manufacture of somatic cell therapy- and tissue-engineered
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Section 6/3 - R. Sanzenbacher
Manufacture of Somatic Cell Therapy- and Tissue-Engineered Products: Considerations on Quality Aspects
Disclosure: I attend this conference as an individual expert. Some views expressed here are my personal views, and may not be understood or quoted as being made on behalf of the PEI or EMEA or reflecting the official position of those.
ISCT Rotterdam, 21. May 2011
Cell-based products: Manufacturing and Control The key material: Cells as starting material and active substance EU Guidance: Overview
Section 6/3 - R. Sanzenbacher
Procedures for Tissue/Cell-Products at PEI Div 6 (2004- 2Q/2010)
(without Therapeutic Tumor Vaccines) (without non-manipulated HSC for heterologous use)
61 26 42 44
2010 (2Q) 2009
2004 2005 2006 2007 2008
centralised national
0
5
10
15
20
25
5
18
4 2
1
3
7
1
10
Section 6/3 - R. Sanzenbacher
Quality Aspects of Cell-based Medicinal Products (CBMPs)
Transport
Manufacturing
Formulation for Administration
Transport Testing
Release Storage
Procurement
Active Substance
Drug Product
Section 6/3 - R. Sanzenbacher
Section 6/3 - R. Sanzenbacher
Manufacturing of Cell-based Products: Qualification / Validation
Transport
Manufacturing
Formulation
Transport Testing
Release Storage
Procurement
Active Substance
Drug Product
Section 6/3 - R. Sanzenbacher
Starting materials Donor Qualification
Staff Training Transport
Materials, Reagents, Exipients
Process Product Characterisation
In Process controls
Testing
Release Specifications
Transport Stability
Packaging materials
Labelling
Traceability
Administration
Process Variations
Handling at clinical site: Staff Training
Procurement Process
Standardisation
All steps have potential impact on the quality/safety of the product !
Section 6/3 - R. Sanzenbacher
human tissues/cells for human application
incl. SCs excl. blood blood components
National Accreditation System
Dir 2004/23/EC Processing, Preservation, Storage, Distribution,…
Tissues, Cells
autologous grafts used within same surgical procedure
(parts of) organs for homologeous use
Dir 2004/23/EC Donation
Procurement Testing
Reproductive cells
Dir 2006/17/EC
Dir 2006/86/EC
Regulatory Environment in the EU
not “prepared“
Tissue Preparations
Section 6/3 - R. Sanzenbacher
Section 6/3 - R. Sanzenbacher
human tissues/cells for human application
incl. SCs excl. blood blood components
National Accreditation System
Dir 2004/23/EC Processing, Preservation, Storage, Distribution,…
Tissues, Cells
autologous grafts used within same surgical procedure
ATMPs Centralised MA Medicinal Products
Organs/ parts of organs for homologeous use
Dir 2004/23/EC Donation
Procurement Testing
Reproductive cells
Dir 2006/17/EC
Dir 2006/86/EC
CBMPs: Regulatory Environment in the EU
Reg (EC)1394/2007 on ATMPs
Dir 2001/83/EC as amended
not “prepared“
National Accreditation (Hospital Exemption)
Tissue Preparations
Section 6/3 - R. Sanzenbacher
Section 6/3 - R. Sanzenbacher
ATMPs: Current EU Guidance
✘ 2008: Potency testing of cell-based immuno- therapy MPs for treatment of cancer Doc Ref: CHMP/BWP/271475/06 ✘ 2008: Guideline on Human cell-based MPs Doc Ref: CHMP/410869/06 ✘ 2010: Reflection paper on Chondrocyte containing MPs for cartilage repair Doc Ref: CAT/CPWP/568181/2009 ✘ 2010: Guideline on Xenogeneic CBMPs Doc Ref: CHMP/CPWP/83508/09 ✘ 2011: Reflection paper on stem-cell based MPs Doc Ref: CAT/571134/09
http://www.ema.europa.eu/ema
Section 6/3 - R. Sanzenbacher
✘ PART IV: Advanced Therapy Medicinal Products
A risk-based approach may be applied to determine the extent of quality, non-clinical and clinical data to be included in the MAA
Special provisions applying for ATMPs ✘ PART I: (Section 3.2)
The Pharm. Eur. monographs shall be applicable to all substances, preparations and pharmaceutical forms appearing in it. Reference shall be given.
In the case of analytical procedure(s) included in the Pharm. Eur., the description shall be replaced by the appropriate reference to the monograph(s) and general chapter(s).
Where starting and raw materials, active substance(s) or exipient(s) are not desribed in a Pharm. Eur. or a EU MS monograph, compliance with a monograph of a third country pharmacopoeia can be accepted.
In case where a specicification in a Pharm. Eur. or in a EU MS monograph might be insufficient to ensure the quality of the substance, the CA may request more appropriate specifications. Where applicable and if needed, a certificate of conformity (CE marking) on medical devices shall be provided.
ATMPs: Dir 2001/83/EC, Annex 1
Section 6/3 - R. Sanzenbacher
✘ 2.6.1. Sterility (Guideline for using the test in in 5.1.9)
✘ 2.6.7. Mycoplasmas
✘ 2.6.14. Bacterial Endotoxins (GL for using the test in 5.1.10)
✘ 2.6.30. Monocyte Activation Test (alternative to rabbit pyrogene test)
✘ 2.7.24. Flow Cytometry
✘ 5.1.6. Alternative Methods for Control of Microbiological Quality
✘ 5.1.7. Viral Safety
(✘ 5.2.3. Cell Substrate for Production of Vaccines)
✘ 5.2.8. TSE
✘ 2.6.27. Microbiological Control of Cellular Products
✘ 2.7.24. Flow Cytometry
✘ 2.7.28. Colony-forming Cell (CFC) Assay
✘ 2.7.29. Nucleated Cell Count and Viability
✘ 01/2008:2262 Bovine Serum
✘ 01/2008:2323 Human Haematopoietic Stem Cells
CBMPs: Relevant Ph.Eur. Chapters and Monographs
Section 6/3 - R. Sanzenbacher
Section 6/3 - R. Sanzenbacher
Section 6/3 - R. Sanzenbacher
CBMPs: Quality Aspects THE MAJOR VARIABLE: Tissues/Cells as starting material
Transport
Formulation for Administration
Transport Testing
Release Storage
IPCs Variations
Procurement Starting Material
Manufacturing
Section 6/3 - R. Sanzenbacher
✘ Origin and banking history of cell lines (History Files, )
✘ Definition of (primary) master/working bank
✘ Performance
✘ Comparability of performance over time (passage numbers, storage)
✘ Phenotype, identity, purity
✘ Genetic stability, karyotype
✘ Virus screening (serology, PCR, indicator cell lines): HIV-1/2, HBV, HCV, HTLV I/II, EBV, CMV, Parvovirus B-19, ..)
✘ Adventitious agents screening (Bovine, mouse, porcine, rabbit; ampho-/xeno-/ecotropic retroviruses,…)
✘ Microbiological screening
Starting Material – Qualification of Cell Banking System CBMPs Quality Aspects
References: EP 5.2.3. Cell substrate for Production of Vaccines ICH Q5a (=CPMP/ICH/295/95/ICHtopicQ5a) ICH Q5d EudraLex Vol 4 (GMP), Annex II
Section 6/3 - R. Sanzenbacher
Section 6/3 - R. Sanzenbacher
CBMPs Quality Aspects Starting Material – Control of a Primary Cell Source
✘ Qualification of Donor - Intensive donor screening must substitute for virus inactivation ✘ Control of Procurement - Standardized procurement of cells/tissues - Training of procurement team - Prevention/Reduction of microbial contamination risk at procurement site ✘ Control on Biopsy Transport and Receipt - Stability considerations (time, temperature, stress conditions,. to preserve functional integrity) - Risk of microbial contamination - X-linking of different traceability systems (30y!!!)
Section 6/3 - R. Sanzenbacher
Section 6/3 - R. Sanzenbacher
Starting Material from Human Source: Viral Safety Principles
Donor Selection Donor Testing Inactivation/
Removal Vigilance / Traceability
Donor compliance Unknown risks Limited tissue resources
Lim
itatio
ns
Unknown viruses Sensitivity Diagnostic window Test interference post-mortem donor: Limited Shelf life for further preparation
Product integrity Virus stability (Residual contam.)
Compliance Detection
Definition of exclusion criteria Donor evaluation: Medical history Behavioural History Physical examination
Procurement report
ELISA PCR
Filtration Thermodesinfection Pasteurisation Chemical (PES,..) Gamma-irradiation
QM-Systems RMP
Met
hods
Section 6/3 - R. Sanzenbacher
Section 6/3 - R. Sanzenbacher
Human Donor Testing
Dir 2006/17/EG Annex 2 Other Guidance, eg. for blood, blood components , blood-rich tissues NAT might be applicable Additional product-specific testing might be requested e.g. ParvoB19, WNV, CMV …
Section 6/3 - R. Sanzenbacher
Section 6/3 - R. Sanzenbacher
Transport
Formulation for Administration
Transport Testing
Release Storage
IPCs Variations
Procurement
Manufacturing
CBMPs Quality Aspects
Section 6/3 - R. Sanzenbacher
Sterility of starting material can not be guaranteed Compare to transfusion medicine where 0.2 to 0.5 %
of cellular blood components (Thrombocytes) are bacterially contaminated,
e.g. Staph. epidermidis (Skin as tissue source)
Increasing incidence of multi-resistent hospital strains
(MRSA, Acenetobacter, vancomycin-resistent Enterococci)
Non-sporocidal disinfection procedures
Starting material cannot be sterilised Final product cannot be sterilised e.g. heat, gas, γ-rays, filtration, 0.2 µm filters
Use of antibiotics mask bacterial contamination, concentration might be lower in patient
CBMPs Quality Aspects Microbiological Safety
Section 6/3 - R. Sanzenbacher
Sterility testing underlay “sampling error” ✘ The potential result “The test sample is sterile” gives no significant information on the whole volume of product/intermediate ✘ Antibiotics in culture medium disguise contamination
Short shelf life of final product ✘ Testing results not available at release / application to patient
CBMPs Quality Aspects Microbiological Safety
Sterility (EP 2.6.1) Method: Membrane filtration or direct inoculation Readout: Turbidity Incubation time: at least 14 days at 30-35°C
Microbiological Control of Cellular Products (EP 2.6.27) Readout: CO2 Production Incubation time: at least 7 days at 35 - 37°C
BacT/Alert, BioMerieux
BACTEC, BD Diagnostics
Established Methods for Sterility Testing might not be appropriate ✘ Media, Temperature, Interference
Section 6/3 - R. Sanzenbacher
Consequences
✘ Implementing of a complex overall microbial safety strategy for cell products
✘ Development of rapid test systems or combination of systems
(PCR, FACS, Substrate, Bioluminescence,…)
✘ If justified by product and indication, CA might accept test limitations
✘ Need for Revision of Guidelines and Monographs
References: EP 2.6.30 Monocyte Activation Test (Pyrogen Testing) FDA 2008 Guidance for Industry: Validation of Growth-Based Rapid Microbiological Methods…
CBMPs Quality Aspects Microbiological Safety
Section 6/3 - R. Sanzenbacher
✘ limited amount as starting and test material
✘ active substance often “cell mixtures” where therapeutic effect cannot be related to single cell type or defined combination of cell types
✘ inherent variability within one cell type (donor age, gender, ethnicity, disease state, comorbidities,…….)
✘ heterogeneity of different cell types upon culture, eg dedifferentiation, genetic instability, malignant transformation,..
✘ fragility ✘ undefined mechanism of action(s)- Controls?
✘ cells interact with/depend on (micro)environment
✘ cells “biodistribute” actively
✘ …..
© Steve Sack -The Minneapolis Star Tribune
CBMPs Quality Aspects Cells as Complex Active Substance
Section 6/3 - R. Sanzenbacher
Keep in mind: Potential Safety Issues associated with CBMPs
Infections / Microbial Contamination Inflammation Immunogenicity, Rejection Immunosuppressive Action Inappropriate differentiation loss of function Malignant transformation, Tumourgenicity Ectopic engraftment to non-target tissues
Cancer Res 2005
Jan 2008
Section 6/3 - R. Sanzenbacher
CBMPs Quality Aspects Cells as Starting Material and Complex Active Substance
Consequences for process development
✘ Due to inherent variability of (primary) cells, variability in some process steps and respective specifications ranges should be included ✘ High impact of process changes /up-out-scaling/ other deviations on products should be considered already in early product development ✘ Biological analytical techniques show a greater variability than physico-chemical tests
✘ For reproducibility other variables must be reduced and/or controlled by QC measures as best possible -staff training -adequate tools to demonstrate lot-to-lot consistency and comparability (relevant IPCs and validated robust accurate tests) -defined quality of reagents and materials -quality risk management system, risk profiling strategy
Section 6/3 - R. Sanzenbacher
CBMPs: Influence of Ancillary Materials
Morphology Metabolic activity
Gene Expression Profile
Proliferation
Intracellular Signalling
Differentiation
Extracellular Signalling
Protein Distribution Profile
Secretory Activity Vitality
Migration, Adherence
Processing Steps
Cell functionalities (mode of action + others), stability, safety
Starting Material
Reagents & Materials
??? ???
Culture Conditions
Section 6/3 - R. Sanzenbacher
CBMPs Quality Aspects Product Characterisation / Release Specifications
✘ ✘ Total Cell Number ✘ ✘ Cell Viability ✘ ✘ Identity (phenotypic and/or genotypic) ✘ ✘ Purity ✘ ✘ Impurities (product-/process-related, degradation products, adventitious agents) ✘ ✘ Potency ✘ ✘ Sterility ✘ Structural Characteristics (3-dimensional shape) ✘ Senescence
Section 6/3 - R. Sanzenbacher
Definition of combined ATMP
• ‘Combined advanced therapy medicinal product’ means an advanced therapy medicinal product that fulfils the following conditions: – it must incorporate, as an integral part of the product, one or
more medical devices within the meaning of Article 1(2)(a) of Directive 93/42/EEC or one or more active implantable medical devices within the meaning of Article 1(2)(c) of Directive 90/385/EEC, and
– its cellular or tissue part must contain viable cells or tissues, or
– its cellular or tissue part containing non-viable cells or tissues must be liable to act upon the human body with action that can be considered as primary to that of the devices referred to.
Art 2(d) of Reg. 1394/2007
Section 6/3 - R. Sanzenbacher
Combined ATMPs are evaluated by EMA as a whole, since the agency is responsible for the final decision and control on the medicinal product
MAA should include results of the NB’s report on the device part in section 3.2.R of CTD; the agency shall recognize this results in its evaluation CAT may demand transmission of evaluation results of the medical device part by a NB If no results are available at time of MAA, CAT shall seek an opinion of a NB which is to be determined together with the applicant However, involvement of a NB is not necessary if the CAT believes to have sufficient expertise
Combined ATMPs: Consultation of Notified Bodies (NB)
Section 6/3 - R. Sanzenbacher
Ralf Sanzenbacher Paul-Ehrlich-Institut Federal Insitute for Sera and Biomedicines Division of Medical Biotechnology Section Tissue-Engineering & Somatic Cell Therapeutics D-63225 Langen/Germany E-mail: sanra@pei.de
Thank you! MAA
accepted
Manufacture of Somatic Cell Therapy- and Tissue-Engineered Products: Considerations on Quality Aspects
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