European Guideline for Virus Safety Evaluation of Clinical Trial Material

Transcription

1 Plasma Product Biotechnology Meeting, May 8 12, 2007 European Guideline for Virus Safety Evaluation of Clinical Trial Material Dr. Hannelore Willkommen Vice President Regulatory Affairs, NewLab Bioquality AG, Germany, and Regulatory Affairs & Biological Safety Consulting, Erzhausen, Germany 1

2 Current Regulations (1) Regulation for Investigational Medicinal Products (IMP) in Europe: Directive 2001/20/EC of the European Parliament and of the Council of Europe on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. (coming into operation: 1 May 2004) Sponsor may not start a clinical trial until the ethic commission has issued favorable opinion and the competent authority has not informed of any grounds of non-acceptance EMEA vs. Competent Authorities of the Member States (MS): In accordance with Regulation (EC) No 726/2004 EMEA is responsible for the MA procedure. Ethic commissions and competent authorities of the 27 MS are responsible for clinical trials and the acceptance of the IMPD even if the centralized procedure (EMEA) is used later for marketing authorization. In the case of cell derived medicinal products there is a need for clarification and harmonization of the requirements regarding the virus safety assessment of clinical trial material prior to and during clinical development. 2

3 Current Regulations for Cell Derived Products (2) Regulations for Virus Safety Assessment for MA/BLA: ICH Q5A or CPMP/BWP/295/95: Note for guidance on quality of biotechnology products: Viral safety evaluation of biotechnology products derived from cell lines of human or animal origin (coming into operation: October 1997). Product specific guidance: MAb PTC (FDA) Points to consider in the manufacture and testing of monocloncal antibody products for human use (coming into operation: February 1997). 3AB4a Guideline Production and quality of monoclonal antibodies (coming into operation July 1995). Concept paper on the need to revise the guideline on production and quality control of monoclonal antibodies (CHMP/BWP/64/04) Ph.Eur. Monograph : Monoclonal antibodies for human use (07/2005:2031) 3

4 Virus safety principles Qualification of source materials and reagents Qualification of source materials: cell line Safety profile of reagents (virus, mycoplasma, TSE) Testing at appropriate stages of the manufacturing process, if appropriate (e.g. cell harvest) Characterization of virus removal/inactivation capacity of the manufacturing process Virus validation/clearance studies Testing of intermediates, if appropriate Products used in clinical trials should be as safe as products on the market! (Volume 4, GMP, Annex 13) 4

5 CHMP: 28 June, 2006 End of consultation: 31 December,

6 Cell Line Qualification: Testing for Viruses (1) MCB: Testing should be performed as described in Q5A WCB: When established should be tested as described in Q5A Cells at the limit of in vitro cell age (EOP): Should be derived from the scale used for the clinical batch and should be tested according to Q5A, unless otherwise justified. PPC: It may be useful to examine cells taken beyond their in vitro cell age in order to allow expansion of the cells during development. Unprocessed Bulk: Q5A requires testing of at least three batches for MAA. The source and viral safety of raw materials should be taken into account when devising the unprocessed bulk testing. 6

7 Characterization of Cell Culture: (ICH Q5A) Tests for retrovirus or other endogenous viruses: MCB WCB Cells at the limit (EOP) Infectivity Electron microscopy Reverse transcriptase (if negative by retrovirus infectivity assay) Other virus specific tests As appropriate - As appropriate Tests for adventitious viruses In-vitro assays + -* + In-vivo assays (adult and suckling mice, embryonated eggs, others if appropriate) + -* + Antibody production test (MAP; RAP; HAP) Other virus specific tests + - -

8 Characterization of Cell Culture: (ICH Q5A)? Tests for retrovirus or other endogenous viruses: MCB WCB Cells at the limit (EOP) Infectivity Electron microscopy Reverse transcriptase (if negative by retrovirus infectivity assay) Other virus specific tests As appropriate - As appropriate Tests for adventitious viruses In-vitro assays + -* + In-vivo assays (adult and suckling mice, embryonated eggs, others if appropriate) + -* + Antibody production test (MAP; RAP; HAP) Other virus specific tests + - -

9 Mammalian Cell Cultures Examples used for Production of Biotech Products Continuous cell lines: CHO-K derivatives (Chinese hamster ovary cells) BHK-21 derivatives (Baby hamster kidney cells) Myeloma, Hybridoma cells mouse, human-mouse, human (EBV) NS0, Sp2/0 Cells produce retrovirus and/or retrovirus like particles, type A and C; bulk harvest may contain up to 10 9 RVL particles / ml. 9

10 Bioproduct Development Path Candidate Selection Pre-clin. Develop. Phase 1 Phase 2 Phase 3 Sub. Prep Rev. Appr. Global Launches Development Time [month] m m m m 3-9 m 9 15 m Cell line MuLV / MVM Cell line? PRV / Reo Typical Development: 6-10 years virus NL virus virus 6-8 years 3-4 years Schmidli, Brett, BioProcess International, San Francisco, Nov

11 Bioproduct Development Path Candidate Selection Pre-clin. Develop. Phase 1 Phase 2 Phase 3 Sub. Prep Rev. Appr. Global Launches Development Time [month] m m m m 3-9 m 9 15 m Cell line MuLV / MVM Cell line? PRV / Reo Typical Development: 6-10 years virus NL virus virus 6-8 years 3-4 years Schmidli, Brett, BioProcess International, San Francisco, Nov

12 Validation of Virus Inactivation/Removal Two Objectives: Firstly, to characterize and evaluate process steps that can be considered to be effective in activating/removing viruses. Secondly, to estimate quantitatively the overall reduction of any virus/viral particle, e.g. endogenous retroviral particles, that are known to be present. Case by case approach Even when no raw materials of biological origin have been used and the cell line is fully tested, viral validation studies will be required as extensive testing cannot guarantee the viral safety due to limitations in viral detection assays. Full viral validation according to ICH Q5A should be initiated as soon as the final production and purification process has been established and should be completed prior to use of the IMP in phase III studies, unless otherwise justified.? 12

13 Validation of Materials for Phase I/II Studies Prior to Phase I Any virus or virus particles known to be present in the bulk harvest has been effectively inactivated or removed during downstream processing; Case B cells retrovirus should be used for validation = full clearance should be demonstrated. Regardless of the extent of direct virus testing of the production cell line, there remains a potential for unknown contamination of the cells with a virus originally present in the cells or arising from material of biological origin. Potential contaminants may be enveloped and non-enveloped viruses. For both Case A and B cells, the process should be evaluated for the inactivation/removal of an enveloped virus (a retrovirus for Case A) and a small non-enveloped virus, unless otherwise justified. In performing the validation study, the limits (worst case) process parameters should be used. 13

14 Cell Derived Products: MAb Typical MAb Process: Protein A Chromatography (alternative capture step) Moderate/variable virus removal Low ph (< 3.8) Inactivation of Retrovirus (Herpes virus) Chromatographic purification: - Anion Exchange Chromatography - Cation Exchange Chromatography - HIC Nanofiltration (~20 nm) High or low virus removal, virus specific Removal of a wide range of viruses including parvovirus RVLP: 10 9 / ml; 1 L / dose Potential RVLP/highest dose: Virus clearance of = 3 log 10 safety factor Virus clearance of = 6 log 10 safety factor 14

15 mab Platform Purification: MuLV Removal Yuling Li & Olga Galperina, HGS; 2005 Viral Safety Workshop, , Langen, Germany Product Capture Low ph Cation Anion HIC mab > 4.44 NA mab > 5.94 NA mab > 4.65 NA > 6.03 > 5.27 mab > 4.01 NA mab > 3.79 NA mab > NA 1.39 Average 4.23 >

16 Reduced Program for Virus Validation The following circumstances might be used to support a reduced program: Extent and use/non-use human/animal derived raw materials, Published data Prior experience of manufacturer with specific downstream processing; validation data (in-house data) from one product might be applicable to a new product for an equivalent process step The step should have been carefully evaluated (including parameters that affect virus reduction) If data for more than one product is available for the specific step, virus reduction should be equally effective in each case, A rational should be provided why in-house data can be applied, e.g. referring to viral clearance data would be possible if the product has similar biochemical properties and is purified by identical methods. A critical analysis should be provided and should provide complete confidence in the conclusion that in both cases the established manufacturing step is similar in its capacity to inactivate/remove potential virus contaminants. one confirmatory experiment might be needed 16

17 Format of the IMPD CTD: Attachment A 2; Adventitious Agents Safety Evaluation. Self-standing document, Complete data package (including raw data and reports). When the applicant makes use of in-house data (e.g. data from other products), an adequate package of data should be provided to allow the assessment of the generic data and provide confidence that these data are valid or supportive for the specific product under development. Particular attention should be paid to raw material of biological origin for which a complete and detailed documentation should be provided. 17

18 Summary: Use of In-House Data: The following general factors should be considered in justifying the omission of any of the virus detection assays listed in Q5A and a reduction of product specific validation studies: the nature of the production cell line, the history of the cell line and its use, the extent of characterization of the cell line use or non-use of raw material of human or animal origin during manufacture potential exposure to adventitious contamination, the stage of development of the product, experience of the company with the cell line involved, experience of the company with specific inactivation/removal procedures to be used, published data. Such in-house experience may also be applicable to the data requirements of an MAA; however, the guideline does not address this point. 18

19 Summary: Where we are 1. Medicinal products intended for human use must be safe independent of the stage of development; risk/benefit assessment is required. 2. The new guideline provides the opportunity to use in-house data for demonstrating the virus safety of investigational medicinal products. 3. If in-house data are used to demonstrate the capacity of the manufacturing process comparability of manufacturing procedures must be justified (operational and analytical data). 4. The current draft will be revised considering the comments from the industry. Some aspects which need clarification are: Testing of EOP cells according to Q5A Virus validation according to Q5A for phase III material; no clarity which data needs to be provided for phase III material vs. MAA Validation of analytical methods 19