Guidance for Industry

1 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 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. 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: 04/30/2021 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: or Office of Training and Communication Division of Drug Information Center for Drug Evaluation and Research Food and Drug Administration 10903 New Hampshire Ave.

2 , Bldg. 51, rm. 2201 Silver Spring, MD 20993-0002 Phone: 301-796-3400 Internet: Contains Nonbinding Recommendations i Table of Contents I. SCOPE .. 2 II. 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 10 VI. REFERENCES .. 14 VII. PAPERWORK REDUCTION ACT OF 1995 .. 16 Contains Nonbinding Recommendations 2 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.

3 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) (42 262). This document is issued jointly between the Center for Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research (CDER).

4 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.

5 Contains Nonbinding Recommendations 3 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 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) (t)).

6 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 (u)). A manufacturer of a biological product must demonstrate responsibility for the manufacturing process as described in its BLA (21 CFR (t)). For example, a manufacturer must avoid introduction of contaminants during production (21 CFR ). 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.

7 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 and for divided manufacturing in 21 CFR (e) and 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 (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.

8 Contains Nonbinding Recommendations 4 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 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 , 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.

9 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.

10 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 Contains Nonbinding Recommendations 5 21 CFR or submit it to either CBER or CDER, as appropriate, as a change to an approved application as described in 21 CFR 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.