Manufacturing Cellular Products for International Clinical Trials

Transcription

1 Manufacturing Cellular Products for International Clinical Trials Q U A L I T Y A N D O P E R A T I O N S T R A C K 7 4 / 2 5 / : : 1 5 Olive J Sturtevant, MHP,MT (ASCP)SBB, CQA Director of CTQA Dana Farber Cancer Institute, Boston, Ma

2 Objectives: To provide an overview of some of considerations and challenges with multi-center / international clinical trials especially for US Academic Institutions & Manufacturing Facilities To review some challenges with the EU PICs and API regulations especially for a US Academic CT manufacturers Discuss the use of new tools to share and capture important trial information and outcome data

3 Brief Overview of Cells Manufactured by DFCI-CMCF Product Volumes and Types Stem Cell Products YEAR Proj Bone Marrow Products Apheresis Products Cord Products DLI Products Total Products Novel CT Proj Gene Therapy-HSCT 8 17 Cancer Vaccines Immunotherapy CAR-T cells 1 15 CD4Treg 5 15 TCRab/CD Viral CTL 8 other T and NK cells 4 Regenerative Med MSC 3 36 Limbal SC 4 DC 5 10 Renal 3 8 Other Other Totals

4 DFCI-CMCF Active Protocols

5 Ambiguous definitions, as identical terms may be interpreted differently from one country to another, or even within the same country. Taken from recent work on clinical research wwww.esf.org/fileadmin/links/emrc/fl_idct.pdf), Difficulties Identified By European Medical Research Councils (EMRC) Three major issues are emerging: Persisting differences in administrative processes and in the interpretation of existing regulations and other processes have led to even higher levels of complexity especially in multinational clinical trials. Today, the sponsor of a clinical trial needs to have a very detailed knowledge of every country s requirements for clinical trial authorizations from both competent authorities and ethics committees. The sponsor has to integrate different national requirements to the protocol and may need parallel submission in multinational trials.

6 Eight Major Issues Lack of knowledge of and applying legislation regulations amongst different countries Differing Ethic Committees /IRBs Lack of expertise/resources across all centers Lack of standard definition of roles and responsibilities of investigators and sponsors Payment for Insurance Standard of care Different rules for ADRx (Adverse Events) Importation of Drug Products Requirements & Compliance with GMPs for Manufacturing of Advance Therapy Medicinal Products

7 Moving Applications and Protocols through Regulatory and Review Boards FDA and EU authorities, local authorities Gene Therapy trials RAC (Recombinant DNA Activities Committee) US Academic based Scientific Review Committees, Biohazard, Institutional Review Boards, Institutional Biosafety committee, etc.

8 Multiple Sites or One? Clinical Patient screening and assessments Collections Donor screening, assessments or testing Manufacturing Processing QC testing Special release testing Treatment Administration of the products Assessment post infusion Immediate and long term follow-up Outcome data gathering

9 Qualifying Other Sites Develop Selection Criteria Site Selection & Feasibility Questionnaire (SSFQ) Send to prospective participating sites to determine if they are able to meet DF/HCC and protocol requirements. Review SSFQs by the DF/HCC Sponsor prior to extending protocol participation to an external site. A Protocol Feasibility Questionnaire(PFQ) may be used for sites that have previously participated in a Multi-Center Protocol conducted by the same disease group and have previously completed the SSFQ for their site within the past year. Prospective participating sites that have satellite sites that will also be participating in the research must complete a Satellite Feasibility Questionnaire for each satellite site.

10 Use of a Similar Questionnaire for Collection and Manufacturing Services Quality Systems Facility Master File Facility site qualifications Classified vs not classified space Equipment Personnel qualifications Accreditations requirements Manufacturing and testing ability Ability to accommodate manufacturing and testing volumes

11 Special Requirements for Testing and Manufacturing Services Ability to screen and tests donors according to local and international regulations Use of a centralized site for some tests Pathology and Genetic assessments Radiological services Similar for QC testing Centralized specialized testing, CFUs, VCN, etc. Centralize testing for product characterization, Sterility, Mycoplasma, Endotoxin

12 PICs Pharmaceutical Inspection Co-operation Scheme (Guide to GMP for Medicinal Products) 20-Sections (Annexes) Relevant sections to Cellular Therapy Manufacturing Annex 1: Manufacture of Sterile Medicinal Products Annex 2 Manufacture of Biological Medicinal Substances and Products for Human Use Annex 8: Sampling of Staring and Packaging Materials Annex 11: Computerized Systems Annex 13: Manufacture of Investigational Medicinal Products Annex 14: Manufacture of Medicinal Product Derived from Human Blood or Plasma Annex 15: Qualification and Validation Annex 18: GMP Guide for Active Pharmaceutical Ingredients Annex 19: Reference and Retention Samples Annex 20: Quality Risk Management Website:

13 Novel Cell Therapy Products Fall Under PICs GMPs

14 Annex 1: Manufacture of Sterile Medicinal Products Facility standards - Classifications Air HVAC requirements In operation classification may be demonstrated during normal operations, simulated operations or during media fills as worst-case simulation is required for this. EN ISO provides information on testing to demonstrate continued compliance with the assigned cleanliness classifications.

15 Environmental Monitoring Aseptic Processing Frequent monitoring methods such as settle plates, volumetric air and surface sampling (e.g. swabs and contact plates). Results from monitoring should be considered when reviewing batch documentation for finished product release. Surfaces and personnel should be monitored after critical operations. Additional microbiological monitoring is also required outside production operations, After validation of systems, cleaning and sanitization. Three media fills per person repeated every 6 months Recommended limits for microbiological monitoring of clean areas during operation: If alert and action limits are exceeded operating procedures should prescribe corrective action.

16 Annex 1 Manufacture of Sterile Medicinal Products Validation of aseptic processing should include a nutrient media fill Process simulation should mimic the actual manufacturing steps as closely as possible Three consecutive satisfactory simulation tests per shift and repeated at defined intervals and after any significant modifications to HVAC Normally at least twice per year per shift / process / person

17 EudraLex Rules Governing Medicinal Products in the EU Vol 4, EU Guidelines to GMP Medicinal Products for Human and Veterinary Use, Part 1, Chapter 3 Quality Management General 3.5 Preventing Unauthorized Entry Premises and Equipment Not only for manufacturing space Manufacturing Badge in and out Limited Access by room

18 EudraLex The Rules Governing Medicinal Products in the European Union Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use Part 1 Chapter 3: Premises and Equipment 3.18 Storage of sufficient capacity to allow orderly storage of various categories of materials and products: starting and packaging materials, intermediate, bulk and finished products, products in quarantine released, rejected or recalled materials

19 or Use of Per Institutional SOPs or Controlled Procedures Consents and protocols Screening tools SOPs Batch Records Labels Data repositories CRF What language(s) or dialect(s) Date format (dd/mm/yyyy) Patient identifiers Name / no name Surname, Study IDs Naming convention

20 Site Master File Part III of the GMP (Good Manufacturing Practice) guidelines on the preparation of the site master file Site master File: document describing the GMP related activities of the manufacturer etail.cfm?&item_id=3944

21 Develop Clinical Protocol Specific Data and Safety Monitoring Plan (DSMP) DF/HCC Multi-Center International Data and Safety Monitoring Plan (DSMP) template. The DSMP should be tailored to the study and serves as a reference for the Participating Site(s) outlining the expectations for participating in a DF/HCC Multi-Center Protocol. DSMP as Attachment/appendix to the protocol.

22 Annex 2 - Part A. General guidance Documentation Biological starting materials Auto and Donor Matched the manufactured product is a batch Full traceability (30 years) For ATMPs, traceability requirement regarding human cells including hematopoietic cells must comply with the principles laid down in national legislation (In the EEA, these are Directives 2004/23/EC and 2006/86/EC) Research and Quality Agreements between the responsible parties should define traceability and retention periods Production -Full traceability of Biological Starting Materials

23 Production Starting Materials Raw Materials (e.g. cryoprotectants, feeder cells, reagents, culture media, buffers, serum, enzymes, cytokines, growth factors) should be clearly defined. Source, qualifications and testing, along with source documents Qualify before use Have process in place to reject CT product batch if QC testing of raw material fail Identification testing of all starting materials Compliance with the requirements appropriate to manufacturing stage Reference: Part I and Annex 8 for biological medicinal products and Part II for biological substances

24 Production Starting Materials (e) The transport of human tissues and cells to the manufacturing site must be controlled by a written agreement between the responsible parties. The manufacturing sites should have documentary evidence of adherence to the specified storage and transport conditions. (f) Continuation of traceability requirements started at tissue establishments through to the recipient(s), and vice versa, including materials in contact with the cells or tissues, should be maintained. (g) A technical agreement should be in place between the responsible parties (e.g. manufacturers, tissue establishment, Sponsors, MA Holder) which defines responsibilities of each party, including the RP.

25 Production Starting Materials for Gene Therapy (a) For products consisting of viral vectors, the starting materials are the components from which the viral vector is obtained, master virus seed or the plasmids to transfect the packaging cells and the MCB of the packaging cell line (b) For products consisting of plasmids, non-viral vectors and genetically modified micro-organisms other than viruses or viral vectors, the starting materials are the components used to generate the producing cell, the plasmid, the host bacteria and the MCB of the recombinant microbial cells (c) For genetically modified cells, the starting materials are the components used to obtain the genetically modified cells, the starting materials to manufacture the vector and the human or animal cell preparations. (d) The principles of GMP apply from the bank system used to manufacture the vector or plasmid used for gene transfer

26 Quality Control for Release Testing Process Control in place for Batch Certification or COA prior to completion of final product QC tests The procedure for batch certification and release may be carried out in stages before and after full QC analytical test results are available: Use of rapid microbiological tests may help Designated review Assessment of batch processing records, Results from environmental monitoring (where available), Deviations from normal procedures, Available analytical results Conditional certification / Sign-off by the Responsible Person.

27 Training Do you train and standardize the whole process patient selection to infusion or just in-lab manufacturing? Patient selection criteria Esoteric markers, pathology slides, radiology, etc Collection Processing Infusion Follow up care

28 Validations How to compare performance Product assessments Single QC lab for all sites vs each processing facility All tests or just esoteric test (RCR, RCL) Source material Supplies/reagents/equipment Periodic reassessments Proficiency testing

29 Same or Equivalent Supplies & Reagents Critical Supplies / Reagents / Study drug Equipment QC tests / methods CLIA approved lab Central lab or each site Flow Cytometry Gating strategies CFU assays ELISA, PCR, etc Pathology Proficiency samples

30 Challenges in Exporting Products to EU Countries Multiple and varying regulations Shipping Advance Therapy Medicinal Products Need of a broker / Competent Authority to accept ATMP Product on your behalf Need to establish a process to qualify US Academic Manufacturing Facilities as EU acceptable GMP facilities

31 Communication is Vital, yet Challenging Face to face vs WebEx Frequency Time zones Language and cultural differences Technical differences

32 Use of Centralized Documents and Clinical Research Documents SOPs, batch records, CRF Measuring performance - Dashboards e-trial Master File documents Inspection ready Audits

33 Challenges of Shared e-information Systems / Data Base Annex -11 Applications should be validated and infrastructure qualified Documented Risk Management System for both clinical and lab based systems Formal agreements with 3 rd party providers (including in-house IT departments) 21 CFR part 11 Compliance Need appropriate Risk Management Patient safety and protection of PHI Data integrity Product quality

34 Cloud Technology vs Portal system etrial Master Files Cloud allows academic centers as well as small and medium businesses with technology Working together in a collaborative space Web-base document management systems Document management, exchange and tracking across all centers and groups (CRO, investigators, sponsors, manufacturing sites, etc) Web-base data capture systems Outsource or not Overcoming IT security

35 Need for Web Based Regulatory Repository Create a common web-based repository of information about national laws and regulations for performing clinical trials. Provide a list the key information and documents; How to start, conduct a clinical trial How to report events List of key contacts and links to the Internet sites of national competent authorities.

36 International Collaborations for Novel CT Trials Continue to work together setting up and managing multi-center clinical trials is complex Academic researchers for non-commercial purposes form a substantial and critical role in medical research and there is an increasing need for Academic Centers to participate in / or run Multicenter Cell Therapy Clinical Trials Rare Diseases Personalized Medicine trials Advancement of Science This will not be possible without national or local support and it is vital to keep patients and general public actively involved to partner and push for national support for the advancement of these novel trials