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. 0910-0629 

Expiration Date: 03/30/2011 

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 Communications 

Division of Drug Information 

Center for Drug Evaluation and Research 

Food and Drug Administration 

10903 New Hampshire Ave., Bldg. 51, Room 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..................................................... 11

VI. REFERENCES................................................................................................................ 15

VII. PAPERWORK REDUCTION ACT OF 1995.............................................................. 17

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Contains Nonbinding Recommendations 

Guidance for Industry 

Cooperative Manufacturing Arrangements for Licensed Biologics 

This guidance represents 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 finalizes the draft guidance of the same title dated July 2007, which 

revised 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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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 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 manufacturing process information and assurances with its original BLA under 

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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). FDA’s experience has shown that the display of names, 

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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.

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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. 7-13). 

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 

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addition to other information in a BLA, the criteria used to determine 

lot-by-lot acceptability of the product (21 CFR 601.2), including: 

• 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. 

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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 

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). 

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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, 

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); 

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• 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). 

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 

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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. 

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). 

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

containers and closures. 

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). 

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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. 

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. 

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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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17 

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 0910-0629 (Expires 09/30/2011).