varies.  
For example, validation  data would be required to be submitted in BLA supplements to support 
certain postapproval changes (21 CFR 601.12).  In another example, for biological  products that 
do not fall within the specified categories of biological  products described in 21 CFR 601.2 
(non-specified  biological  products), compliance with the establishment standards set forth 
under 21 CFR 600.10, 600.11, 600.12, and 600.13 may be required for a BLA supplement to 
support certain postapproval  changes (e.g., addition  of a new facility).   
 
Application  holders that intend to propose manufacturing changes are encouraged to contact 
OPQ/OPRO at CDER-OPQ-Inquiries@fda.hhs.gov.  FDA is committed to working with 
application  holders to minimize  any potential burden. 
 
1.  Data Necessary to Support a Process or Manufacturing Site Change 
 
Supplements to applications  for biological  products subject to the transition provision  that 
remain under review after the transition  date, including  supplements submitted prior to the 
transition date, must comply with 21 CFR 601.12 and other applicable regulations.  Applicants 
should also consult relevant guidances for biological  products.  A supplement submitted to a 
deemed BLA to support process or manufacturing  site changes must contain, for the lots 
manufactured using the postchange process, manufacturing process validation  data (see 21 CFR 
601.12).  Specifically,  process validation  for a BLA should be performed at commercial 
manufacturing scale, prior to submission  of a supplement.  Process validation  information  should 
  19  Contains Nonbinding Recommendations 
 
be included in the supplement as this may affect submission  and implementation  timelines  of the 
changes for commercial distribution.   
 
A supplement requesting approval of a proposed change to the manufacturing site for a 
biological  product also must assess the effects of the change and contain sufficient information  to 
support the safety, purity, and potency of material manufactured with the change (21 CFR 
601.12(a)(2); compare 21 CFR 314.70).  In assessing the effects of the change, information 
demonstrating  comparability  of the pre and postchange material should also be submitted, 
consistent with the International  Council for Harmonisation  of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) guidance for industry Q5E Comparability of 
Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process (June 
2005) and the recommendations  below. 
 
  Comparability  data. 
 
-  The type and amount of data needed to support a comparability  exercise depends on 
the extent of the changes and the potential  risk to product quality.   A robust control 
strategy for drug substance and drug product is critical in generating comparability 
data.  For example, a potency assay that is accurate, precise, and reliable will 
facilitate the review of manufacturing changes.  In some cases, in addition  to the 
typical battery of release tests, extended characterization may be necessary for 
comparison, in particular for process changes that may affect purity, potency, or 
safety of the product. 
 
  Batch analysis data. 
 
  Appropriate stability  data. 
 
-  Generally,  limited  real-time stability  data for the postchange product and 
comparability  study results, including  stability  data under accelerated and stressed 
storage conditions,  are sufficient to leverage existing  stability  data to support the shelf 
life of the postchange product.   
 
As with all biological  products, FDA may recommend changes to the control strategy throughout 
the product life cycle to modernize outdated assays, to address product-specific issues, and to 
help ensure that biological  products remain safe, pure, and potent for their approved conditions 
of use. 
 
  2.  Facility Inspections Related to Certain Supplements to a Deemed 351(a) BLA 
 
Whether a biological  product is regulated under the FD&C Act or the PHS Act, application 
holders for biological  products should be ready for FDA inspections to assure such compliance 
with the conditions  of approval.   
 
After March 23, 2020, supplements submitted to deemed BLAs, including  supplements 
submitted prior to the transition  date but with an action date after the transition  date, must 
  20  Contains Nonbinding Recommendations 
 
comply with the inspection  requirements as specified in the relevant regulations  in 21 CFR part 
600.  
 
In particular, supplements for site changes where facilities  are added to the license or 
supplements for major manufacturing changes may be subject to an inspection.  FDA intends to 
contact the holder of a deemed BLA to schedule any such inspection  during the review of the 
supplement.  After March 23, 2020, holders of deemed BLAs that submit a site change or major 
manufacturing change supplement are advised that, as with the holder of any BLA, they should 
be ready for an inspection  while in operation and manufacturing the product for which the 
change is requested during the supplement review timeframe.  
 
Q17.  Can the application holder for a deemed 351(a) BLA for a biological product 
originally approved through the 505(b)(2) pathway submit a supplement that relies, 
in part, on FDAs finding of safety, purity, and potency for another licensed 
biological product? 
 
Supplements to a deemed 351(a) BLA, like any supplement to any 351(a) BLA, must meet the 
requirements of section 351(a) of the PHS Act.  The holder of a deemed BLA for a biological 
product originally  approved through the 505(b)(2) pathway may not, for example, submit an 
efficacy supplement to the deemed 351(a) BLA that relies on FDAs finding  of safety, purity, 
and potency for another licensed biological  product (e.g., for a newly approved indication  or 
other condition  of use for a related biological  product). 
 
There might be instances where there is a pending 505(b)(2) efficacy supplement to a stand-
alone NDA or a pending 505(b)(2) efficacy supplement to a 505(b)(2) application  that would be 
administratively  converted to a pending efficacy supplement to the corresponding  deemed 351(a) 
BLA on the transition date.  To obtain approval under section 351(a) of the PHS Act, the 
applicant may need to amend the administratively  converted supplement to provide the scientific 
data necessary to meet the requirements of section 351(a) of the PHS Act, or a right of reference 
to such data, for the change proposed in the supplement. 
 
Q18.   Can a biological product approved in an NDA that is deemed to be a 351(a) BLA on 
the transition date subsequently be a reference product for a proposed biosimilar 
or interchangeable product?  
 
A biological  product approved in an NDA (including  a 505(b)(2) application)  that is deemed 
licensed under section 351(a) of the PHS Act may be a reference product for a 351(k) BLA.  The 
term reference product is defined as the single biological  product licensed under section 351(a) 
of the PHS Act against which a biological  product is evaluated in an application  submitted under 
section 351(k) of the PHS Act (see section 351(i)(4) of the PHS Act).   
 
Sponsors may request advice from FDA regarding proposed biosimilar  or interchangeable 
product development programs that identify  a biological  product approved under section 505 of 
the FD&C Act as the intended reference product.  A sponsor will be able to submit a 351(k) 
BLA that references the biological  product approved under section 505 of the FD&C Act as its 
reference product after the NDA for the biological  product is deemed to be a 351(a) BLA.   
  21  Contains Nonbinding Recommendations 
 
 
Q19.  Can an application holder for a biological product that is the subject of a deemed 
351(a) BLA seek a determination of biosimilarity or interchangeability under 
section 351(k) of the PHS Act to another biological product licensed under section 
351(a) of the PHS Act? 
 
Any person (including  an application  holder for a biological  product that is the subject of a 
deemed 351(a) BLA) may seek to establish the biosimilarity  or interchangeability  under 
section 351(k) of the PHS Act of a proposed biosimilar  or interchangeable product to another 
biological  product licensed or deemed licensed under section 351(a) of the PHS Act.  FDA 
intends to work with applicants to address scientific or regulatory issues that may arise in the 
context of these 351(k) development  programs, and to provide additional  procedural information.   
Any sponsor or applicant may contact the relevant review division  within  the Office of New 
Drugs in FDAs CDER to request advice on a 351(k) development  program. 
 
D.  Transition of Biological Products from the Orange Book to the Purple Book 
 
Q20.  Will any therapeutic equivalence evaluations for biological products previously 
listed in the Orange Book be reflected in the Purple Book?   
 
No, the Purple Book does not include therapeutic equivalence evaluations as reflected in the 
Orange Book.  The Purple Book identifies,  among other things,  whether a biological  product 
licensed under section 351(k) of the PHS Act has been determined by FDA to be biosimilar  to, or 
interchangeable with, an FDA-licensed biological  reference product.  
 
E.  Designation of Proper Name  
 
Q21.  What will be the proper name for a biological product that has been approved in an 
NDA that is deemed to be a BLA?  
 
The proper name is the nonproprietary  name designated by FDA in the license for a biological 
product licensed under the PHS Act (section 351(a)(1)(B)(i) of the PHS Act and 21 CFR 
600.3(k)).  FDA does not intend to apply the nonproprietary  naming convention (in which the 
proper name is composed of a core name and a four-letter distinguishing  suffix) to biological 
products that are the subject of an approved application  under section 505 of the FD&C Act that 
is deemed to be a license under section 351(a) of the PHS Act.  This is consistent with what was 
previously  communicated in FDAs draft guidance for industry Nonproprietary Naming of 
Biological Products: Update (March 2019).20   
 
 
                                              
20 When final, this guidance will represent the FDAs current thinking on this topic.  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. 
  22  Contains Nonbinding Recommendations 
 
IV.  COMPLIANCE POLICY FOR REQUIREMENTS RELATED TO LABELING  
 
To minimize  possible disruption  to the distribution  of biological  products that are the subject of 
the transition provision  and to minimize  burden on holders of deemed BLAs, FDA generally 
does not intend to object to the labeling  of biological  products that are marketed under a deemed 
BLA with labeling  that does not conform to certain labeling  requirements for BLAs until March 
23, 2025, provided that all other applicable labeling  requirements are met.  The compliance 
policy set forth in this guidance would apply only as described below.   
 
FDA generally does not intend to object to the labeling  of biological  products that are marketed 
under a deemed BLA and that are introduced or delivered for introduction  into interstate 
commerce between March 23, 2020, and March 22, 2025, where the package is not marked with: 
 
  The proper name of the biological  product contained in the package (provided that the 
current packaging is plainly  marked with the established name of the biological  product); 
 
  The name and address of the manufacturer of the biological  product (provided that the 
current packaging is plainly  marked with the name and place of business of the 
manufacturer, packer, or distributor  as required in 21 CFR 201.1); 
 
  The applicable license number; or 
 
  Other information  required by 21 CFR 610.60 through 610.64, for which there is not a 
corresponding  requirement under 21 CFR 201.1. 
 
FDA also generally does not intend to object to the labeling  of biological  products that are 
marketed under a deemed BLA and that are introduced or delivered for introduction  into 
interstate commerce between March 23, 2020, and March 22, 2025, where the content and 
format of labeling  required by 21 CFR 201.56, 201.57, 201.80, and/or 208.20, as applicable, 
does not include the following  information: 
 
  The proper name of the biological  product, including  any appropriate descriptors 
(provided that the current labeling  uses the established name of the biological  product); 
 
  The name and address of the manufacturer of the biological  product (provided that the 
current labeling  includes the name and place of business of the manufacturer, packer, or 
distributor  as required by 21 CFR 201.1); 
 
  The applicable license number; or 
 
  For biological  products with approved labeling  in the format described by 21 CFR 
201.56(d) and 201.57 (PLR format), the year of Initial U.S. Approval of the new 
biological  product (provided that the current labeling  includes the year of Initial U.S. 
Approval of the new molecular entity). 
 
  23  Contains Nonbinding Recommendations 
 
FDA notes that the timing  of BLA-specific revisions to the prescribing  information  should be 
coordinated with the corresponding  revisions to the container labels, carton labeling,  and any 
FDA-approved patient labeling  for the biological  product to ensure consistency among the 
different types of product labeling.   
 
If the holder of a deemed BLA for a biological  product has an administratively  converted 
supplement that includes proposed revisions to product labeling  or submits a supplement that 
includes proposed revisions to product labeling  before March 22, 2025 (i.e., the end of the 
compliance period), and the required BLA-specific labeling  revisions to container labels, carton 
labeling,  and prescribing information  referenced in this guidance have not already been 
addressed, such revisions would need to be addressed before the supplement could be approved 
(see, e.g., 21 CFR 610.60).  A changes-being-effected (CBE-0) supplement may be submitted 
prior to submission  of a prior approval supplement that includes the BLA-specific labeling 
revisions.  However, the prior approval supplement would need to be approved before or 
concurrent with approval of the CBE-0 supplement.  Under this approach, holders of deemed 
BLAs may coordinate BLA-specific labeling  updates with their plans for other proposed 
revisions to product labeling.   
 
After FDA approval of a supplement for the BLA-specific labeling  revisions, FDA understands 
that application  holders may need to wait to implement these labeling  revisions until their next 
printing  of the labels and labeling.   Accordingly,  to enable such application  holders to exhaust 
existing inventory,  FDA generally does not intend to object to the labeling  of biological  products 
that are marketed under a deemed BLA where FDA has already approved a supplement that 
includes the BLA-specific labeling  revisions but the labels and labeling  do not include the BLA-
specific labeling  revisions prior to March 22, 2025. 
 
 
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