WANG, DER-YUAN Ph.D. ISCT GRP, Paris April 23 rd 2014 衛生福利部食品藥物管理署

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1 WANG, DER-YUAN Ph.D. ISCT GRP, Paris April 23 rd 2014 衛生福利部食品藥物管理署 Food and Drug Administration, Ministry of Health and Welfare Republic of China (Taiwan)

2 Declaration This presentation is a personal viewpoint and binds in no way the agency mentioned before, and might not be the current thinking of the Taiwan FDA. 2

3 Cell Therapy Product in Taiwan Scope Human somatic cells (including adult stem cells) and tissues, not including reproductive cells/tissues Regulatory hierarchy Law Medical Care Act (cell therapy as medical treatment/practice, before 2010) Pharmaceutical Affairs Act (cell therapy as biologics, after Jan 1 st 2010) Guidance related to cell products Good tissue practice (2003); PIC/S GMP (2009) Guideline of IND application for somatic cell therapy (2011) Minimal requirement for biological products (annual publication) Notice of cold chain integrity for biological product delivery (revised draft, 2014) 3

4 Regulatory System for Biologics Research Pre Clinical Clinical Trials Product Launch Production Marketing & Sales Review: Safety, Efficacy, Quality Inspection: GLP GCP GTP, PIS/S GMP GPvP, GDP Evaluation: Pre market Monitoring BLA Testing Lot Release Testing Post market Monitoring 4

5 Cooperation in Taiwan FDA Division of Controlled Drugs Division of Food Safety Division of Research & Analysis Division of Planning & Research Development Division of Medical Devices & Cosmetics Evaluation Testing Division of Risk Management Division of Medicinal Products Regulations Review GLP/GMP/GTP Inspection Regulations Review Combination Products Center for Drug Evaluation 5

6 From IND to Market for Biologics Research Pre Clinical Clinical Trials Product Launch Production Marketing & Sales Pre IND Phase 1 Safety (Immunogenicity) Reactogenicity IND Phase 2 Reactogenicity, Dose finding, Safety Phase 3 Safety, Reactogenicity, Scale up production? NDA Data to support approval, Testing, Inspection Lot Release Active surveillance SAERS Passive surveillance Post approval changes 6

7 Characters of Cell Products Small Molecules Biologics Cell Products Size Nano scale Nano to micron scale >Micron scale Ingredient Purified and/or synthesizes pure compounds Living or dead microbials, their derivatives and/or parts of themselves Living cells, tissues and/or cellular and tissue based products Sterilization Terminal sterilization Fully aseptic process Fully aseptic process SAL (by method) *** *** Biosafety risk None Adventitious agents Human communicable disease agents and diseases Production Large scale Large to middle scale Small scale Thermosensitivity Some products All products are heat sensitive Human communicable disease agents and diseases Adventitious agents All products are thermo sensitive 7

8 Cell Product Integrity (1) Purity Free of human communicable disease agents and diseases Free of adventitious viruses Free of non targeting cells TSE Identity DNA fingerprinting, karyotyping, isozyme assay, cell morphology, etc Potency Relative activity, expression of specific biomarker, cell numbers etc Safety No contamination with mycoplasma, bacteria, yeasts/molds (sterility) Residual endotoxin, etc Stability Cell morphology, cell survival rate, etc 8

9 Cell Product Integrity (2) Source materials Cells (including MCB, WCB) Animal derived materials (ex, fetal bovine serum,, bovine serum albumin, porcine trypsin, etc) Risk assessment for TSE Adventitious virus tests Zoonotic disease agent tests In processing and final products Distribution 9

10 Recovery Comprehensive Controls Cell Identity Cell Identity Morphology Cell Harvesting/ Expansion Control of Cell Quality Cell Processing/ Modification Cell Identity Potency Total cell # Cell survival Morphology Potency Total cell # Cell survival Morphology Cold chain integrity Product Package/ Distribution Package integrity Cryopreservation Sterility test Mycoplasma test Endotoxin Test Infusion/ Transplantation Donor Screen/Testing for HCDADs AVT for animal materials CJD, nvcjd Sterility test Mycoplasma test AVT for animal materials TSE Sterility test Mycoplasma test Endotoxin Test AVT for animal materials Sterility test Mycoplasma test Endotoxin Test Control of Microbial Contamination Recipient SAE report Control of Traceability 10

11 Points to Consider (1) Risks from donor human communicable disease agents and diseases (HIV, HBV, HCV, TB, etc) CJD/nvCJD Non targeting cells Risks form animal TSE from bovine PCV1/2 from porcine Zoonotic disease agents Risks from technician, environment, accessory equipment, etc Mycoplasma, bacteria, yeasts & molds Non targeting cells 11

12 Points to Consider (2) Cell therapy products need unique testing methods Cell product has very short half life Lack standardized method and reference materials for specific testing Adequate testing methods for living cells are annually published in Minimal Requirement for Biological Products by Taiwan FDA. Testing methods published in Minimal Requirement for Biological Products will be contained in the new version of Chinese Pharmacopeia. 12

13 Specific Testing Methods Rapid microbiological method for cell product sterility test Mycoplasma NAT tests and validation protocol Monocyte activation test (MAT) for cell product endotoxin (pyrogen) evaluation 13

14 Methods for Sterility Test Sterility test (membrane filtration/direct inoculation) had been internationally harmonized in different Pharmacopeia USP <71>; US FDA <21 CFR 610> EP <2.6.1> ChP <7001> JP XIV Rapid microbiological method Only in EP < Microbiological Control of Cellular Products > US FDA Guidance for Industry: Validation of growth Based Rapid Microbiological Methods for Sterility Testing of cellular and gene therapy Products Taiwan FDA Minimal Requirement for Biological Products II: Microbiological control for somatic cell therapy 14

15 Membrane Filtration Method Culture media and incubation temp FTM, o C (bacteria) TSB, o C (yeasts/molds) Incubation time: At least 14 days Inoculum Depend on lot quantity and volume of container Analysis: (in valid test) No growth (clear) Growth (turbidity) 15

16 Limitation Membrane filtration method could not remove the antibiotics effectively from cell culture medium (ex, penicillin, streptomycin, gentamycin, fungizon) has lower sensitivity/higher LoD (~ 100 CFUs/test) need more specimen volume (usually >20 ml/test) Components from complex cell culture medium could inhibit microbial growth in TSB/FTM Microbial growth or not is determined by observation (cell culture media are not transparent) Long incubation/observation period (at least 14 days) is not adequate for release test of cell product 16

17 Rapid Microbiological Method RMM is shown the features to be preferable to sterility test for cell products, since RMM has better sensitivity and broader detecting range, and is more rapid. Use at least 2 suitable enriched culture media for detection of fungi and aerobic/anaerobic bacteria. Easier Positive determination Sample Sample + Spike Negative Sample Sample + Spike 17 Nov 19,

18 Validation Characteristics of RMMs Sensitivity (limit of detection): CFU/challenge organism) Specificity (a panel of challenge organisms) Reproducibility (ruggedness) Robustness 18

19 Appropriate Challenge Microorganisms Gram +/ bacteria Aerobic/anaerobic bacteria Slow growing bacteria (Proprionobacter acnes) fungi Isolates detected in starting materials, in process testing, environmental monitoring Isolates from production areas which represent low nutrient/high stress environments Common isolates from a particular product type 19

20 Recommended Challenge Panel Culture Medium FTM TSB Incubation Temp o C o C Microorganism Bacillus subtilis Clostridium sporogenes Environmental isolates Candida albicans Micrococcus luteus Propionibacterium acnes* Bacteroides vulgaris Environmental isolates Bacillus subtilis Propionibacterium acnes Aspergillus niger Environmental isolates Microorganism Characteristics Organisms that produce spores under anaerobic conditions Organisms that grow well under anaerobic conditions Organisms that produce spores under aerobic conditions Candida albicans Micrococcus luteus Organisms that grow well Staphylococcus capitis Staphylococcus epidermidis under aerobic conditions Environmental 20 isolates Nov 19,

21 Points to Consider (3) Control of biological product distribution Thermo stability for product transport and storage Traceable system from donor, source material to recipient 21

22 Cold Chain System Thermo impact is a seriously interfering factor for maintaining the bioactivity (potency) of biologics. Cold (2 8 o C) chain system is a tool requested by World Health Organization (WHO) to maintain vaccine potency during transportation. At release End of lifespan At release End of lifespan Bioactivity Bioactivity Thermal Impacts Release Spec. Release Spec. Live Time Live Time 22

23 Notice of Cold Chain Integrity for Biological Products The current version for vaccines was announced by Taiwan FDA on May 23 rd 2010 and enforced on Jan 1 st The revised version will cover all kinds of biological products. Based on the storage temp (e.g., 2~8 o C; < 15 o C, etc.) labelled on package/insert WHO certified electronic temperature device for real time temp monitoring Jan 1 st,

24 Thermo Stability for Living Cells The delivery of living cell products also need a thermostatic system. The CPCs have to define an adequate temperature for transport and storage of their living cell products. 37 o C 2 8 o C 80 o C (container integrity) Liquid N 2 (container integrity) 24

25 THANKS FOR LISTENING Questions? 25

26 安全 安門 安通 安定 安產 26