draft guidance for industry minimally manipulated, unrelated, allogeneic placental/umbilical cord...

Download Draft Guidance for Industry Minimally Manipulated, Unrelated, Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution in Patients

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  • Draft Guidance for Industry Minimally Manipulated, Unrelated, Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution in Patients with Hematological Malignancies CTGTAC meeting March 30, 2007
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  • Overview Background/History Purpose/Scope of Guidance License Application Procedure Chemistry, Manufacturing & Controls Applicable Regulatory Requirements HCT/Ps, Compliance with cGMPs Postmarketing activities Next steps
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  • Background (1) History of promulgation of HCT/P regulations Proposed a tiered approach Implemented by promulgating 3 final rules Unrelated allogeneic hematopoietic stem/progenitor cells including cord blood (HPC-C) meet criteria for regulation as biological products under PHS Act (systemic effect) Subject to IND and BLA requirements
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  • Background (2) Summary of 1998 FR notice: Request for Proposed Standards Requested submission of comments Establishment controls CMC controls-processing & product standards For minimally manipulated unrelated allogeneic cord blood and PBSC
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  • Background (3) Summary of 2003 BRMAC on cord blood FDA provided analysis of clinical outcome data Committee discussed safety & efficacy issues CBER task force determined data submitted to docket and published literature permit development of recommendations for applying for licensure Published draft guidance January 2007
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  • Draft Guidance Open for public comment Comment period ends April 17, 2007 Represents FDAs current thinking; does not establish legally enforceable responsibilities Recommendations, unless specific regulatory or statutory requirements cited Can use an alternative approach
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  • Purpose Recommends ways for cord bank to apply for licensure for specified indications Explains applicable regulations in Title 21 of the Code of Federal Regulations Provides other information about the manufacture of HPC-C and how to comply with the applicable regulatory requirements
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  • Scope (1) Covers cord blood products that are: Minimally manipulated; and Intended to be used in recipients unrelated to the donor
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  • Scope (2) Does not cover: PBSC Other cord blood products (e.g. more than minimally manipulated, and/or for other indications) Cord blood for autologous/family-related use (though encourage following these recommendations)
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  • Indication specified in Draft Guidance Hematopoietic reconstitution (engraftment) outcomes defined in 1998 FR notice Preponderance of data submitted to docket describing cord blood transplant outcomes in patients with hematologic malignancies (approximately 65-70%) Numerous other indications much less data (all genetic disease 25%, SAA/FA 5%)
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  • Data needed to support other indications Data demonstrating safety and efficacy of HPC-C for transplantation in patients with other diseases/disorders, for example Engraftment Survival Measures of mitigation of defect (e.g. immune reconstitution; increase in level of metabolic enzyme; correction of hemoglobinopathy) Subject of committee discussion
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  • Use of this Guidance to apply for a Biologics License Manufacturer demonstrates in application that they have followed guidance recommendations Manufacturer may modify any procedure in guidance Evidence demonstrating modification will provide assurances of safety, purity, potency, and effectiveness Guidance provides specific recommendations if manufacturer wishes to rely on data in the docket Biologics license would apply to HPC-C manufactured at time of and subsequent to approval of the license application
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  • Do cord blood manufacturers have to use this Guidance when applying for a license ? No. However, a manufacturer who does not use this guidance must submit a BLA for their HPC-C containing the following data: Studies demonstrating that the product meets requirements of safety, purity, and potency (21 CFR 601.2) nonclinical laboratory studies clinical studies Recommend consultation with CBER about alternative approaches
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  • License Application Procedure
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  • Form FDA 356h Application to Market a New Drug, Biologic, or an Antibiotic Drug for Human Use Where to submit Document Control Center (address provided) Guidance describes information to include and What action FDA will take
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  • Information to Include Index Representative draft labeling Summary of information submitted CMC 21 CFR 314.50(d); 601.2 Full description of manufacturing process and SOPs for critical procedures, assays Summary validation data Establishment description 600.10 Other attachments, including citation to data in docket
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  • What action will FDA take? Review application Schedule prelicense inspection as soon as possible after receiving complete application If application not complete, FDA will identify/advise establishment of additional information that they will need to submit
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  • Chemistry, Manufacturing and Controls (CMC)
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  • CMC: HPC-C Description and Characterization (1) Table A: Required and recommended tests and results Safety ID testing required (maternal blood sample) All tests negative except for non-treponemal test for syphilis when confirmatory test negative; CMV Sterility testing required (cord blood* and pre-cryopreservation sample) Negative Hemoglobin (cord blood sample) No homozygous hemoglobinopathy * Cord blood = cord blood before undergoing volume reduction
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  • CMC: HPC-C Description and Characterization (2) Table A: Required and recommended tests and results Purity and potency (pre-cryopreservation sample) TNC 5.0 x 10 8 /HPC-C Based on 20 kg recipient dose of 2.5 x 10 7 /kg and 70% post-thaw recovery = 1.7 x 10 7 /kg Viable nucleated cells 85% Viable CD34+ cells 1.25 x 10 6 /HPC-C Based on CD34+ cells 0.25% prior to freezing
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  • CMC: HPC-C Description and Characterization (3) Table A: Required and recommended tests and results Identity HLA typing (cord blood sample) Confirmatory HLA typing (attached segment) ABO/Rh (cord blood sample)
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  • CMC: Manufacturer information (1) Identification Name(s), address(es), FDA registration number(s), other organizational information for each manufacturer Including those under contract, agreement, other arrangement to perform a manufacturing step; for example, Collection sites Laboratories performing donor testing for relevant communicable disease agents and product sterility testing
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  • CMC: Manufacturer information (2) Contamination precautions Description of in-process controls to prevent or identify contamination or cross-contamination Avoid simultaneous manipulation of more than one HPC-C in a single area Precautions taken to prevent contamination and cross- contamination by equipment Narrative description of procedures/facility/equipment design features Narrative description of manufacturing area collection, volume reduction, packaging, labeling, cryopreservation, storage, and shipping
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  • CMC: Methods of manufacturing (1) SOPs to submit with license application Collection Processing Volume reduction; cryopreservation; frozen storage; lot release Selection Data management; search request; donor matching to candidate recipients; selection of HPC-C Shipping and handling Shipping to transplant center; thawing and preparation for administration; emergency product recovery Validation data summary Recommend data from 3 consecutive, separate HPC-Cs
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  • CMC: Methods of manufacturing (2) Flow charts Complete visual representation of manufacturing process flow, including list of in-process controls, and tests performed at each step Includes information on transfers Microbiology Includes description of presterilized equipment and containers Control of aseptic manipulations Includes description of process parameters that are monitored; procedures used to monitor bioburden/sterility; conditions and time limits for process steps
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  • Other Important CMC Information Description of container closure system Can reference NDA, 510(k), or MF Provide evidence of container and closure integrity for duration of proposed storage period Environmental assessment 21 CFR Part 25 Applicant may submit request for categorical exclusion
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  • Other Important CMC Information Methods validation/verification Infectious disease tests licensed/approved/cleared Other tests sterility, TNC, HLA, ABO/Rh, other Labeling see Guidance Section VII.B.2
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  • HPC-C previously manufactured Subject of committee discussion
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  • HPC-C previously manufactured using the same procedures License would apply to HPC-C previously manufactured in accordance with the information provided in the license application, where documentation is provided to demonstrate their comparability to HPC-C currently manufactured
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  • HPC-C previously manufactured using different procedures Cord blood processing methods have changed over time Any change has potential to affect safety and quality To include under BLA: Must dem


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