GXPs. 18 February Daisaku Sato, PhD

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1 IABS, JST (NIBIO), PMDA and WHO joint Workshop GXPs 18 February 2015 Daisaku Sato, PhD Director, Office of Cellular and Tissue-based Products (PMDA), Japan Disclaimer: The views and opinions expressed in this presentation are those of the presenter and should not necessarily represent the views and opinions of the PMDA. 1

2 Introduction of PMDA Pharmaceuticals and Medical Devices Agency (PMDA) an Incorporated Administrative Agency (IAA) PMDA s Safety Triangle Tokyo, JAPAN 2

3 Two Japanese Regulatory Authorities Ministry of Health, Labor and Welfare (MHLW) Planning basic policy, enforcement of administrative measures based on the law Marketing authorization of pharmaceuticals and medical devices Issue emergency safety information and direct product withdrawal Safety measures for emergent and significant cases (PMDA) Review, examination and data analysis Scientific review, GMP/GLP/GCP inspection and consultation on the development of pharmaceuticals and medical devices for marketing authorization Collection, analysis and dissemination of information relating to quality, efficacy and safety of pharmaceuticals and medical devices 3 3

4 Two Acts regulating regenerative medicine & cell therapy MHLW process Regenerative Medicine PMDA process * Two laws were enacted on 25 November 2014 All medical technologies using processed cells which safety and efficacy have not yet been established Production and marketing of regenerative and cellular therapeutic products by firms The Act on the Safety of Regenerative Medicine The Act on Pharmaceuticals and Medical Devices (PMD Act)* It may be similar to Hospital exemption of the Pharmaceuticals EU or PHS and Medical 361 in Devices the US Agency 4 4

5 Regenerative medicine & cell therapy in Japan The Act on the Safety of Regenerative Medicine Medical care Clinical Research using human stem cells (under the Guideline for Human Stem Cell Clinical Research - since 2006) Pharmaceuticals and Medical Devices Act (PMD Act) Product Marketing Authorization Academic Research Purpose Purpose Cancer immunotherapy Six types of therapy are currently provided in approved university hospitals as advanced care * Partially covered by national health insurance 108 protocols approved (as of November 2014) Covered by MHLW Cellular/Tissue based Products 2 approved products JACE (autologous cultured epidermis) JACC (autologous cultured cartilage) 2 products under review Process 19 clinical trials initiated (including 5 gene therapy products) (~January 2015) Covered by PMDA 5

6 Today s Topics 1. What are GXPs? 2. GTP 3. GMP (=GCTP) 4. Other GxPs 6

7 What are GXPs? Broader term of Good Tissue Practice (GTP) is aimed at source material handling requirement such as: Source material selection, Donor eligibility Personnel, procedure Facility, Equipment, process control (Contamination prevention / sterility) Validation Record keeping, traceability Storage, shipment, distribution Reporting In cellular product manufacturing, the down stream of GTP regulation may be included in GMP type regulation 7

8 Purpose of GTP to prevent the introduction, transmission, and spread of communicable diseases by HCT/P's. 8

9 GTP in the regulations US GTP = 21 CFR 1271 (Donor Eligibility + cgtp) Japanese GTP = Minimum requirement of biological ingredients + cgmp Good gene, Cellular and Tissue-based product manufacturing Practice (GCTP) biologics GMP 9

10 GTP is an operational part of quality assurance in a constant and routine manufacturing basis Inactivation and/or Elimination of Undifferentiated Cells Final Products Intermediate(s) Quality system to secure consistent manufacturing of safe and effective products Evaluation of Q/S/E Relevant Cells Can Be Processed (e.g. differentiate).to Desired Product Characterization Constant Supply, Stability& Renewal Characterization, Stability Cell Bank Cell Line Potency of Differentiation to Next Target Cells, Potency of Self- Renewal, Stability Relevant Pluripotency to Differentiate into the Target Cells, Potency of Self- Renewal Cell Collection Source, Biological Features Selection of Cells that are Suitable for Reprogramming etc

11 Basic Scientific Issues for Product Development, Evaluation and Control Suitability and quality control of raw materials and manufacture-related substances other than target cells Indicate their appropriateness for their intended use, and if necessary establish their specifications. Perform proper quality control for these materials. Prevent the contamination of bacteria, fungi, viruses, and abnormal prions from biological materials 11 11

12 Basic Scientific Issues for Product Development, Evaluation and Control Justification of source and selection of human cells that serve as raw materials including autologous or allogeneic donor screening criteria and eligibility Justification of source and selection of animal materials that serve as culture medium, scaffold, etc. in terms of virus inactivation/removal and ruminant prion transmission 12 12

13 Justification of Source and Selection of Human Cells that serve as Raw Materials Select the source and origin of the cells used as raw materials, and justify the reasons for selecting these cells. Autologous or allogeneic somatic cells Autologous or allogeneic stem cells Autologous or allogeneic ips(-like)cells ES cells (Any other human cells) 13 13

14 Principle of Donner eligibility criteria When collecting human cell / tissue raw material, depending on the purpose of their use, relevant bacteria, fungal and viral infection and the like have been denied through interview, screening and testing. The test parameters and method methods used are appropriate in light of the latest knowledge of infectious diseases, etc.. The Donor s presence or absence of experience that received blood transfusion or transplantation must be taken into consideration when determining donor eligibility. 14

15 Considering Donner eligibility criteria According to the test parameters and test methods, the re-testing and other infection controls at the right time have been made, taking into consideration the window period. However, it does not necessarily require a donor screening when the donor is the same person as recipient. 15

16 Points to Consider for doner eligibility on Autologous CT & Allogeneic CT Autologous Human Cell/Tissue Infectious status of donor, including infections of HBV, HCV, HIV, and HTLV. Risk of proliferation or reactivation of virus in manufacturing processes Robust process control to minimize unevenness of Custom-Made products Limited amount of samples for quality evaluation of products Allogenic Human Cell/Tissue History, source, derivation Donor screening/testing and donor eligibility (compatibility with donor qualification criteria, including ethical and medical aspects; freedom from the presence of HBV, HCV, HIV, HTLV and pulvovirus B19 by screening and testing; exclusion of potential infection of CMV, EBV and WNV by testing; clinical history; experience of blood transfusion or implanting;genetic etc.) Records of donor Derivation of cell strain Cell banking Viral assay at the final product level Immunological problems (eg., rejection, GVHD etc.) 11 16

17 Geographic difference These principles may have been derived from the experiences of blood transfusion, so that some different views may exist in the western world reflecting the different medical environment Infectious disease demography Remunerated/non-remunerated donor 17

18 Social and ethical context In the Japanese regulation The provision of human tissue material shall be made free of charge. However, this shall not apply to the compensation equivalent of transportation expenses and other actual expenses that occurred upon the provision of human tissue materials. 18

19 Other infectious agents Determine eligibility as a donor, considering the presence or absence of experience of blood transfusion and transplantation as well as interviewing anamnesis of the following listed disease: Infection by treponema pallidum, chlamydia, neisseria gonorrhoeae, bacterial such as Mycobacterium tuberculosis Sepsis Malignant tumor Severe metabolic and endocrine disorders Collagen disease and blood disorders Liver disease Transmissible spongiform encephalopathy(tse) and its suspicion and other dementia Specific genetic diseases and family history 19

20 Cell collection, preservation(1) 1. Eligibility of cell/tissue collectors and collecting medical institutions Clarify technical requirements for cell/tissue collectors and collecting medical institutions, handling source materials 2. Justification of cell/tissue harvest site and collection method Show the selection criteria and collection method for collecting site of cells or tissues, clarify that they are scientifically and ethically appropriate choices. Regarding cell / tissue collection method, describe and demonstrate instruments and drugs used, concrete measures to prevent microbial contamination, mix-up and cross-contamination. 20

21 Cell collection, preservation(2) 3. Prior Informed consent to Donors Define the contents of the informed - consent to cells and tissue donors, including anticipated clinical applications. 4. protection of personal information of donor Specifically regulatory and protective measures of personal information of donors 5. Storage and mix-up prevention measures Clarify the justification of the storage conditions and storage period and setting, If the collected cells or tissues are necessarily to be stored in a certain period. In addition, explain the means and procedures to prevent mix-up and confusion. 21

22 Elements of Donor informed-consent (A) (B) (C) (D) (E) (F) (G) (H) (I) (J) Use and application of collected human cell and tissue as raw materials Risk and disadvantage expected by the provision of human cell and tissue To be a donor is the arbitrary Right to withdraw the consent The donor shall not take disadvantage by withdrawal of the consent of the provision or by non provision of human cell and Expenses related to the provision of human cell and tissue Compensation for health damage caused by the provision Protection of personal information of donor Patent rights relating to the product derived from the collected human cell and tissue, copyright and other property rights Give priority to collection of human cell and tissue materials, not the cell and tissue diverted from medical treatment, surgery and other therapeutic treatment. 22

23 Donner records Recordkeeping The record of donor shall be maintained and stored so as to verify information required to secure safety of the cell and tissue as raw material. In addition, for each experimental sample of the donor and the patient, the content of information and its storage measure may depend on the intended use. 23

24 Basic Scientific Issues for Product Development, Evaluation and Control Justification of source and selection of animal materials that serve as culture medium, scaffold, etc. in terms of virus inactivation/removal and ruminant prion transmission Justification of source and selection of human cells that serve as raw materials including autologous or allogeneic donor screening criteria and eligibility 24 24

25 The Risk based approach to be taken: When conducting or evaluating tests on individual product, it is necessary to take risk based approaches on a case-by-case basis, in terms of type, characteristics and intended clinical use of the product in question. For example: In the use of such an advanced therapeutic product for treating patients (First-in-Man) with severe and life threatening diseases or injuries, the risk/risk balance with/without the advanced treatment should be also taken into account, rather than just discussing unknown potential risk of a product. Reflection of scientific progress and accumulation of experience in relevant field is always encouraged for unexpected risk. Decision making by a patient after extensive IC should be a crucial element. 25

26 Constant revisit on the requirements for the donor eligibility are needed based on scientific knowledge For the safe and rapid clinical translation of cellular and tissue based products, source material eligibility requirements are to be revised, based on the latest scientific knowledge on viral safety, the international views on the risk of BSE, etc. From sound scientific viewpoints, taking into account of characteristics of cellular and tissue based products and their clinical applications. 26

27 Example of requirement for biological source materials (Japanese Minimum Requirements for Biological Ingredients) MHLW Public Notice No.375 (2014)/No.210 (2003) The purpose is to ensure the quality, efficacy and safety of pharmaceutical products, quasi-pharmaceutical products, cosmetics and medical devices (hereafter pharmaceuticals, etc. ) by establishing standards related to the measures that are required in the event that materials and ingredients used in the manufacturing of these pharmaceuticals, etc. are derived from biological sources (excluding plants) other than the person using the product (including those used during the manufacturing process, such as additives and media components). 27

28 Examples of Revisions of requirements (Japanese Minimum Requirements for Biological Ingredients) MHLW Public Notice No.375 (2014) 1. Countries that can be an origin of ruminant animal-derived ingredients are expanded to those whose BSE risk became negligible, according to the latest risk assessment by OIE. (e.g. Japan and the U.S.) 2. Inactivation and removal of infectious agents from humanderived ingredients can be omitted, if the reason is justified and described in the certificate of marketing authorization (e.g. patient s serum for culturing an autologous cellular and tissue based product) 3. the confirmation of the donor animal eligibility and its record as well as the storage of the record are not required any more, as long as the therapeutic products have been used at clinical setting and the animal cell/tissue-based products are produced by culturing cells derived from a well-characterized cell bank. 28

29 Recordkeeping requirement examples in Japan Japanese GCTP and PMD Act. Ordinance How long are the source material records retained as a part of GMP(GCTP)? Record of source information of ingredients derived from allogenic human derived source materials (except using small quantity of albumin as excipient ) : 30 years since the product expiry date Record for other source materials : 10 years: since the product expiry date In the US, 21CFR years For the product containing the above human derived source materials, The source material specimens must be archived for 10 years since the expiry date Medical institutions are required to retain patient record of for 20 years Taking into account of vcjd window period, like European blood regulations 29

30 Quality System Structure to be Management & Supervision System (release, deviation, change control, self-inspection, Training/education, complaint management, recall) Product quality review Quality control system (labo. system) Supplier control system Validation / Verification Manufacturing control system (operation performance of process, Sterility assurance, Product quality monitoring) Facility & equipment system (qualification, calibration, maintenance) Document management system (Product master file, specification, statement, SOPs, record) Reflecting product marketing authorization documents Quality Pharmaceuticals Risk and Medical Management/ Devices Agency Knowledge management 30

31 Consideration for GMP part of GTP Quality System Requirement for regenerative medical technologies / products, considering the characters of these products; such as raw materials that cannot be sterilized Quality Risk Management Manufacturing Control (Sterility assurance, Prevention of Cross-contamination..) Quality control (Verification / validation, Quality review) Facility requirement It is necessary to consider whether the risk is manageable, - not only from the facility point of view, - but from the effects of the manufacturing operation, such as the evaluation of performance. 31

32 Example of Japanese GMP(GCTP) regulation Medical technologies using processed cells (except clinical trials under PMD Act. ) Regenerative Medical Products Manufacturer (Licensed) The Act on the Safety of Regenerative Medicine Hospital Obtaining Cell PMD Act. (revised PAL) Manufacturer (Licensed) Outside hospital Cell processing Commission Cell processing Cell collection Transplant GMP(GCTP) Delivery of cell product Cell Processing GCTP : Good, gene, Cellar and Tissue-based product manufacturing Practice 32 32

33 Aseptic operation in Manufacturing Control Unique challenges in sterile control of cellular and tissue based product Difficult to sterilize tissue and cell raw materials themselves, prior to use in the manufacturing process. Difficult to set the sterilization step in the manufacturing process. High risk of microorganism proliferation if contaminated in the manufacturing process Unavoidable human intervention may impact consistent contamination risk in the manufacturing. No methodology of bioburden control has been established Sterility assurance of cellular and tissue based products organize sterility assurance and its risk management, based on the characteristics of the product, equipment and manufacturing operations. 33

34 Points to consider in Quality Risk Management Significance and essence of QRM QRM will promote understanding of products and processes, so that you will obtain stronger ability to assure quality of products manufactured, leading to more robust quality assurance. Risk cannot be eliminated Recognize the risk Predict, prevent and manage the risk 34

35 Understanding of process Tissue collection cells Primary culture Expansion culture Process to obtain / extract the target cells from messy group of cells Process to propagate only the target cells Differentiation Purification Filling Product formulation Process to make the cells in the formulation 35

36 Quality Risk Management Process (ICH Q9) in a series of manufacturing processes Quality Risk Assessment Risk identification Risk Analysis Risk Evaluation Quality Risk Control Acceptance of risk Risk reduction Balance with profit, risk and resources New risk caused by controling specified risk Quality Risk Review Build in review and monitoring system Review risk acceptance level 36

37 Philosophy of Quality Risk Management From both sides of the equipment and facilities (hard), quality system (software), set the achievement level of control, continue to manage it and to improve, based on whether the potential risk of individual products is acceptable and manageable. To achieve the control level, the philosophy of GMP/GTP is to implement each documented quality system in a complementary manner. 37

38 Evaluation of risk in the quality, based on scientific knowledge, ultimately should be consequences to patient protection. 38

39 Facility and Equipment Facility and equipment of cleanliness controlled area and aseptic operation area The air conditioning facilities in the aseptic operation area The facility for cleaning, disinfection and sterilization of equipment used in aseptic areas and for processing waste 39

40 Contamination prevention Prevention of mix-up and crosscontamination of human cells during the manufacturing process is important, so that the preventive measure measure in process control should be clarified. 40

41 Operational issues for contamination and crosscontaminations (example 1) Method of risk reduction for the contamination and cross-contamination Where it is necessary to handle as a product having an infectivity to impact on the other product, the dedicated working chamber handling the products should be considered, unless the validated inactivation and cleaning procedures were established and carried out. The necessary measures to prevent contamination and cross contamination for each step should be carried out in a series of manufacturing processes., such as inactivation and removal of bacteria, fungi and viruses, Cells or tissues harvested from different donors should not be handled simultaneously in the same location in order to prevent mix-up of the cells and cross contamination by bacteria, fungi, viruses, etc., The necessary measures should be made not to perform improper storage so as to prevent the risk of mix-up and cross-contamination. 41

42 Operational issues for contamination and crosscontaminations (example 2) Method of reduction of contamination risk by mistake As quality control operations of products, in order to prevent mix-up and cross-contamination of the samples, to separate the analyte by appropriate labels and display. The specimen should be collected from the product, in the place that was determined in advance, in accordance with the procedure to prevent contamination of the collected product or material as well as to prevent cross contamination of other products and materials. 42

43 More important things (Knowledge management ) At this point in some site, you have experienced the followings, don t you? : Ms. X can only culture the cells Dr Y can only identify the target cells Mr Z can only find the result is correct Deviation happened!!, but the test result was OK, so the batch was OK 43

44 From Knowledge Management to Control Strategy R&D, clinical trials Product development Commercial production Personal silent knowledge Group knowledge R&D report Knowledge for verification Knowledge for validation Manufacturing and quality documentation Knowledge for Technical transfer Quality risk management Organizational Knowledge Accumulation of Knowledge Control Strategy Manufacturing and quality control 44

45 GMP in each stage of development Human subject protection Level of quality assurance Required assurance level Investigational product Exploratory Trial In an early development phase, acquired knowledge is limited, so that implementable assurance level may be lower, however, risk based flexibility is needed to keep higher level of assurance Confirmatory Trial In the development phase, quality is also under development. It would be unreasonable to apply GMP of the commercial product level. Flexible risk based approach would be more appropriate. Development stage 45

46 Validation or verification 1. validation or verification The purpose is to validate the facility and equipment and procedure at the manufacturing site are giving the expected result, or to verify they have given the expected result. The documentation of validation or verification is intended to allow constant manufacturing of quality compatible products. After identified variables, normally the sponsor validates three lots of manufacturing control and quality control methods give the expected results.(prospective validation) 2. Verification The implementation of process validation is difficult manufacturing process Manufacturing experience is limited Quantitative limitation of the specimen due to ethical reasons, technical limitations To verify and document manufacturing procedures have given the expected results for each product for each lot number or batch number 46

47 GXPs are not only for quality assurance in a product life cycle GTP GLP (Good Laboratory Practice) for animal study GCP (Good Clinical Practice) for human clinical trials GVP (Good Vigilance Practice) for postauthorization safety practices including handling AE reporting and post-authorization studies 47

48 System of general guidelines for quality and safety(pre-clinical) for Human Cell & Tissue- Based Products since Standard for Biological Ingredients MHLW Public Notice No.210 (2003) General Principles for the Handling and Use of Cells/Tissue-Based Products PFSB/MHLW Notification No.1314 Appendix1(2000) Guideline on Ensuring Quality and Safety of Products Derived from Engineered Human Cells/Tissue PFSB/MHLW Notification No.1314 Appendix 2 (2000) Good Tissue Practice Basic Technical Requirements Guideline on Ensuring Quality and Safety of Products Derived from Processing Human (Autologous) Cells/Tissue PFSB/MHLW Notification No (2008) Guideline on Ensuring Quality and Safety of Products Derived from Processing Human (Allogenic) Cells/Tissue PFSB/MHLW Notification No (2008) Guidelines on Ensuring Quality and Safety of Products Derived from Processing : Human (Autologous) Somatic Stem Cells PFSB/MHLW Notification No (2012) Human (Autologous) ips-like Cells PFSB/MHLW Notification No (2012) Guidelines on Ensuring Quality and Safety of Products Derived from Processing : Human (Allogenic) Somatic Stem Cells PFSB/MHLW Notification No (2012) Human (Allogenic) ips-like Cells PFSB/MHLW Notification No (2012) Human Embryonic Stem Cells PFSB/MHLW Notification No (2012) 48 48

49 Thank you for your attention Daisaku Sato, PhD. Director, Office of Cellular and Tissue-based Products (PMDA), Japan Regenerative medicine literature available in English Special thanks to our staff members! Hara A. Sato D. Sahara Y. New Governmental Regulatory System for Stem Cell Based Therapies in Japan. Therapeutic Innovation & Regulatory Science. 2014; 48(6):