The “Deemed to be a License” Provision of the BPCI Act: Questions and Answers : Guidance for Industry

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

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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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
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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 FDA’s 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 FDA’s 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 Agency’s
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).

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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, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s 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.

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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 product”6 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 FDA’s
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).

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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 FDA’s interpretation of this
“transition” provision, please refer to FDA’s 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 FDA’s 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 Innovatio n
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).

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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 FDA’s 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 FDA’s 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 s tatutory 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.

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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 FDA’s 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 FDA’s Approved Drug
Products With Therapeutic Equivalence Evaluations (the Orange Book) on March 23, 2020, and
will be listed in FDA’s 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 FDA’s 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 FDA’s 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.

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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 FDA’s 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 FDA’s 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).

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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 product’s 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.

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state whether an approved NDA will be deemed to be a 351(a) BLA or a 351(k) BLA. The
Agency’s 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 Agency’s 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 Agency’s 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, FDA’s approval of a 505(b)(2) application reflects the Agency’s 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 be en 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., FDA’s finding of safety and/or effectiveness
for a listed drug or published literature).

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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 applicant’s 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)).

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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 CDER’s Office of New Drugs (OND) after the transition date, subject to
any reassignments related to any reorganization of CDER’s 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 responsibilit ies within CDER’s 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.

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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 Agency’s 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.

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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 Agency’s 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 Agency’s 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.

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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.

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Table. Selected Requirements for Container Labels and Carton Labeling for Biological
Products
Labeling
Information
Change From NDA Labeling Requirements
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
Name, Address,
and License
Number
The name and address of the manufacturer (i.e., the BLA holder) must appear on
container labels and carton labeling in the format specified by the regulations (see 21
CFR 610.60(a)(2) and 610.61(b); see 21 CFR 600.3(t) for the definition of manufacturer
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
Product When a
Factor in Safe
Administration
Carton labeling must include the source of the product when a factor in safe
administration, such as products made from sources that may be allergenic (see 21 CFR
610.61(p)).
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

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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.”

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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.

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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 holder’s
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

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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 products—whether approved under
the FD&C Act or licensed under the PHS Act—to 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

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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

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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 FDA’s 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 FDA’s 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.

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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 FDA’s 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 FDA’s draft guidance for industry Nonproprietary Naming of
Biological Products: Update (March 2019).20
20 When final, this guidance will represent the FDA’s 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.

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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).

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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.