Guidance for Industry 
 
Cooperative Manufacturing 
Arrangements for Licensed Biologics 
 
 
 
 
 
 
 
Additional copies of this guidance are available from the Office of Communication, Training and 
Manufacturers Assistance (OCTMA) (HFM-40), 1401 Rockville Pike, Rockville, MD 20852-
1448 or by calling 1-800-835-4709 or 301-827-1800, or from the Internet at 
http://www.fda.gov/cber/guidelines.htm. 
 
For questions on the content of this guidance, contact OCTMA (Center for Biologics Evaluation 
and Research) at the phone numbers listed above 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  
November 2008 
 
OMB Control No. 0910-0338 
Expiration Date:  02/28/2023 
See additional PRA statement in Section VII of this guidance  Contains Nonbinding Recommendations 
 
 
 
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 Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 51, rm. 2201 
Silver Spring, MD 20993-0002  
Phone:  301-796-3400 
Internet:  http://www.fda.gov/cder/guidance/index.htm 
  Contains Nonbinding Recommendations 
 
 
 
Table of Contents 
 
I.  SCOPE ............................................................................................................................... 2 
II.  INTRODUCTION............................................................................................................. 3 
III.  SHORT SUPPLY ARRANGEMENTS .......................................................................... 4 
IV.  DIVIDED MANUFACTURING ARRANGEMENTS .................................................. 5 
A.  General ............................................................................................................. 5 
B.  Recordkeeping Requirements ........................................................................ 5 
C.  Labeling ........................................................................................................... 5 
V.  SHARED AND CONTRACT MANUFACTURING ARRANGEMENTS ................. 6 
A.  Shared Manufacturing Arrangements .......................................................... 6 
B.  Contract Manufacturing Arrangements..................................................... 10 
VI.  REFERENCES ................................................................................................................ 14 
VII.  PAPERWORK REDUCTION ACT OF 1995 .............................................................. 16 
i  Contains Nonbinding Recommendations 
 
 
 
Guidance for Industry 
 
Cooperative Manufacturing Arrangements for Licensed Biologics 
 
 
This guidance represents the Food and Drug Administrations (FDAs) 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 FDAs Policy Statement Concerning Cooperative Manufacturing 
Arrangements for Licensed Biologics published in the Federal Register of November 25, 1992 
(57 FR 55544) (Ref. 1), and finalizes the draft guidance of the same title dated July 2007, which 
revised the draft guidance of the same title dated August 1999. 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the FDAs current thinking on a topic and should be 
viewed only as recommendations, unless specific regulatory or statutory requirements are cited.  
2  Contains Nonbinding Recommendations 
 
 
 
The use of the word should in FDAs 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. 
 
FDAs 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. 
3  Contains Nonbinding Recommendations 
 
 
 
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 purposes;  
  FDA makes a finding agreeing with the licensed manufacturers 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 manufacturing process information and assurances with its original BLA under 
4  Contains Nonbinding Recommendations 
 
 
 
21 CFR 601.2 or submit it to 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).  FDAs experience has shown that the display of names, 
5  Contains Nonbinding Recommendations 
 
 
 
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. 
 
6  Contains Nonbinding Recommendations 
 
 
 
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 products 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 
7  Contains Nonbinding Recommendations 
 
 
 
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 manufacturers 
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 manufacturers 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. 7-13). 
 
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: 
8  Contains Nonbinding Recommendations 
 
 
 
  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 
9  Contains Nonbinding Recommendations 
 
 
 
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, 
10  Contains Nonbinding Recommendations 
 
 
 
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). 
 
11  Contains Nonbinding Recommendations 
 
 
 
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 facilitys 
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 
manufacturers 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 manufacturers 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 facilitys 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.  FDAs 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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VII.  PAPERWORK REDUCTION ACT OF 1995 
 
This guidance contains information collection provisions that are subject to review by the Office 
of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 
3501-3520). 
 
We believe that the information collection provisions in the guidance do not create a new burden 
for respondents.  We believe the reporting and recordkeeping provisions are part of usual and 
customary business practices.  Licensed manufacturers would have contractual agreements with 
participating licensed manufacturers, final product manufacturers, and contract manufacturers, as 
applicable for the type of cooperative manufacturing arrangement, to address all these 
information collection provisions.  Send comments regarding this burden estimate or suggestions 
for reducing this burden to: 
 
Food and Drug Administration 
Center for Biologics Evaluation and Research (HFM-99) 
1401 Rockville Pike, Suite 200N 
Rockville, MD 20852-1448 
 
This guidance also refers to previously approved collections of information found in FDA 
regulations at parts 201, 207, 211, 600, 601, 606, 607, 610, 660, 803, and 807 (21 CFR parts 201, 
207, 211, 600, 601, 606, 607, 610, 660, 803, and 807).  The collections of information in 
 606.121, 606.122, and 610.40 have been approved under OMB Control No. 0910-0116; 
 610.2 has been approved under OMB Control No. 0910-0206;  600.12(e) and 600.80 have 
been approved under OMB Control No. 0910-0308;  601.2(a), 601.12, 610.60, 610.61, 610.62, 
610.67, 660.2(c), 660.28(a) and (b), 660.35(a), 660.35(c) through (g), 660.35(i) through (m), 
660.45, and 660.55(a) and (b) have been approved under OMB Control No. 0910-0338; 
 803.20, 803.50, and 803.53 have been approved under OMB Control No. 0910-0437; and 
 600.14 and 606.171 have been approved under OMB Control No. 0910-0458.  The current 
good manufacturing practice regulations for finished pharmaceuticals (part 211) have been 
approved under OMB Control No. 0910-0139; the establishment registration regulations (parts 
207, 607, and 807) have been approved under OMB Control Nos. 0910-0045, 0910-0052, and 
0910-0387; and the labeling regulations (part 201) have been approved under OMB Control Nos. 
0910-0340 and 0910-0370. 
 
An agency may not conduct or sponsor, and a person is not required to respond to, a collection of 
information unless it displays a currently valid OMB Control No.  The OMB Control No. for this 
information collection is 0910-0338 (Expires 02/28/2023). 
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