SME Workshop on CMC of Biological Medicinal Products EMA London 14.-16.4.2015 CMC ISSUES for Cell based ATMP Presented by: Margarida Menezes Ferreira CAT alternate member, BWP member, INFARMED, Portugal An agency of the European Union
1 1 1 Businessweek July 1998
ADVANCED THERAPY MEDICINAL PRODUCTS - ATMP National TEP not defined authorisations • Somatic cell therapy DE, IT, FR, AU … • Gene therapy TEP / regenerative medicine Combined products Non-substantial manipulation Centralised marketing Long term efficacy follow up authorisations (MA) from Hospital exemption Tissue engineered 1/2009 ... ATMP specific Dossier Directive 2001/83/EC revised requirements for MA • NEW DEFINITIONS for GeneTherapy and 2 Somatic Cell Therapy 2 Margarida Menezes Ferreira
ATMP REGULATION 1397/2007 • Definitions suporting regenerative medicine TEP / Combined - medical devices • Clarfying fronteers - Non-substantial manipulation to separate from transplantation • Centralised MA from Jan 2009 / new Committee CAT • Traceability – flow between cell donation vigilance - pharmacoviglance • national system for hospital exemption for named patient and non routine • Specific GMP requirements • Long term efficacy follow up • hESC - national prohibitions apply • I ncentives for SME • Revise Annex 1 of Directive 2001/ 83/ EC to establish new dossier requirements Direc ective 2009/ 2009/120 20/EC – spec pecific r requi equirem ements f for or MA of of ATMP’s 3 3 Margarida Menezes Ferreira
Cell Based Medicinal Products (Directive 2009/120/EC + Regulation 1394/2007) Somatic ic c cell ll therapy py medic dicin inal pr l produ duct Tissue eng Ti ue engineer neered ed Product ucts - TEP EP ject to su subst bstantia ial m l manipu ipula latio ion Incl nclud ude cel cells or tissue ues sub ubjec “ cells or tissues subject to substantial manipulation so that biological characteristics, physiological functions or structural properties relevant for the intended clinical use have been altered “ or het heter erologous us us use Or indi dicate ted for “not intended to be used for the same essential function(s)” • us used ed to trea eating ng, prev even enting or diagno nosing ng a disea ease thr hroug ugh the he . = = pha harmaco cologica cal, immun unological or met etabolic act ction n of f its s cells s or tiss ssues. so somatic ic c cell ll therapy py e = = TEP EP • us used ed with h a view ew to, reg egen ener erating, rep epairing ng or rep eplacing a hum human tissue 4 4 Margarida Menezes Ferreira
hierarchy of guidelines ! An agency of the European Union Margarida Menezes Ferreira
Human cells = starting materials author horisation on of tissues es and d cells proc ocur urem ement nt + dono nor testing ng by transplantation authority authorisation of collection and testing and tissue establishments (TE) for banking Export / Import activities in the EU Ex EU by authorised TE TE ensures that impor orted ed cells from om 3rd d coun untries es allows traceability to donor and collection and testing under equivalent standards as Directive Cells expor ported ed from EU comply with this Directive Not possible in Medical Devices – Directive 93/ 42/ EEC, article 1 point 5. Not possible in Cosm etics - Regulation 1223/ 2009 Annex 2 substances 6 6 Prohibited (416) Margarida Menezes Ferreira
APL APLIGRAF – Approved as medical device in the USA since 1998 Replacement / repair bilayer of allogeneic human fibroblasts and keratinocytes isolated from boys’ foreskin on a bovine collagen matrix Submitted in the EU in 2001 - application withdrawn 7 Margarida Menezes Ferreira
NOT subst stant antial al = = NOT medici cinal nal p product uct : : Regulation 1394/ 2007/ EC • – cutting; • – grinding; • – shaping; • – centrifugation; • – soaking in antibiotic or antimicrobial solutions; • – sterilization; • – irradiation; • – cell separation, concentration or purification; • – filtering; • – lyophilization; • – freezing; • – cryopreservation; • – vitrification; • … “heterologous use” = medicinal product 8 8 8 Margarida Menezes Ferreira
BORDER LINE PRODUCTS - under ATMP Regulation or T&C Directive or none! • AUTOLOGOUS NON SUBSTANTIALLY MANIPULATED GENERATED ON THE BED SIDE Not under T&C / not under ATMP Adipose derived stromal fraction / Celution • BANKED CELLS EXPANDED AND CRIOPRESERVED – NOT YET DEDICATED Under T&C / not ATMP yet but will be when processed Accept T&C instead of GMP for initial manufacturing and storage? • HUMAN CELLS IN RESEARCH Research excluded from T&C Directives – eg. iPS cells may not be under T&C if developed for research … Reflection Paper on classification of ATMPs is being updated for m ore clarity 9 Margarida Menezes Ferreira
TO BE A MEDICINAL PRODUCT not a TRANSPLANT • CERTIFIED GMP UNDER MUTUAL RECOGNITION WITHIN EU AND WITH OTHER AGREED NON EU MEMBERS • SUPPLIER QUALIFICATION FOR ALL RAW MATERI ALS AND TRACEABILITY • VALI DATI ON OF ASSEPTI C MANUFACTURI NG PROCESS – GMP ANN1 • EQUIPMENT QUALIFICATION – GMP ANN15 • BATCH RELEASE BASED ON PRODUCT TESTI NG BY QP • PRE-ASSESSMENT FOR PRODUCT QUALITY , SAFETY EFFICACY AND FOLLOW-UP • MODE OF ADMI NI STRATI ON UNDER MANUFACTURER SUVERVISI ON • PHARMACOVI GI LANCE FOR LIFE LI ABI LI TY ON ALL PARTS OF THE PROCUREMENT / PROCESS / PRODUCT / USE • 10 Margarida Menezes Ferreira
http://ec ec.eur urop opa. a.eu/ eu/heal ealth/ h/files es/eudr udralex ex/vol ol-4/vol ol4-an2_ n2__201 2012-06 06_en. en.pd pdf 11 11 Margarida Menezes Ferreira
• GMP mandatory for all products entering clinical trials • GMP or equivalent quality system for Hospital Exemption • Many trials from academic / hospital investigators • Consideration of other quality systems in use in tissue banks Revision of the GMP fram ew ork for ATMP’s GMP specific for ATI MP 12 Margarida Menezes Ferreira
Cell – product definition - diversity • Autologous or allogeneic • Toti – pluri – adult starting material • Separated – enriched - clonal • Single population – multifactorial complex combination • Cultured – cell divisions – genetic stability • Cell bank or cell stock - • Differentiation to be concluded prior or post administration • Cell suspension – matrix - combined • Genetically modified CAT CLASSI SSIFICATION P PROCE CEDURE • … 13 Margarida Menezes Ferreira
CARDIAC REPAIR CELL STRATEGIES heterogenious cell preparations FOR MI or CHF 1ST WAVE bone marrow aspirate - autologous Cell MSC + EPC ? Moderate results / no results Minimal manipulation - Separation / centrifugation 2ND WAVE MSC immuneselected / MPC - EPC Inconclusive Cell expansion Other sources – PBMC / adipocytes / placenta allogeneic Commited cells - Cardiomyocytes results ? 3RD WAVE ? Embryonic stem cells iPSC 14 Margarida Menezes Ferreira - CAT Workshop for cell-based therapies for Cardiac Repair May 2014 Margarida Menezes Ferreira
CARDIAC REPAIR Product definition Cells from … Autologous MSC’s in AMI Act where … Bone m arrow MSC’s – how pure? Doing what … Enriched - Com plex distribution of various types of cells Interact with … W hat cells relevant for various functions Response is … + deleterious cells + no effect Different roles not w ell assigned – im m unesupression - m odulating inflam ation, paracrine, engraftm ent? Functionality – m ultiple Safety - Tum origenic ? on target? 15 Margarida Menezes Ferrei
Sources of variability in cell therapy MANUFACTURE MATERIALS • Same process different Donor dynamics Collection • Length of process • different differentiation Dynamic starting cell material stages Biological raw materials • Complex process – multiple stages CONTROL • Bioanalytical methods ADMINISTRATION • No standardised • Complex system often reference materials surgical procedures • Patient response 16 Margarida Menezes Ferreira
Raw materials : reagents general text in the Eur Phar (in 2015) serum/medium Identity cytokines / growth factors Purity Biological Activity / Functionality enzymes (such as trypsin) Specific Activity Total Protein content antibodies Impurities, Product-related Impurities, Process-related individual proteins Viral Safety / TSE compliance Microbial Contamination buffers Stability / Storage conditions plasmids/ viral vectors -GUIDELINE the use of bovine serum in the manufacture of human biological medicinal products (EMA/ CHMP/ BWP/ 457920/ 2012 rev.1) UNDER NEW REVISION - GUIDELINE the use of porcine trypsin used in the manufacture of human biological medicinal products (EMA/ CHMP/ BWP/ 814397/ 2011) DRAFT 17 Margarida Menezes Ferreira
MANUFACTURING PROCESS CELL SOURCING • Standardise collection • Commercial devices SEPARATION GMP • Not substantial manipulation • Developpment studies to Generally not define critical raw materials EXPANSION critical steps and cQA • Upscale - comparability • Developpment studies to MODIFICATION define critical raw materials critical steps and cQA • Combination - biocompatibility FORMULATION • Criopreservation FINAL PRODUCT • Bedside preparation administration • Standardise practice 18 Margarida Menezes Ferreira
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