Case Study: Examples Relating to the Quality Control of Cell-based Products

Transcription

1 Case Study: Examples Relating to the Quality Control of Cell-based Products CMC Strategy Forum Japan 2014 Yuuki Miyatake1), 2) 1) TEIJIN PHARMA LIMITED 2) Japan Pharmaceutical Manufacturers Association (JPMA) 1

2 Supposition of Several Cases Factor Example of Case Cell source Autologous Allogeneic Heterogenic Cell type Stem cell (adherent) Stem cell (floating) Somatic cell Bank of cell source Bank of intermediate No bank Transfection Episomal vector Virus vector No Transfection No differentiation Product Form Cell 2D structure 3D structure Action Mechanism Paracrine Engraftment Combination Drug Medical device No combination Storage Condition In-hospital preparation Not specific (2 25 ºC) Dry ice ( -20 ºC) Liquid nitrogen ( -150 ºC) Rinse Activation No preparation 2

3 Selection of Model Case Factor Model Case Cell source Autologous Allogeneic Heterogenic Cell type Stem cell (adherent) Stem cell (floating) Somatic cell Bank of cell source Bank of intermediate No bank Transfection Episomal vector Virus vector No Transfection No differentiation Product Form Cell 2D structure 3D structure Action Mechanism Paracrine Engraftment Combination Drug Medical device No combination Storage Condition In-hospital preparation Not specific (2 25 ºC) Dry ice ( -20 ºC) Liquid nitrogen ( -150 ºC) Rinse Activation No preparation 3

4 *1 es under GCTP control in CPF GCTP: Good Gene, Cellular, and Tissue-based Products Manufacturing Practice (i.e. GMP for Cell-based Products in Japan) CPF: Cell ing Facility (it is usually called as Cell ing Center (CPC), in Japan) *1: It is necessary to manufacture plasmid used for transfection also in compliance with GCTP. 4

5 Quality Control 5

6 Quality Control Donor Screening *1 Medical Checkup/Medical interview * Virus tests *2 Acceptance Visual Inspection / Microscopy Inspection Viable cells number / rate *1: Mandatory requirements for Japanese regulation are described in Standards for Biological Materials. *2: "Standards for Biological Materials" requires to repeat the same virus tests to donor after Window period. Virus tests and cell collection The collected cells have the contamination risk by viruses less than detection limit. Window period Virus re-tests The re-tests guarantee the virus safety of the donor and collected cells at that time of cell collection. 6

7 Quality Control Characterization *1 Viral safety evaluation based on ICH Q5A Genetic analysis Analysis of characteristic factor Quality tests for thawed cells *2 Visual inspection / Microscopy Viable cells number / rate Test for identification transfected cells Test for transfected gene *1: Characterization is not Quality Control such as routine tests performed under GCTP control. *2: Quality tests are established based on the results of Characterization, and have a criteria / acceptable range to judge if cells are maintaining an adequate quality. 7

8 Quality tests for Final Product *1, *2 Quality Control Viable cells number / rate Test for identification Test for cell purity Test for process-related impurities Test for unintended bioactive component derived from cells Test for sterility Test for mycoplasma Test for endotoxin Test for viruses (Specific / Nonspecific) Test for efficacy / potency / mechanical compatibility *1: Reference: Guideline for human (allogeneic) ips (like) cells-processed products to ensure their basic quality and safety *2: If transfected gene remains in final product, the product will need to be evaluated as the product for gene therapy also. 8

9 Establishment of preparation procedure Quality Control Preparation of manual / work sheet Preparation of training method of clinical staff Preparation of test for residual cryopreservative solution Preparation of test for safety Evaluation of procedure by validation / actual results in clinical trial 9

10 Key points GCTP encompasses the processes from the acceptance of cells to the release of final product in CPF. As for the justification of cells collection, transportation of cells and final product, and in-hospital preparation, companies of cell-based products shall have the responsibility, but they will not be encompassed to GCTP. Acceptance criteria shall be established to each raw material used to manufacturing for quality control under GCTP. As for the infectious agents such as viruses, it will be important to perform the test at raw materials and to prevent the contamination of manufacturing line by them. And, it will be advisable to confirm the characteristic of manufacturing process, which is the potential for a increase of virus by the combination of intended cells and manufacturing condition, if possible. Though reagents for research use often will be used for the manufacturing of cell-based products, as for the justification of use, the companies of cell-based products shall have the responsibility. In the case of cell-based products, it might be difficult to change the raw materials at the late stage of development. Regarding the raw materials, it will be advisable to assess if that each raw material is acceptable as the ones for clinical use or not, at the timing of early stage of development. 10

11 Key points (cont.) In the case of cell-based products, cells might ingest the components of raw materials. As for the process-related impurities that have safety concern, it will be important not only to estimate the theoretical dilution factor but also to establish the analytical method and actually measure the residual amount in product. In the case of cell-based products, their action mechanism might not be clarified and it might be difficult to establish the tests for efficacy. However, it will be important to establish the test condition that can extrapolate the action in vivo and to establish the criteria based on the actual results of multiple lot, at the timing of early stage of development. It will be useful for understanding the relationship between the quality test results and the efficacy, and for ensuring a certain quality of product. In the case of cell-based products, it will be important to establish the storage condition and transportation condition. If it was impossible to cryopreserve the product, the products will be produced by small-lot production and then distributed to each clinical site immediately because of difficulty of long-term storage. Additionally, as for the autologous cells-derived products, it will be necessary to take measures against the mix-up during transportation. Therefore, the companies of cell-based products can not use the present transportation using distributors, and will need to create the unique distribution system for products by themselves at the present time. 11