Draft Guidance for Industry: Cooperative Manufacturing Arrangements for Licensed Biologics

Guidance for Industry
Cooperative Manufacturing
Arrangements for Licensed Biologics
DRAFT GUIDANCE – NOT FOR IMPLEMENTATION

For questions on the content of this guidance, contact the Office of the Director (Center for
Biologics Evaluation and Research) at 301-827-0373 and the Office of Pharmaceutical Science
(Center for Drug Evaluation and Research) at 301-796-2400.

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research
Center for Drug Evaluation and Research
July 2007

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Guidance for Industry
Cooperative Manufacturing
Arrangements for Licensed Biologics
Additional copies of this guidance are available from:
Office of Communication, Training and
Manufacturers Assistance, HFM-40
Center for Biologics Evaluation and Research
Food and Drug Administration
1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448
Phone: 800-835-4709 or 301-827-1800
Internet: http://www.fda.gov/cber/guidelines.htm
or
Office of Training and Communication
Division of Communications Management
Drug Information Branch, HFD-210
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane, Rockville, MD 20857
Phone: 301-827-4573
Internet: http://www.fda.gov/cder/guidance/index.htm

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Table of Contents
I.

SCOPE ............................................................................................................................... 2

II.

INTRODUCTION............................................................................................................. 3

III.

SHORT SUPPLY ARRANGEMENTS........................................................................... 4

IV.

DIVIDED MANUFACTURING ARRANGEMENTS .................................................. 5
A.
B.
C.

V.

SHARED AND CONTRACT MANUFACTURING ARRANGEMENTS ................. 6
A.
B.

VI.

General................................................................................................................... 5
Recordkeeping Requirements.............................................................................. 5
Labeling ................................................................................................................. 5
Shared Manufacturing Arrangements................................................................ 6
Contract Manufacturing Arrangements........................................................... 10

REFERENCES................................................................................................................ 14

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Guidance for Industry
Cooperative Manufacturing Arrangements for Licensed Biologics
This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s)
current thinking on this topic. It does not create or confer any rights for or on any person and
does not operate to bind FDA or the public. You can use an alternative approach if the
approach satisfies the requirements of the applicable statutes and regulations. If you want to
discuss an alternative approach, contact the appropriate FDA staff. If you cannot identify the
appropriate FDA staff, call the appropriate number listed on the title page of this guidance.

I.

SCOPE

The development of complex and highly specialized technology and equipment for the
manufacture of biological products has fostered the emergence of many companies that perform
only limited aspects of manufacturing processes. Consequently, many manufacturers are
interested in sharing or contracting parts of manufacturing in order to facilitate product
development and manufacturing flexibility. Cooperative manufacturing arrangements enhance
the development of new products.
Therefore, we, the Food and Drug Administration (FDA), are issuing this guidance on
cooperative manufacturing arrangements applicable to biological products subject to licensure
under section 351 of the Public Health Service Act (PHS Act) (42 U.S.C. 262). This document
is issued jointly between the Center for Biologics Evaluation and Research (CBER) and the
Center for Drug Evaluation and Research (CDER). This guidance describes our current thinking
on licensing strategies for meeting the increased need for flexible manufacturing arrangements.
Since cooperative manufacturing arrangements can take a considerable amount of time to
develop, this guidance may also be useful for planning purposes in the early phases of product
development.
FDA registered manufacturers of biological products and transfusion services may also choose to
follow this guidance.
This guidance supersedes “FDA’s Policy Statement Concerning Cooperative Manufacturing
Arrangements for Licensed Biologics” published in the Federal Register of November 25, 1992
(57 FR 55544) (Ref. 1), and revises the draft guidance of the same title dated August 1999.
FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the FDA’s current thinking on a topic and should be
viewed only as recommendations, unless specific regulatory or statutory requirements are cited.

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The use of the word should in FDA’s guidances means that something is suggested or
recommended, but not required.

II.

INTRODUCTION

Under section 351(a)(2)(C) of the PHS Act, FDA will approve a biologics license application
(BLA) on the basis of a demonstration that the biological product is safe, pure, and potent, and
that the facility in which the biological product is manufactured meets standards designed to
assure that the biological product continues to be safe, pure, and potent. 1 Section 351(c) of the
PHS Act authorizes FDA to conduct a pre-approval inspection of the facility in which the
product is manufactured.
FDA’s biologics regulations define “manufacturer” as “any legal person or entity engaged in the
manufacture of a product subject to license under the PHS Act,” including “any legal person or
entity who is an applicant for a license where the applicant assumes responsibility for
compliance with the applicable product and establishment standards” (21 Code of Federal
Regulations (CFR) 600.3(t)). A manufacturer thus includes a license applicant, who may or may
not own the facilities engaged in significant manufacturing steps, when such an applicant
assumes responsibility for compliance with the applicable product and establishment standards,
including, but not limited to, 21 CFR Parts 210, 211, 600 through 680, and 820.
“Manufacture” is defined as “all steps in propagation or manufacture and preparation of products
and includes but is not limited to filling, testing, labeling, packaging, and storage by the
manufacturer” (21 CFR 600.3(u)).
A manufacturer of a biological product must demonstrate responsibility for the manufacturing
process as described in its BLA (21 CFR 600.3(t)). For example, a manufacturer must avoid
introduction of contaminants during production (21 CFR 610.13).
Adequate supervision and control over the manufacture of a biological product has often been
achieved by a single manufacturer performing all steps in the production of a product within
facilities owned and operated by that manufacturer. However, as described in our 1992 policy
statement on cooperative manufacturing arrangements, we have accepted various alternative
arrangements involving more than one manufacturer. These alternative manufacturing
arrangements include short supply and divided manufacturing, as well as shared and contract
manufacturing arrangements. Certain regulatory requirements are partially described for short
supply in 21 CFR 601.22 and for divided manufacturing in 21 CFR 600.12(e) and 610.63.
We previously published guidance that clarified that small scale or pilot facilities are eligible for
licensure provided they are fully qualified and validated, operate in accordance with CGMP
1

FDA has interpreted the definition of the term “potency” in 21 CFR 600.3(s) to include effectiveness.
Furthermore, biological products also meet the definition of “drug” or “device” under the Federal Food, Drug, and
Cosmetic Act (FDC Act), and therefore are also subject to certain requirements in the FDC Act and its implementing
regulations such as current good manufacturing practice (CGMP) provisions.

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requirements, and otherwise comply with applicable laws and regulations (Ref. 2). The
principles described in this guidance are designed to assure that the safety, purity, and potency of
biological products will not be compromised as a result of innovative, flexible manufacturing
arrangements.

III.

SHORT SUPPLY ARRANGEMENTS

Under 21 CFR 601.22 if a product is in short supply, a licensed biologic manufacturer may
obtain the initial and partially-manufactured version of the product from unlicensed facilities
when the following conditions are met:
•
•
•
•
•

manufacturing at the unlicensed location is limited to the initial and partial manufacturing
of a product for shipment solely to the licensee;
the name and place of the unlicensed location are registered with FDA (see e.g.,
registration and listing provisions in 21 CFR Parts 207 and 607);
the licensed manufacturer files an application explaining that the product is in short
supply due either to peculiar growth requirements of the organism involved or to the
scarcity of the source required for manufacturing purpose;
FDA makes a finding agreeing with the licensed manufacturer’s explanation; and
the licensed manufacturer can ensure that, through inspections, testing, or other
procedures, the product made at the unlicensed facility will be made in full compliance
with applicable regulations.

The short supply provisions have limited applicability. Although some industries, such as those
involving recovered plasma deal with these provisions more often, they are generally used in
unusual circumstances where the licensed product is scarce or growth requirements are so
peculiar that production is infrequent.
Licensed manufacturers may use these provisions to obtain source materials only. Such source
materials undergo specified limited processing only. Examples of materials that might be
obtained under short supply include:
•
•
•
•
•
•

certain source materials used in producing allergenic extracts;
specific types of human plasma containing rare antibodies;
venoms used in producing antitoxins and antivenins;
recovered plasma;
unlicensed Red Blood Cells used to manufacture blood bank reagents; and
materials made in non-human animals.

Suppliers of source materials are subject to FDA inspection under section 704(a) of the FDC Act.
A licensed manufacturer desiring to enter into a short supply arrangement should either file the
required information and assurances with its original BLA under 21 CFR 601.2 or submit it to

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either CBER or CDER, as appropriate, as a change to an approved application as described in
21 CFR 601.12.

IV.

DIVIDED MANUFACTURING ARRANGEMENTS

Divided manufacturing is an arrangement in which two or more manufacturers, each registered
with FDA in accordance with 21 CFR Parts 207, 607, or 807 as applicable, and licensed to
manufacture a specific biological product in its entirety, participate jointly in the manufacture of
that product.
A.

General

We recommend that manufacturers desiring to enter into a divided manufacturing
arrangement describe the role of each manufacturer in an original application or
supplement(s) to the manufacturers’ BLAs, as appropriate. We recommend that the
application(s) or supplement(s) describe the steps to be performed at each facility and
include the labeling that will be used on any intermediate and final products.
Factors we consider in determining whether to approve these submissions include, but are
not limited to:
•
•
•
•

conformance to licensed manufacturing procedures and specifications;
equivalence of the intermediate products;
ability of the manufacturers to demonstrate the stability of the intermediate
product during shipment; and
adequacy of intermediate and finished product labels and labeling.

Each licensed manufacturer in a divided manufacturing arrangement must notify the
appropriate FDA Center regarding proposed changes in the manufacture, testing, or
specifications of its product, in accordance with 21 CFR 601.12 (see Refs. 3, 4, and 5).
Each licensed manufacturer that proposes such a change should inform other
participating licensed manufacturer(s) of the proposed change.
B.

Recordkeeping Requirements

All manufacturers participating in a divided manufacturing arrangement must comply
with the recordkeeping requirements of 21 CFR Parts 210 and 211, and
21 CFR 600.12(e) as applicable, and the other applicable CGMP regulations.
C.

Labeling

The name, address, and license number of each participating licensed manufacturer must
appear on the package label, and on the label of the container if capable of bearing a full
label (21 CFR 610.63). FDA’s experience has shown that the display of names,
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addresses, and license numbers of all participating manufacturers on container labels has
not always been feasible, particularly in the case of multiple party manufacturing
arrangements.
FDA is concerned that the appearance of multiple names and addresses on the outer label
affixed to a package may cause confusion and limit the prominence of more important
labeling statements. Under 21 CFR 600.3(cc), the term “package” is defined to include
the package insert. To comply with 21 CFR 610.63, we recommend that you do the
following:
•
•

place the name, address, and license number of the manufacturer of the finished
dosage form and the manufacturer responsible for reporting adverse events of the
biological product on the outer label affixed to the package; and
place the names, addresses, and license number(s) of all manufacturer(s)
participating in the divided manufacturing arrangement in the product package
insert.

A licensed intermediate product will be approved for further manufacturing use, and
accordingly, we recommend that the phrase, “for further manufacturing use” be included
as part of the proper name. If included as part of the proper name, the phrase must appear
on the label affixed to each package containing the product (21 CFR 610.61), as well as
the container label if capable of bearing a full label (21 CFR 610.60).
Blood products are often the subject of divided manufacturing arrangements. Under
21 CFR 606.121(c)(2), a registration number must also be on the container label for
blood and blood components for transfusion, and if a licensed product, the license
number of each manufacturer.

V.

SHARED AND CONTRACT MANUFACTURING ARRANGEMENTS

We recognize that a biologic manufacturer seeking licensure may not have the capability or may
choose not to perform all operations at an establishment under its legal ownership. Where a
license applicant decides not to manufacture the biological product in its entirety (beginning with
raw materials through final formulation, filling, packaging, and labeling), the license applicant
may seek to enter into either a shared or contract manufacturing arrangement with one or more
manufacturers, as described below.
A.

Shared Manufacturing Arrangements

Shared manufacturing is an arrangement in which two or more manufacturers are
licensed and responsible for specific aspects of the manufacture of a product but none is
licensed for all aspects of the manufacture of the product.

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A common shared manufacturing arrangement is one in which one manufacturer is
responsible for an intermediate product and another for the final product.
1.

General

A participating manufacturer may perform the specified manufacturing steps
and/or contract with another entity(ies) and assume responsibility for compliance
with the applicable product and establishment standards as described for an
applicant in 21 CFR 600.3(t). A participating manufacturer that performs (or is
responsible for the performance of) significant product manufacturing is
considered eligible for separate licensure under this arrangement.
Significant manufacturing steps that may affect a product’s safety, purity, or
potency and, which we have considered adequate for separate licensure include,
but are not limited to, the following:
•
•
•
•
•
•
•
•

inoculation of vessels or animals for production;
cell culture production and characterization;
fermentation and harvesting;
isolation;
purification;
physical and chemical modifications;
required infectious disease testing of blood and blood components; and
blood donor recruitment and maintenance of donor deferral registries.

Manufacturing steps that would not by themselves ordinarily warrant separate
licensing, even though important to the purity and integrity of the final product,
include:
•
•
•
•
•

chemical and biological testing other than blood infectious disease testing;
formulation;
sterile filling;
lyophilization; and
labeling.

When any of these steps are proposed to be performed by another manufacturer,
we will generally view it as a procedure that may be performed under a
contractual arrangement (see section V.B below). However, we also recognize
that companies may conceive and develop innovative products through extensive
preclinical and clinical testing, but choose to limit their participation in product
manufacturing. Therefore, we will consider a manufacturer eligible for separate
licensure if that manufacturer is both instrumental in product development and
performs (or is responsible for the performance of) several final manufacturing

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steps, such as formulation, sterile filling, lyophilization, labeling, packaging, and
final release testing.
Manufacturers desiring to enter into a shared manufacturing arrangement must
register with FDA in accordance with registration and listing provisions in
21 CFR Part 207, 607, or 807, as applicable.
2.

BLAs

Each manufacturer must submit a separate BLA describing the manufacturing
facilities and operations applicable to the preparation of that manufacturer’s
biological substance or product (21 CFR 601.2(a)). Each BLA must meet the
requirements of 21 CFR 601.2 and fully describe:
•
•
•
•
•
•
•

the extent of manufacturing and testing performed by that participating
manufacturer;
the specifications;
the storage and shipping conditions;
the manufacturing methods;
stability data;
product lots available for examination; and
the labeling that will accompany that manufacturer’s product.

We recommend that all license applications/supplements that pertain to a
particular product to be manufactured under a shared manufacturing arrangement
be submitted concurrently (i.e., on the same date) so that we can conduct a
complete review of the product, since we will depend on information contained in
all related applications when determining whether to issue the biologics license.
Lack of one or more related applications may be a basis for a refusal to file action
(Ref. 6).
Please consult the appropriate guidance document regarding submission of
chemistry, manufacturing, and controls information for technical guidance on the
content and format of a license application (Refs. 7-14).
a.

Intermediate products

A common shared manufacturing agreement is one in which one
manufacturer is responsible for an intermediate product and another for
the final product. An application/supplement for an intermediate
product licensed “for further manufacturing use” must include, in
addition to other information in a BLA, the criteria used to determine
lot-by-lot acceptability of the product (21 CFR 601.2), including:

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•
•
•
•
•

sterility (or bioburden);
stability;
product characterization;
potency; and
purity specifications.

Manufacturers of all intermediate products must demonstrate that their
products will consistently meet established specifications
(21 CFR 601.2).
We intend to accept only those BLAs/supplements for biological
products intended for further manufacture in a shared manufacturing
arrangement that specify the licensed manufacturer or manufacturers to
which the intermediate product will be shipped. These
BLAs/supplements will be approved only after demonstration of safety
and efficacy of the final product.
b.

Final product

We will accept only those BLAs/supplements for final products in a
shared manufacturing arrangement that specify the source(s) of the
intermediate product(s) to be used. The approval of the final product
will be dependent upon established criteria for receipt and acceptance of
the intermediate(s).
We expect the manufacturer that prepares (or is responsible for the
preparation of) the product in final form for commercial distribution to
assume primary responsibility for providing data demonstrating the
safety, purity, and potency of the final product. We also expect the
licensed finished product manufacturer to be primarily responsible for
any postapproval obligations, such as postmarketing clinical trials,
additional product stability studies, complaint handling, recalls,
postmarket reporting of the dissemination of advertising and
promotional labeling materials as required under 21 CFR 601.12(f)(4)
and adverse experience reporting. We recommend that the final product
manufacturer establish a procedure with other participating
manufacturer(s) to obtain information in these areas.
3.

Responsibilities of Each Participating Manufacturer

Each licensed manufacturer in a shared manufacturing arrangement must notify
the appropriate FDA center regarding proposed changes in the manufacture,
testing, or specifications of its product (21 CFR 601.12; see Refs. 3, 4 and 5); and

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should notify other participating licensed manufacturer(s) of such proposed
change.
We expect license manufacturers to have the technical knowledge and expertise
needed to identify manufacturing problems or deviations and take responsibility
for conducting preventive and/or corrective action to ensure the safety and
effectiveness of the product (21 CFR 211.25).
All manufacturers participating in a shared manufacturing arrangement must also
comply with the recordkeeping requirements of 21 CFR Parts 210 and 211, and
the other applicable CGMP regulations.
Each manufacturer in a shared manufacturing arrangement who holds a biological
product license is responsible for reporting biological product deviations that
occurred when the product was in its control (21 CFR 600.14).
4.

Labeling

The labeling for products prepared in a shared manufacturing arrangement must
comply with applicable provisions of 21 CFR 610.60 through 610.67, including
identification of all participating licensed manufacturers.
FDA interprets 21 CFR 610.63 for divided manufacturing arrangements to apply
to products manufactured by more than one licensed manufacturer, including
shared manufacturing arrangements. In such cases, the package label provisions
of that section may be met by placing the name, address, and license number of
the final product manufacturer and the manufacturer responsible for reporting
adverse events on the outer label affixed to the package, and by placing the
names, addresses, and license numbers of manufacturers participating in the
shared manufacturing arrangement in the product package insert. The end user
may then identify contributing manufacturing firms more efficiently.
Since a licensed intermediate product will be approved for further manufacturing
use, we recommend that the phrase, “for further manufacturing use” be included
as part of the proper name. If included as part of the proper name, the phrase
must appear on the label affixed to each package containing the product
(21 CFR 610.61), as well as the container label, if capable of bearing a full label
(21 CFR 610.60).
B.

Contract Manufacturing Arrangements

For the purposes of this document, contract manufacturing refers to a situation in which a
license manufacturer establishes a contract with another entity(ies) to perform some or all
of the manufacture of a product as a service to the license manufacturer. This includes,

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for example, required infectious disease testing of blood and blood components
conducted by licensed blood establishments for another manufacturer.
A contract facility that is engaged in significant manufacturing is not required to be
separately licensed, as is the case in a Shared Manufacturing Arrangement.
1.

Responsibilities of License Manufacturer

A license manufacturer that establishes a contract with another entity to perform
some or all of the manufacture of a product is responsible for:
•
•
•

the safety, purity, and potency of the product (PHS Act; 21 CFR Parts 600
through 680);
ensuring that manufacture of the product complies with the provisions of
the BLA and the applicable regulations, including, but not limited to,
21 CFR Parts 210, 211, 600 through 680, and 820; and
compliance with both product and establishment standards.

Product and establishment standards, and applicable regulations may include, but
are not limited to, the following:
•
•
•
•
•
•
•
•
•
•
•
•

product release and in-process specifications (21 CFR 211.110 and 610.1);
adverse experience reports, biological product deviation reports, medical
device reporting systems (21 CFR 600.14, 600.80, 606.171, 803.20,
803.50, and 803.53);
production and process controls (21 CFR Part 211.100 through 211.115);
reporting changes to the production process and all facilities as required
by 21 CFR 601.12;
maintenance of master production records and control records for drug
products and device master records and device history records for devices
(21 CFR 211.186, 820 181, 820.184);
laboratory controls, including testing and release for distribution
(21 CFR 211.160 through 176);
submission of protocols and samples for lot release, where applicable
(21 CFR 610.2);
labeling (21 CFR Part 201, 610.60 through 610.62, 606.120 through 122,
660.2(c), 660.28, 660.35, 660.45, 660.55, and Parts 801 and 809);
systems to ensure continued CGMP functioning of equipment and
facilities (21 CFR Part 211, Subpart D);
environmental monitoring (21 CFR 211.42(c)(10)(iv));
infectious disease testing of blood and blood components
(21 CFR 610.40); and
training of personnel (21 CFR 211.25 and 600.10).

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The contract manufacturer should share with the license manufacturer all
important proposed changes to production and facilities (including introduction of
new products or at inspection). The license holder is responsible for reporting
these changes to FDA (21 CFR 601.12; see Refs. 3, 4, and 5).
2.

Responsibilities of the Contract Manufacturer

Because the contract manufacturer is engaged in the manufacture of a drug or
device, it must comply with applicable provisions of the FDC Act (21 U.S.C. 301
et. seq.) and applicable regulations.
Contract facilities are subject to FDA inspection under section 351(c) of the PHS
Act and section 704(a) of the FDC Act. Facilities performing contract operations
for biological products must register with FDA in accordance with registration
and listing provisions in 21 CFR Parts 207, 607, or 807.
Because the license manufacturer must ensure that the contract site complies with
applicable product and establishment standards, the license manufacturer should
have access to floor plans, equipment validation, and other production
information. The license manufacturer must have a procedure in place for
receiving information from the contract facility on all deviations, complaints, and
adverse events (21 CFR 600.14(a); 606.171(a); 803.10).
We reiterate that the contract manufacturer should fully inform the license
manufacturer of the results of all tests and investigations regarding or possibly
having an impact on the product.
We remind the license manufacturer that the license manufacturer assumes
responsibility for compliance with the applicable product and establishment
standards (21 CFR 600.3(t)). Therefore, if the license manufacturer enters into an
agreement with a contract manufacturing facility, the license manufacturer must
ensure that the facility complies with the applicable standards. An agreement
between a license manufacturer and a contract manufacturing facility normally
includes procedures to regularly assess the contract manufacturing facility’s
compliance. These procedures may include, but are not limited to, review of
records and manufacturing deviations and defects, and periodic audits.
The license manufacturer should be aware that all contract manufacturing
locations must be in compliance with CGMP regulations and are subject to
inspection from the time of the submission. We also recommend that the license
manufacturer obtain assurance from the contractor that any FDA list of
inspectional observations will be shared with the license manufacturer to allow
evaluation of its impact on the purity, potency, and safety of the license
manufacturer’s product.

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In accordance with 21 CFR 200.10, FDA may disclose any information obtained
during the inspection of a contract facility having a specific bearing on
compliance with the FDC Act to the license manufacturer.
Compliance actions, such as license revocation, may be considered against the
license manufacturer for failure of the contract manufacturer to comply with
CGMP regulations or otherwise fail to fulfill requirements of the license for
which the contract manufacturer is contractually responsible.
Please consult the appropriate guidance document regarding submission of
chemistry, manufacturing, and controls information for technical guidance on the
suggested content and format of a license application, including a complete
description of all contract manufacturing operations (Refs. 7-13).
For each contract arrangement, the license manufacturer’s BLA/supplement
should describe the product subject to contract manufacturing, including:
•
•
•
•

the product stability and the manner of shipment to and from the contract
facility;
the responsibilities of each participating entity;
contract manufacturers’ names, address, license number, if applicable, and
registration number; and
a list of all standard operating procedures applicable to the contract
arrangement.

Contract firms that do not wish to provide all necessary information to the license
manufacturer should consider a shared manufacturing arrangement.
3.

Master Files

We recommend that a license manufacturer cross reference a contract
manufacturing facility’s Master Files only in circumstances involving certain
proprietary information of the contract manufacturer, such as:
•
•

a list of all products manufactured in a contract facility (in this situation
the license manufacturer should be kept informed of the types or
categories of all products manufactured in the contract facility).
noncompendial test procedures (standard operating procedures) (provided
there is assurance that both the license manufacturer and FDA will be
informed of all changes in these procedures).

The BLA/supplement(s) may also refer to Master Files for information regarding
containers and closures.

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4.

Labeling

The labeling for final products prepared under a contractual agreement must
comply with the applicable provisions of 21 CFR 610.60 through 610.65, and
21 CFR Parts 201 and 809, where applicable. Because the contract facilities are
considered to be under the control of the license holder, specific identification of
the contractor in the product labeling is not required.
We recommend that the labeling for an intermediate product intended for
shipment to or from a contract facility include a statement that it is intended for
further manufacture. We recommend that licensed intermediate products include
“for further manufacture” as part of the proper name. If included as part of the
proper name, the phrase must appear on the label affixed to each package
containing the product (21 CFR 610.61), as well as the container label, if capable
of bearing a full label (21 CFR 610.60). Licensed intermediates must also bear a
U.S. license number (21 CFR 610.61).

VI.

REFERENCES

1. FDA’s Policy Statement Concerning Cooperative Manufacturing Arrangements for Licensed
Biologics, November 25, 1992, 57 FR 55544.
2. FDA Guidance Document Concerning Use of Pilot Manufacturing Facilities for the
Development and Manufacture of Biological Products, July 11, 1995, 60 FR 35750.
3. Guidance for Industry: Changes to an Approved Application: Biological Products, July
1997.
4. Guidance for Industry: Changes to an Approved Application for Specified Biotechnology
and Specified Synthetic Biological Products, July 1997.
5. Guidance for Industry: Changes to an Approved Application: Biological Products: Human
Blood and Blood Components Intended for Transfusion or for Further Manufacture, July
2001.
6. Center for Biologics Evaluation and Research Refusal to File (RTF) Guidance for Product
License Applications (PLAs) and Establishment License Applications (ELAs), July 12, 1993.
7. Guidance for Industry: For the Submission of Chemistry, Manufacturing and Controls and
Establishment Description Information for Human Blood and Blood Components Intended
for Transfusion or for Further Manufacture and For the Completion of the Form FDA 356h
“Application to Market a New Drug, Biologic or an Antibiotic Drug for Human Use,” May
1999.

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8. Guidance for Industry: On the Content and Format of Chemistry, Manufacturing and
Controls Information and Establishment Description Information for an Allergenic Extract or
Allergen Patch Test, April 1999.
9. Guidance for Industry: Content and Format of Chemistry, Manufacturing and Controls
Information and Establishment Description Information for a Biological In Vitro Diagnostic
Product, March 1999.
10. Guidance for Industry: For the Submission of Chemistry, Manufacturing and Controls and
Establishment Description Information for Human Plasma-Derived Biological Products,
Animal Plasma or Serum-Derived Products, February 1999.
11. Guidance for Industry: Content and Format of Chemistry, Manufacturing and Controls
Information and Establishment Description Information for a Vaccine or Related Product,
January 1999.
12. Guidance for the Submission of Chemistry, Manufacturing, and Controls Information and
Establishment Description for Autologous Somatic Cell Therapy Products, January 1997.
13. Guidance for Industry for the Submission of Chemistry, Manufacturing, and Controls
Information for a Therapeutic Recombinant DNA-Derived Product or a Monoclonal
Antibody Product for In Vivo Use, August 1996.

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