CASSS CMC Strategy Forum Barcelona, Spain. EBE Satellite Session Comparability Concept Paper 21 st March 2011

Transcription

1 CASSS CMC Strategy Forum Barcelona, Spain EBE Satellite Session Comparability Concept Paper 21 st March 2011

2 Aim of concept paper Points to consider in planning and undertaking of comparability exercise of biotechnological products during product lifecycle Evaluation of process changes during different stages of development Sharing of Industry experiences and best practices in applying the principles for demonstrating comparability Well-characterized proteins/polypeptides 2

3 Aim of concept paper Not in scope: formulation changes, new routes of administration, vaccines, blood-based products, biosimilars, or design of clinical studies if required to demonstrate comparability

4 Terminology Comparability is not equal to identical The quality attributes pre- and post-change need not be identical, but need to demonstrate no impact on the quality, safety and efficacy

5 Regulatory guidelines Quality Non-clinical/clinical aspects Regulatory guidelines form the basis for the concept paper, but focus is on Industry experience and best practices (see Concept paper for list of guidelines) 115

6 Comparability - ICH Highly comparable? Some differences Are analytical procedures capable? Can they be justified? Yes Doubt Yes No Quality Clinical, Nonclinical Quality Clinical, Nonclinical 6

7 Comparability assessment Manufacturers often introduce changes into the manufacturing process For changes that may potentially impact the product quality (identity, purity, potency and stability) comparison of drug substance and/or drug product, pre- and post-change is undertaken Changes in expression system Changes in manufacturing process Raw materials Scale Facilities Changes listed not all inclusive

8 Considerations for comparability Nature of change in the manufacturing process (ie are downstream processes impacted by changes upstream) Suitability and capability of analytical methods Acceptance criteria to demonstrate comparability Potential impact to product quality, safety and efficacy

9 Considerations for comparability Stage of development/marketed product Complexity of the product Understanding the mechanism of action Clinical characteristics Regulatory guidelines and regulatory authority advice

10 Extent of comparability through product lifecycle Extent of comparability Process/product development Complexity of process/product Analytical development/capability Preclinical Clinical phase 1 clinical phase 2 Clinical phase 3 Approval/lifecycle management

11 Quality by design Comparability study design based on the knowledge of product and process Understanding criticality of process parameters and critical quality attributes Quality by design can be used to support the comparability study If a design space is not yet established, QbD principles can still be applied, where CQAs are defined as according to ICH Q8(R1), using risk assessments to evaluate the impact of the changes (Q9)

12 Design of comparability Design of comparability study based on knowledge of product and process Essential to transfer/document the knowledge gained during process validation lifecycle Adequate analytical tools are key to assessing comparability using predefined criteria

13 Analytical testing Assessment of new or unknown impurities Additional analytical and characterisation tests as well as routine testing Prospective acceptance criteria should be defined for comparability exercises from late phase development/marketed products Small trends in data beyond the normal variation for pre-change product should still be evaluated for impact on quality, safety and efficacy Comparison of several batches to see if there is any variation

14 Analytical testing Development of analytical methods during development Need to assess whether analytical methods are still sufficient to detect new impurities/increased levels of impurities

15 Example of methods used for comparability Analytical method Method performed for release Release method tested side-by side for comparability in the same analytical run General quality (e.g. ph, appearance, osmolality) - Content (e.g. protein concentration, HPLC) - Identity (e.g. ELISA, peptide map) - Purity (e.g. RP-HPLC, IE-HPLC, SEC-HPLC, SDSPAGE, csds, IEF, cief, CZE, CE-NGS etc.) Potency (e.g. inhibition of binding, cell toxicity, cell proliferation) Process and product related impurities (e.g. residual Protein A, host cell protein, residual DNA etc.) Bacterial endotoxin, bioburden -

16 Example of product characterisation methods for comparability assessment Analytical Characteristics and Techniques Characterisation methods Characterisation methods tested side-by-side for comparability Primary structure (e.g. N-linked oligosaccharide profiling, peptide mapping) Secondary/tertiary structure (e.g. circular dichroism, FTIR) Posttranslational modifications (e.g. free thiol, glycosylation profile, sialic acid content, fucose content, oxidation, deamidation) Orthogonal purity (e.g. LC-MS, MS-MS, SPR (Biacore), cellular electrophoresis, capillary isoelectric focussing, AUC) Biological activity and/or binding (ELISA)

17 Host cell proteins Host cell proteins (HCP) are linked to the expression system and assess capability of purification steps for removal of HCPs Reevaluation of HCP method/reagents for changes in the expression system or cell culturing Build a knowledge base on the HCP method during development (quantification and characterisation of HCPs (eg SDS-PAGE/Western blot Retained samples during development for later comparison

18 Immunogenicity Immunogenicity can be affected by several factors: Structure Post-translational modifications Pegylated, oxidised, dimeric forms Product- and process-related impurities Aggregates DNA, HCP, protein A, etc Assess need for non-clinical and clinical immunogenicity studies based on risk-assessments, knowledge of product with regard to immunogenicity

19 Stability Stability studies on pre- and post-change product in real-time stability study Comparison of stability profiles for pre- and post-change product Accelerated stability studies to compare degradation profiles, and consider stress studies and forced degradation studies For changes in the drug substance it is recommended to place final drug product batches on stability (any bracketing approaches to be justified)

20 Example #1 Case 3: Phase 3/MAA Changes introduced for a complex glycoprotein throughout clinical development and also postphase 3 Clone 1 toxicology studies Clone 2 - Clinical studies Clone 2 + change in chromatography step and scale commercial product

21 Comparability study #1 Physicochemical data: Not possible to compare clone 1 vs clone 2 due as analytical methods not fully developed during toxicological studies Retained samples deteriorated so a comparison using the analytical methods not possible The Agency required that toxicological studies was repeated for Clone 2 to show comparability Important to demonstrate that a comparable product has been used throughout clinical development

22 Example # 2 Marketed product Case 4: Antibody manufactured by cell culturing + purification steps New manufacturing site for drug substance Scale up (2x) for both upstream and downstream processes Process changes (upstream and downstream)

23 Comparability study #2 EPC testing Virus testing (early/mid/late bioreactor) Viral clearance studies Comparability of DS (early/mid/late bioreactor) Removal of impurities (media components, additives, HCPs) Comparison of in-process controls Comparison of DS lots (pre-change vs post-change)

24 Results Example #2 All results were comparable (incl. viral clearance and impurity removal studies), release testing of DS lots and comparative characterisation Differences in the C-terminal lysine content observed during later stages of bioreactor process compared to pre-change process The C-terminal lysine residue was found not to affect the pharmokokinetics or functionality in vivo, and therefore was not considered to be critical Commitment to demonstrate no drift in the oligosaccharide profile for post-change batches

25 Conclusion Comparability studies should be undertaken throughout clinical development to link the product used in pivotal non-clinical and clinical studies to the commercial product Recommend seeking Agency advice on comparability strategies/protocols

26 Conclusion The following should be considered when designing comparability studies: Stage of development/product lifecycle, complexity of the product/process (early clinical phases vs MAA) Knowledge of process and product Impact on quality safety, efficacy and immunogenicity Consider using risk-based approaches If comparability is demonstrated, Agency may still request a bioequivalence study

27 Acknowledgements Claudia Meyer (Chair), Human Genome Sciences Caroline Doodkorte, Centocor Markus Goess, Novartis Pharma AG Ronald Imhoff, Centocor Niels Kristian Klausen, Novo Nordisk A/S Alenka Paris, Sandoz Karin Sewerin, MedImmune Sirkka Thomé, Swedish Orphan International Valerie Wolfe, Pfizer Sandra Auguste-Bowler, Genmab Abbot Laboratories, LFB Biotechnologies, Amgen, Merck/MSD, Sanofi-Aventis and Schering Plough