PMDA Perspective on Specifications for Biotechnological Products

Transcription

1 WCBP 2016, January 26 28, 2016, The Mayflower Hotel, Washington, DC, USA PMDA Perspective on Specifications for Biotechnological Products Yasuhiro Kishioka, Ph.D. Principal Reviewer Office of Cellular and Tissue based Products (PMDA) 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 this plenary session will explore through case studies the industry s desire to move to a scientifically sound, patient centered and riskbased approach to developing and defending specifications, with the goal of ensuring and maintaining the integrity of global supply. 2

3 Outline Introduction Frequently discussed points in the application in Japan Future perspectives 3

4 ICH Q6B Adopted in 1999 by ICH SC (published in Japan in 2001) Key principles described in ICH Q6B are still fundamental to set specification. Specifications are one part of a total control strategy designed to ensure product quality and consistency. Specifications are chosen to confirm the quality of the drug substance and drug product rather than to establish full characterization and should focus on those molecular and biological characteristics found to be useful in ensuring the safety and efficacy of the product. Acceptance criteria should be established and justified based on data obtained from lots used in preclinical and/or clinical studies, data from lots used for demonstration of manufacturing consistency and data from stability studies, and relevant development data....etc. 4

5 Biotech. Products approved in Japan 140 No. of approved biotechnological products mabs, Fusion proteins, 38 Cytokines, 25 Vaccines, 5 Hormones, 27 Coagulation factors, Albumin, 11 Enzymes, 15 5

6 Frequently Discussed Points Identity test System suitability for liquid chromatography Potency assay Regional testing 6

7 What is PMDA s recommendation on setting identity tests for biotech. products? Q6B: The identity test(s) should be highly specific for the drug substance and should be based on unique aspects of its molecular structure and/or other specific properties. BioPharm International APRIL 2003: Using Peptide Maps as Identity and Purity Tests for Lot Release Testing of Recombinant Therapeutic Proteins...a peptide map may not be needed as a lot release test as another or a combination of other analytical tests can suffice to appropriately establish product identity or purity. PMDA strongly recommends applicants should first consider a peptide map for the identity test for the drug substance of biotech. products, as it s highly productspecific in its own ability and suitable for confirming the stability of the primary structure of proteins in detail. 7

8 What considerations should applicants make concerning the system suitability for liquid chromatography? Japanese Pharmacopoeia (JP): (General Tests 2.01) System suitability... is used to ensure that the performance of the chromatographic systems used is as suitable for the analysis of the drug as was at the time when the verification of the test method was performed. System suitability testing should be carried out at every series of drug analysis. The test procedures and acceptance criteria of system suitability testing must be prescribed in the test method of drugs. In system suitability testing of the chromatographic systems, the evaluation of System performance and System repeatability is usually required. For quantitative purity tests, the evaluation of Test for required detectability may also be required. PMDA recommends applicants should follow the key principles described in JP. If applicants think of alternative ways, we encourage early communication and discussion. 03/09/8c28a611-40f4-45d2-81e1-f1fb5582b749/fig6web.jpg 8

9 Examples of system suitability (1) Epoetin Alfa (Genetical Recombination) (JP16th Editon Suppl. I) Purity (1) Oligomers Perform the test with a volume of Epoetin Alfa (Genetical Recombination), equivalent to 50 mg of protein, as directed under Liquid Chromatography <2.01> according to the following conditions. Determine each peak area by the automatic integration method, and calculate their amounts by the area percentage method: the total amount of the peaks other than epoetin alfa is not more than 2%. JP 16 th Edition (in English) sb std/standards development/jp/0005.html 9

10 Examples of system suitability (2) Test for required detectability the range of expected response to the injection of To 1 volume of Epoetin a certain Alfa volume (Genetical of target Recombination) impurity solution (EA) at the add 49 volumes of the mobile phase, and concentration use this solution of its specification as the solution limit for system suitability test. Confirm that the peak area of EA obtained with a volume, equivalent to 1 mg of protein, of the solution for system suitability test is equivalent to 1.5 to 2.5% of that obtained with the same volume of EA. the resolution and the order of elution (when appropriate) System performance Dissolve 40 mg of bovine serum albumin number of for theoretical gel filtration plates molecular and symmetry mass factor marker and 20 mg of chymotrypsinogen for gel filtration molecular mass marker in 100 ml of the mobile phase. When the procedure is run with 50 ml of this solution under the above operating conditions, bovine serum The allowable albumin and limit chymotrypsinogen is normally defined are eluted in this order with the resolution between as the relative these peaks standard being deviation not less (RSD) than 4. of the response of the test ingredient in System repeatability replicate injections. When the test is repeated 6 times with a volume of EA, equivalent to 50 mg of protein, under the above operating conditions, the relative standard deviation of the area of the principal peak of EA is not more than 2.0%. 10

11 What should applicants consider when setting potency assays for mabs (and Fc fusion proteins)? Potency assays should reflect the clinical mechanism of action in indications for use. PMDA generally requests bioassays (e.g. cell based assays) be used as potency assay as they ensure the biological activity of the product regardless of unexpected changes. If applicants (should) propose binding assays as potency assays, many factors should be considered, including: Relationships between the results of bioassays and the results of binding assay/ other physicochemical assays (lot release, stability) Involvement of effector functions Extensive characterization and manufacturing experience dia/images/article/thermo_lc Edgeplate jpg 11

12 Do the final release tests of biotech./biological products have to be performed in Japan? In principle, all final release tests of biotech./biological products must be performed in Japan. If the results of release tests are certified in MOU countries (Germany, Sweden, Switzerland, Australia), only appearance and identity test are required to be performed in Japan. PMDA recommends applicants should plan a technology transfer of test methods (specifically, potency assays) from the early stage of development. content/uploads/2009/08/tech transfer.jpg 12

13 Future perspectives Product Lifecycle Management? Standard program (QbD approach) Standard program (Traditional approach) Knowledge Post Approval Residual Risk Control Strategy Approval Approval Product Lifecycle 13

14 Thank you for your attention! Yasuhiro Kishioka, PhD. Office of Cellular and Tissue based Products kishioka Acknowledgements Colleagues in the Office of Cellular and Tissue based Products 14