דרישות איכות ורגולציה בשלבים הראשונים של תרפיה תאית ד"ר עפרה אקסלרוד המכון לביקורת ותקנים של חומרי רפואה יוני 2013

Transcription

1 דרישות איכות ורגולציה בשלבים הראשונים של תרפיה תאית ד"ר עפרה אקסלרוד המכון לביקורת ותקנים של חומרי רפואה יוני 2013

2 Advanced Therapy Medicinal Products ATMPs - European Term Gene Therapy Somatic Cell Therapy cell based products Tissue Engineered Combination Products

3 Somatic Cell-Based Therapy-Definition Somatic cell therapy medicinal products: Substantially manipulated cell/tissue- to treat, prevent or diagnose a disease (through pharmacological, immunological, or metabolic action) or Cell/tissue not intended to be used for the same essential function(s) in the recipient and the donor

4 cutting grinding shaping centrifugation Non-substantial Manipulation - soaking in antibiotic or antimicrobial solutions sterilization irradiation cell separation, concentration or purification filtering lyophilization freezing cryopreservation vitrification Everything else is considered as substantial minimal manipulation

5 General Comments Regulation according to EU regulation Reg/1394/2007/EC on Advanced therapy medicinal products Because of the huge potential variation in product type, one size fits all is not applicable. The amount of data required to proceed FIM will vary according to product type, extent of processing, anticipated MoA and the benefit risk balance for the intended indication. Risk based approach is recommended GUIDELINE ON HUMAN CELL-BASED MEDICINAL PRODUCTS (EMEA/CHMP/410869/2006) Draft guideline on the risk-based approach according to Annex I, part IV of Directive 2001/83/EC applied to Advanced Therapy Medicinal Products(EMA/CAT/CPWP/686637/2011)

6 Regulation Human Medicinal product Biological product Advanced Therapy Medicinal products -Somatic cell therapy medicinal products

7 Donor suitability Procurement Testing Non-clinical Framework Pharmacovigilance Manufacture Clinical Trial MAA GMP (ATMP) GLP GCP (ATMP) EudraLex Vol 9 Tissues and Cells Dir/2004/23/EC Dir/2006/17/EC Dir/2006/86/EC Medicinal Product Dir/2001/83/EC Dir/2009/120 Dir/2001/20/EC Reg/1394/2007/EC on Advanced therapy medicinal products Dir/2003/94/EC Dr. Ilona Reischl BASG AGES PharmMed Austria

8 Clinical studies - Quality Starting point Guideline on the requirements for Quality documentation Concerning Biological Investigational Medicinal Products in Clinical Trials (EMA/CHMP/BWP/534898/2008) Although ATMPs are not in scope, the guideline represents the expectation of the regulators regarding biotechnology products Guideline on cell based medicinal products (EMEA/CHMP/410869/2006) Guidance for FDA Reviewers and Sponers: Content and Review of Chemistry, Manufacturing, and Control Information for Human Somatic Cell Therapy Investigational New Drug Applications, April 2008

9 Main topics IMPD (Investigational Medicinal Product Dossier) or Equivalent IND GMP Issues of concern

10 Quality Issues IMPD (Investigational Medicinal Product Dossier) or Equivalent IND GMP Issues of concern

11 IMPD Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials (CHMP/QWP/185401/2004 ) ATMPS - Drug Substance vs. Drug Product: The distinction is not always clear. It is important to set out in the IMPD how this distinction is made.

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15 Quality Aspects IMPD (Investigational Medicinal Product Dossier) or Equivalent IND GMP Issues of concern

16 GMP Manufacturer(s )must comply with the principles of GMP Inspection - Phase III Declaration of compliance Phase I + II Directive 2003/94/EC- laying down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use Annex 13 to volume 4 Eudralex - Investigational Medicinal Products Annex II to volume 4 Eudralex - Manufacture of Biological Active Substances and Medicinal Products for Human use Annex I to volume 4 Eudralex Annex 1-Manufacture of Sterile Medicinal Products תקנות הרוקחים )תנאי ייצור נאותים לתכשירים( תשס"ט נוהל יצור וייבוא תכשיר ניסיוניים במדינת ישראל (EX-012/01(

17 Increasing GMP requirements annex II

18 Intersection Blood/Tissues/Cells and GMP Tissues and Cells Donation Procurement Testing Processing Storage Responsible person ATMPs GMP Manufacture Qualified person Dr. Ilona Reischl BASG AGES PharmMed Austria

19 Heterologous use and GMP Scenario: ATMP definition applies - heterologous use of a non-substantially manipulated product The GMP aspects: Product definition (specifications) Release testing Release by Qualified Person Stability QC including sterility and environmental control Dr. Ilona Reischl BASG AGES PharmMed Austria

20 Unique Features Sterilization of the finished product can not be achieved Temperature sensitive Release testing - sometimes limited Limited sample sizes Short life time Availability of potency test Microbial purity Tight Control strategy and tests throughout manufacture at early stages of development Safety, Consistency

21 Quality Issues IMPD (Investigational Medicinal Product Dossier) or Equivalent IND GMP Issues of Concern

22 Issues of Concern Manufacturing Process Starting Materials Raw materials / excipients Process Validation SpecificationStability Tumorigenicity Traceability

23 Manufacturing Process (1) Definition of batch and scale Flowchart of all successive steps IPC the results may be reported as action limits or preliminary acceptance criteria (should be reviewed when more knowledge is gained)

24 Manufacturing Process (2) Potential risk of contamination Manufacturing steps should be conducted aseptically segregation of autologous materials obtained from infected donors the robustness of the control and test measures put in place for these source materials should be ensured.

25 Starting Materials (1) Variability in quality and/or composition may be unavoidable and this should be explained in the context of being fit for purpose.

26 Starting Materials (2) Donations All human cells and tissues must be donated, procured and donor tested in accordance with EU Directives of quality and safety of human cells and tissues(dir/2004/23/ec, Dir/2006/17/EC, Dir/2006/86/EC) Where relevant, a rational programme for extended viral safety testing based on relevant factors (location, history of foreign travel) should be established. For autologous therapies, the directive does not exclude the use of cells of virus positive individual. Information is important for: risks to employees, facility, cross contamination, increased expression of virus as a result of extended processing.

27 Starting Materials (3) Cell Banks MCB - should be established prior to the initiation of phase I trials. WCB - may not always be established prior to the initiation of phase I The generation and characterization of the cell banks should be performed in accordance with principles of ICH guideline Q5D (Derivation and Characterization of Cell substrate used for Biotechnological/Biological products) Adventitious agents Cell substrate stability (including PDL) Tumorigenicity The principle of ICH Q5A (Viral safety evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin) should be applied, but it should be kept in mind that cells tissues become the IMP.

28 Raw Materials The sourcing of a Pharmaceutical grade material for ATMPs manufacturing is not always possible and therefore challenging Usage of non pharmaceutical grade (research grade) should be justified Description of their quality control should be provided Information demonstrating that materials meet standards applicable for their intended use should be provided. Summaries of adventitious agents safety information for biologicallysourced materials should be provided. Collaborating CAT/BWP/EDQM on standardization of raw materials for production of ATMPs

29 Excipients Animal/Human Origin Information regarding adventitious agents safety evaluation (e.g. sources, specifications, description of the testing performed) and viral safety data should be provided. Compliance with the TSE guideline (EMA/410/01, current version) should be documented. If human albumin or any other plasma derived medicinal product is used as an excipient, information regarding adventitious agents safety evaluation should follow the relevant chapters of the Guideline on Plasma-Derived Medicinal Products (CPMP/BWP/269/95). If the plasma derived component has already been used in a product with MA then reference to this can be made. Specifications For non-compendial excipients, the in-house specifications should be justified.

30 Process validation (1) Process validation/evaluation data should be collected throughout the developement Process establishment and validation can be done using cells from healthy donors. BUT verify sufficiently with patient material PRIOR to initiation of clinical trials, because The characteristics of Patients cells might differ i.e. degree of adherence, expression of markers Impact on critical product parameters Impact on dose

31 Process validation (2) Validation of aseptic process (Simulation of aseptic manufacturing) validation of sterilizing processes should be of the same standards as for products authorized for marketing.

32 Specifications (1) The following tests are mandatory: Identity Clear evidence of identity and purity of cell population Purity should be available before FIM Potency (Biological activity) Some evidence of relevant biological functionality Marker based assays + functional assays Should be related to clinical response In place As Soon As Possible and as a must before phase III (usually required before) To improve the ability of linking the functional quality of cells from each study and maximizing the relevance of the information gained.

33 Specifications (2) Sterility IMP may be released before final sterility testing result May be released on the basis of rapid methods (validated) Parallel pharmacopoeial testing is expected for post release confirmation of product microbiological quality PhEur MICROBIOLOGICAL CONTROL OF CELLULAR PRODUCTS MICROBIOLOGICAL CONTROL OF CELLULAR PRODUCTS An action plane/procedure should be developed in conjunction with clinical investigator(s) in the event that positive results are received after the product has been administrated to a patient Endotoxins

34 Specifications (3) Impurities - upper limits Product characteristics: that are not completely defined at a certain stage of development, or for which the available data is too limited to establish acceptance criteria such product characteristics could be included in the specifications, without pre-defined acceptance.

35 Impurities Process related impurities and product related impurities should be addressed. Quantitative information on impurities should be provided including maximum amount for the highest clinical dose. For certain process-related impurities estimation of clearance may be justified. In case only qualitative data are provided for certain impurities, this should be justified.

36 Analytical procedures The analytical methods should be described for all tests included in the specifications. Validation phase I suitability of the analytical methods used should be confirmed. The acceptance limits and the parameters for performing validation should be presented in a tabulated form. Phase II/III A tabulated summary of the results of the validation carried out should be provided. It is not necessary to provide a full validation report.

37 Tumorigenicity Tumorigenicity assessment Must be investigated prior to FIM Must be performed with cells at the limit of routine cell culturing or beyond.

38 Stability Stability studies should provide sufficient assurance that the IMP will be stable during its intended storage period. Hold times and storage conditions for process intermediates should be justified and supported by data. Shipping conditions It is advisable, prior to starting of FIM study, to conduct some studies confirming the ability of proposed transport containers to maintain critical conditions.

39 Product Traceability Coding System A system connecting the required traceability from cell donation and procurement to the manufacturer and user. At the tissue establishment: link between donor and donation At the manufacturing site: link between donation and product. Hospital/practice: link between product and recipient. The systems should allow full traceability from donor to recipient through anonymous coding systems. Dr. Ilona reschl, Ages Austria 39

40 Final Remarks No compromise on safety issues Sterility, viral safety, impurities, certain characteristics Quality attributes to control the IMP are important to demonstrate pharmaceutical quality, product consistency and comparability after process changes, while process validation is incomplete. Upcoming guideline Reflection Paper on Investigational CBMP Quality and non-clinical issues at various stages of development Minimal Quality requirements for FIM clinical studies

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