points to consider in the manufacture and testing of MAB products for human use

1 Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use U. S. Department of Health and Human Services Food and Drug Administration Center for Biologics Evaluation and Research February 28,1997 2 Date: February 27, 1997 From: Kathryn C. Zoon , Ph.D., Director Center for Biologics Evaluation and Research Food and Drug Administration Subject: Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use To: Manufacturers of Biological Products and Other Interested Persons This Points to Consider (PTC) document has been developed for manufacturers of monoclonal antibody products for human use. These “Points” are not regulations nor are they guidelines, but represent the current thinking that the Center for Biologics Evaluation and Research (CBER) staff believe should be considered at this time. This 1997 PTC document supersedes the 1994 PTC document of the same title, announced in the Federal Register of August 3, 1994 (59 FR 39571). It is our intention to continuously update and revise this document in order to improve its usefulness. We invite your review and comment on the “Points”. Comments should be identified with the docket number 94D-0259. Two copies of any comments should be submitted except that individuals may submit one copy. All comments should be addressed to: Dockets Management Branch (HFA-305) Food and Drug Administration 12420 Parklawn Drive, Room 1-23 Rockville, MD 20857 _______-s-_______________ Kathryn C. Zoon, Ph.D. 3 Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use [Docket No. 94D-0259] For further information regarding this document, contact: Sharon Carayiannis Center for Biologics Evaluation and Research (HFM-630) Food and Drug Administration 1401 Rockville Pike, Suite 200N Rockville, MD 20852-1448 301-594-3074 Submit written comments on this document to: Dockets Management Branch (HFA-305) Food and Drug Administration 12420 Parklawn Drive, Room 1-23 Rockville, MD 20857 Comments should be identified with the docket number found in the heading of this page. Submit written requests for additional copies of this document or any other CBER guidance to: Office of Communication, Training, and Manufacturers Assistance (HFM-40) Food and Drug Administration 1401 Rockville Pike, Suite 200N Rockville, MD 20852-1448 Send one self-addressed adhesive label to assist that office in processing your request. These documents may also be obtained by mail by calling the CBER Voice Information System at 1-800-835-4709 or 301-827-1800, or by fax by calling the FAX Information System at 1-888-CBER-FAX or 301-827-3844. Persons with access to the INTERNET may obtain these documents using, the World Wide Web (WWW), or bounce-back e-mail. For WWW access, connect to CBER at "http://www.fda.gov/cber/cberftp.html". To receive this document by bounce-back e-mail , send a message to "ptc__mab@A1.CBER.FDA.GOV". 4 TABLE OF CONTENTS Note: Page numbering may vary for documents distributed electronically. I. INTRODUCTION..........................................................................................................................................................................6 A. BACKGROUND.......................................................................................................................................................................6 B. DEFINITIONS...........................................................................................................................................................................6 C. FILING INFORMATION.........................................................................................................................................................7 II. PRODUCT MANUFACTURE AND TESTING........................................................................................................................8 A. GENERAL PRINCIPLES AND DEFINITIONS.....................................................................................................................8 B. MANUFACTURE AND CHARACTERIZATION OF MONOCLONAL ANTIBODIES ...............................................8 1. Cell lines ...............................................................................................................................................................................8 2. Production in cell culture.................................................................................................................................................9 3. Production in animals or plants .....................................................................................................................................10 4. Purification ........................................................................................................................................................................10 5. Characterization of purified unmodified mAb............................................................................................................12 6. Anti-idiotype vaccines......................................................................................................................................................13 7. Monoclonal antibodies conjugated with toxins, drugs, radionuclides or other agents (immunoconjugates).13 C. QUALITY CONTROL AND PRODUCT TESTING...........................................................................................................15 1. Cell line qualification .......................................................................................................................................................15 2. Lot-to-lot quality control monitoring of unprocessed bulk lots and purified bulk lots, and final product specifications..........................................................................................................................................................................19 3. Stability of product...........................................................................................................................................................23 4. General considerations on quantitation and removal of a retrovirus contaminant...............................................23 5. General considerations on the design and interpretation of virus clearance studies ..........................................24 6. Generic or modular virus clearance studies..............................................................................................................24 7. Product testing requirements for mAb used as ancillary products.........................................................................25 D. PRODUCT SAFETY TESTING FOR FEASIBILITY CLINICAL TRIALS IN SERIOUS OR IMMEDIATELY LIFE- THREATENING CONDITIONS................................................................................................................................................26 1. General considerations ....................................................................................................................................................26 2. Product safety data needed before the initiation of feasibility trials in serious or immediately life- threatening conditions..........................................................................................................................................................27 E. ISSUES RELATED TO MANUFACTURING CHANGES (DEMONSTRATION OF PRODUCT COMPARABILITY)....................................................................................................................................................................28 1. General................................................................................................................................................................................28 2. In vitro evidence of product comparability ....................................................................................................................28 3. Animal studies ...................................................................................................................................................................29 4. Clinical studies to support manufacturing changes...................................................................................................29 III. PRECLINICAL STUDIES .......................................................................................................................................................29 A. TESTING CROSS-REACTIVITY OF MAB........................................................................................................................29 1. In vitro testing for cross-reactivity ..............................................................................................................................30 2. In vivo testing for cross-reactivity ................................................................................................................................30 B. PRECLINICAL PHARMACOLOGY AND TOXICITY TESTING....................................................................................31 1. General considerations ...................................................................................................................................................31 2. Animal toxicology studies................................................................................................................................................31 3. Pharmacokinetics and pharmacodynamics ..................................................................................................................32 4. Preclinical in vivo studies with immunoconjugates..................................................................................................33 IV. CLINICAL STUDIES ...............................................................................................................................................................34 A. CLINICAL CONSIDERATIONS FOR PHASE 1 AND 2 STUDIES ................................................................................34 1. General................................................................................................................................................................................34 5 2. Dose-setting .......................................................................................................................................................................35 B. IMMUNOGENICITY: CLINICAL CONSIDERATIONS....................................................................................................37 1. Monitoring the development of antibodies to mAb......................................................................................................37 2. Clinical consequences of immunogenicity ..................................................................................................................38 C. PRODUCT-RELATED CONSIDERATIONS FOR PHASE 3 STUDIES ..........................................................................39 D. ADMINISTRATION OF RADIOLABELED ANTIBODIES ...........................................................................................39 1. Dosimetry ...........................................................................................................................................................................39 2. Early clinical development of therapeutic radiolabeled mAb....................................................................................41 3. Adverse events for patients enrolled in trials of therapeutic radiolabeled mAb....................................................43 4. Clinical development of radiolabeled mAb used as imaging agents.........................................................................43 V. APPENDIX I: NORMAL HUMAN TISSUES USED IN CROSS-REACTIVITY TESTING..........................................46 VI. APPENDIX II: MOUSE ANTIBODY PRODUCTION TEST............................................................................................47 VII. APPENDIX III: ORGANS TO BE CONSIDERED IN DOSIMETRY ESTIMATES .....................................................48 VIII REFERENCES .........................................................................................................................................................................49 6 Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use February 1997 I. INTRODUCTION A. BACKGROUND Points to Consider documents provide a flexible approach in which FDA provides and updates its guidance on regulatory issues in many areas of drug development. Such documents are particularly useful in the rapidly evolving field of biotechnology-derived drugs and other biologics. The Center for Biologics Evaluation and Research (CBER) set out to revise the "Points to Consider (PTC) in the Manufacture and Testing of Monoclonal Antibody Products for Human Use" with several objectives. An important goal was to facilitate initial development of monoclonal antibodies for serious or life threatening indications. Additionally, it was felt that some of the information in the 1994 document required updating and streamlining. Finally, it was necessary to review this document for consistency with current CBER policy and with International Conference on Harmonisation (ICH) documents dealing with this category of products. This updated document supersedes the 1994 version, and is designed to assist sponsors and investigators regarding monoclonal antibody (mAb) product development, including information to submit when filing Investigational New Drug Applications ("INDs") and License Applications. Although this document does not create or confer any rights for or on any person and does not operate to bind FDA or the public, it does represent the agency’s current thinking on monoclonal antibody products for human use. For mAb, as for other biologics, certain regulations contained in 21 CFR Parts 200-299 and 600-680 apply and should be consulted. In common with the other PTC, the mAb PTC are not intended to be all- inclusive. They represent recommendations on how to conduct the clinical development of a product up to and after licensure, not checklists of items to be provided before or after phase 1 trials are initiated. Specific products which raise issues that are not considered in these "Points" will be evaluated on a case- by-case basis. The discussion on abbreviated product testing for feasibility trials in serious and immediately life-threatening conditions and on generic and modular virus clearance studies does not apply to human products made in human cell substrates. Consultation with CBER is strongly advised for sponsors considering the application of abbreviated testing policies to products that have the potential to be contaminated by human pathogens. For aspects of manufacturing and of the production facility that are not included in this discussion or in applicable regulations, sponsors should consult with the Office of Therapeutics Research and Review and the Office of Establishment Licensing and Product Surveillance respectively. B. DEFINITIONS For the purpose of this document, the terms "antibody" and "monoclonal antibody" (mAb) may be used interchangeably and refer to intact immunoglobulins produced by hybridomas, immunoconjugates and, as appropriate, immunoglobulin fragments and recombinant proteins derived from immunoglobulins, such as chimeric and humanized immunoglobulins, F(ab') and F(ab')2 fragments, single-chain antibodies, recombinant immunoglobulin variable regions (Fvs) etc. Recommendations on the manufacture of recombinant products are contained in other PTC documents from CBER (1,2). Some of these recommendations pertaining to recombinant mAb produced in cell substrates other than hybridomas are reiterated in this document for convenience of consultation. This document applies to mAb used as therapeutic or in vivo diagnostic agents, as well as to ancillary products, i.e. mAb used in the manufacture of other products for in vivo use. The latter include mAb that are used alone or in 7 conjunction with devices, for example, for ex vivo purging of cells to remove immune or tumor cells, for ex vivo cell collection (e.g. hematopoietic stem cells), or for purification of other products intended for in vivo administration. Generally, these mAb should meet the same criteria for safety and freedom from adventitious agents as mAb intended for direct administration to patients. Likewise, reagents that are commonly used in conjunction with mAb for ex vivo manipulations of cellular products intended for in vivo administration (e.g. complement, DNAase) should meet the same safety standards as mAb intended for direct administration to patients. However, in such cases, some procedures for virus inactivation or removal may be performed on the downstream product rather than on the mAb or other reagent (see II.C.7). Complete information on products that will be used in conjunction with the mAb, such as rabbit complement or DNAase, should be submitted before clinical studies begin. This information can be submitted as a part of the original IND submission or in the form of a Master File. As used in this document, "cocktails" are defined as two or more mAb administered at a fixed ratio. Relevant targets may include multiple antigens on infectious pathogens and multiple tumor-associated antigens. The rationale for combining the products should be clear and based on the clinical context or previous clinical experience with individual products. Lack of interference among the mAb in the combination should be shown and synergistic or additive effects should be characterized. Dose-ranging for each of the components is highly desirable. In some instances, dose-setting may be based on preclinical or clinical data that show the necessity or superiority of a particular dose and ratio of mAb in the combination. As used in this document, "panels" are defined as sets of mAb directed against related antigens from which one or more members would be used for an individual patient based on target antigen characterization. Such panels could be submitted for approval in a single license application. Examples of panels might include anti-idiotype mAb for lymphoma and mAb directed against different bacterial or viral serotypes. Dose-ranging for each mAb would be necessary. During the phase 3 trials to establish efficacy of the entire panel, some clinical experience with each member of the panel should be obtained. C. FILING INFORMATION It is not necessary to have all of the information discussed in this document available in the initial IND submission. Rather, much of the information may be developed during clinical development, with guidance from CBER or other appropriate Centers by means of frequent dialogue. At pre-IND meetings, CBER staff may provide guidance in planning clinical development and establishing the format and content of initial IND submissions. Such meetings may be particularly useful when the product is a novel molecular entity or is produced by a novel process, and when drug development plans are unusually complex. The manufacture of mAb that are produced and controlled by similar procedures in the same facility may in some cases be documented in a single Master File. This may be particularly helpful when data from generic or modular virus clearance studies are used for multiple antibodies that differ only in the variable (v) or complementarity-determining region (CDR) and when multiple antibodies are purified by identical procedures (see Section II.C.6). See references 3 and 4 for information on filing biologics license a