Comparability to establish Biosimilarity

Transcription

1 Comparability to establish Biosimilarity CMC Strategy Forum Europe 2014, Sorrento, Italy Jan Visser, Head Global Analytical Characterization & Bioanalytics Sandoz Biopharmaceuticals, Hexal AG, Germany 2014 Sandoz. All rights reserved. All trademarks are the property of their respective owners.

2 Variability is inherent in biologics Batch-to-batch Non-identicality is a normal principle in biologics No batch of any biologic is identical to the other batches Variability is natural even in the human body and usually not problematic C. Schneider: Biosimilarity: A better definition of terms and concepts. 25th Annual DIA EuroMeeting, 04-06/03/2013, Amsterdam Manufacturing changes Manufacturing changes occur due to process improvements, scale up, etc Differences in attributes sometimes significantly larger than batch-to-batch variability G2F glycans [rel. area %] Pre-shift Post-shift Expiry date Basic variants [rel. area %] Pre-shift Post-shift Expiry date M. Schiestl et al. : Acceptable Changes in Quality Attributes of Glycosylated Biopharmaceuticals. Nature Biotechnology, 29: , CMC Strategy Forum Europe 2014, Sorrento, Italy

3 Characterization of commercial batches of MabThera /Rituxan M. Schiestl et al. : Acceptable Changes in Quality Attributes of Glycosylated Biopharmaceuticals. Nature Biotechnology, 29: , supplemented with new data! Significant structural change leading to a functional change and probably related to a change in the manufacturing process Different product qualities interchangeably on the market No change in product label indicating comparable safety and efficacy extrapolated to all indications 3 CMC Strategy Forum Europe 2014, Sorrento, Italy

4 Manufacturing changes are made frequently C. Schneider, Ann Rheum Dis March 2013 Vol 72 No 3 Changes include e.g. Change in the supplier of a cell culture media New purification methods New manufacturing sites Changes occur at various points in the product life cycle However, the impact of manufacturing changes are well understood by means of comparability exercises (ICHQ5E) and tightly controlled by regulators 4 CMC Strategy Forum Europe 2014, Sorrento, Italy

5 Comparability exercises to assess Manufacturing changes ICHQ5E: Comparability of biotechnological/biological products subject to changes in their manufacturing process The goal of the comparability exercise is to ensure quality, safety and efficacy of drug product produced by a changed manufacturing process A determination of comparability can be based on a combination of analytical testing, and, in some cases, nonclinical and clinical data. The demonstration of comparability does not necessarily mean that the quality attributes of the pre-change and post-change product are identical, but that they are highly similar The concept behind comparability generally functions with many postmarketing manufacturing changes being approved based on analytical testing alone 5 CMC Strategy Forum Europe 2014, Sorrento, Italy

6 Revised comparability guideline as basis for biosimilar guideline Martina Weise, DIA Euro Meeting, March CMC Strategy Forum Europe 2014, Sorrento, Italy

7 Biosimilars and comparability EMA Guideline on Similar Biological Medicinal Products (Draft 2013) and Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (Draft 2012) A biosimilar demonstrates similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise. A stepwise approach is normally recommended throughout the development programme, starting with a comprehensive physicochemical and biological characterisation. The extent and nature of the non-clinical in vivo studies and clinical studies to be performed depend on the level of evidence obtained in the previous step(s).. It is not expected that all quality attributes will be identical and minor differences may be acceptable, if appropriately justified. The scientific principles of such a biosimilar comparability exercise are based on those applied for evaluation of the impact of changes in the manufacturing process of a biological medicinal product (as outlined in ICH Q5E). 7 CMC Strategy Forum Europe 2014, Sorrento, Italy

8 Continuum of comparability allows for appropriate control of variability in biologics Clinical studies Biological/Preclinical data Physicochemical characterization Extent of comparability exercise Release analytics Comparable Identical However, an originator biologic after an approved manufacturing change is as safe and efficacious as the pre-change product! However, an approved biosimilar is as safe and efficacious as its reference product! 8 CMC Strategy Forum Europe 2014, Sorrento, Italy

9 Analytical comparability The evaluation of biosimilarity is based on comparability gained at all levels Clinical PK/PD Preclinical Biological Physicochemical characterization and biological characterization Physicochemical characterization Lower Higher Sensitivity to detect differences A comprehensive analytical comparability exercise forms the foundation for establishing biosimilarity as very sensitive to differences Once a proposed biosimilar is shown to be highly similar at the analytical level, this demonstration should allow for tailored pre-clinical and clinical studies 9 CMC Strategy Forum Europe 2014, Sorrento, Italy

10 Sensitivity of analytics has greatly improved during the last decades Sensitivity increase in mass spectrometry Year Detection limit of peptide (pmol) Adapted from: Mire-Sluis, T.: The Regulatory Implications of the ever increasing power of Mass Spectrometry and its role in the Analysis of Biotechnology Products Where do we draw the line? CASSS MassSpec CMC Strategy Forum Europe 2014, Sorrento, Italy

11 State-of-the-art analytics allow for the thorough characterization of biosimilars and its reference Attributes e.g.: Primary structure Mass Disulfide bridging Free cysteines Higher order structure N- and C-terminal heterogeneity Glycosylation Glycation Fragmentation Oxidation Deamidation Aggregation Particles Target-binding Fc effector functions Primary Structure Biological functions Glycosylation Combination of attributes MVDA, mathematical algorithms Higher Order Structure Charge Variants Size variants Methods e.g.: MS Peptide mapping Ellman s CGE SDS-PAGE CD, FT-IR H-D exchange NMR, X-ray HPLC HPAEC IEF 2AB NP-HPLC SE-HPLC FFF AUC DLS MALLS Bioassays SPR 11 CMC Strategy Forum Europe 2014, Sorrento, Italy

12 Biosimilars must be systematically engineered to match the reference product (QbD) 2. Target directed development Biological variability 3. Confirmation of biosimilarity Recombinant cell line development Process development Bioprocess development Analytics Purification process development Drug product development Target range Reference product variability 1. Target definition 12 CMC Strategy Forum Europe 2014, Sorrento, Italy

13 QbD elements directing biosimilar development - Quality Target Product Profile QTPP contains the elements/considerations as described in ICH Q8 (R2) Intended use in clinical setting, route of administration, dosage form, delivery systems; Dosage strength(s) Container closure system Drug product quality criteria (e.g., sterility, purity, stability and drug release) For biosimilar based on reference product characteristics Additionally specific for biosimilars Ranges of quality attributes of marketed reference product Quality attribute ranges are based on analytical data of many individual reference product batches of different shelf life age 13 CMC Strategy Forum Europe 2014, Sorrento, Italy

14 Quality attribute ranges - Target definition At project start: Several originator batches are being purchased from main geographic regions Basic analytical methods are being developed The amino acid sequence of the originator is being determined Preliminary originator ranges (target specifications or goal posts) are set During the project: Continue to purchase originator batches and analyze upon purchase and end-of-shelf life Update target specifications & QTPP 14 CMC Strategy Forum Europe 2014, Sorrento, Italy

15 % N-terminal Variant % N-terminal Variant Target definition: global biosimilar development Showing that reference products (RP) from main geographic areas are analytically indistinguishable aids global biosimilar development US and EU reference product indistinguishable for all quality attributes with the apparent exception of N-terminal variants Days of Remaining Shelf-Life (when analyzed) Days of Remaining Shelf-Life (when analyzed) EU intact molecule US intact molecule US Leu N-terminal clipped variant 1 EU Leu N-terminal clipped variant 1 EU Leu+Pro N-terminal clipped variant 2 US Leu+Pro N-terminal clipped variant 2 N-terminal variants were found to significantly change during shelf life To have good guidance during early development purchase old and new RP batches and perform a dev. stability study with RP For 15 CMC regulatory Strategy Forum Europe filing 2014, analyze Sorrento, Italy RP batches upon purchase and at end of shelf life

16 Impact Uncertainty QbD elements directing biosimilar development - Criticality assessment of Quality Attributes API-related quality attributes e.g. deamidation, oxidation, afucoslylation,... High = 20 High = 7 Efficacy / Potency Criticality Criticality Criticality Score Very High High Moderate CQA by definition e.g. strength, composition, appearance, potency,... PK/PD Immunogenicity Safety Low Very Low 2 30 Low = 2 Low = 1 Process- and excipientrelated quality attributes e.g. HCP, antifoam, endotoxins, CMC Strategy Forum Europe 2014, Sorrento, Italy Criticality Calculation Criticality Score (2-140) Quantitative measure for an attribute s impact on safety and efficacy. Using best possible surrogates for clinical safety and efficacy Impact (2-20) Known or potential consequences on safety and efficacy, considering, biological activity, PK/PD, immunogenicity, safety Uncertainty (1-7) Relevance of information e.g. literature, prior knowledge, in vitro, preclinical clinical or combination of information

17 How comparable do biosimilars need to be? Biosimilar needs to be as safe and efficacious as the reference product The more critical a quality attribute is, the more comparable it should be knowing your protein is essential! The more comparable a biosimilar is to the reference analytically, the smaller the residual uncertainty, the more tailored the non-clinical and clinical program Criticality Criticality Score Higher Very High High Moderate Low Very Low 2 30 QA criticality Stringency comparability range 17 CMC Strategy Forum Europe 2014, Sorrento, Italy Lower

18 How comparable do biosimilar mabs need to be? M. Shapiro, ACR annual conference 2012 Know your protein and analyse it using state-ofthe-art analytical methods! 18 CMC Strategy Forum Europe 2014, Sorrento, Italy

19 Analytical comparability exercises during biosimilar development Year Target specification: Originator characterization Analytical tool box TPoS Confirm comparability Confirm comparability Final comparability Cell line dev. Full process dev. Formulation Dev. Process Opt. Process Charact. Val Clin. man Clin. man Val Comm man Exploratory PC studies GLP PC PK/PD study Conf. clin. study Develop highly similar product Confirm biosimilarity 19 CMC Strategy Forum Europe 2014, Sorrento, Italy

20 Final comparability exercise Use of a wide range of sensitive and orthogonal analytical methods Head-to-Head (H2H) analysis with selected originator batches Comparison of physicochemical and biological characterization results with H2H originator batches and historical target specification Identification of variants in both biosimilar and originator Justification of differences in QAs Comparison of stability data: intended conditions (=> stability profile) accelerated, stress conditions (=> forced degradation profile) 20 CMC Strategy Forum Europe 2014, Sorrento, Italy

21 CQA control strategy for biosimilars Quality Attribute Criticality Quality Attribute Criticality considering impact on safety and efficacy Capability of the process to control the quality attribute Process Control Design Control Elements Process Control Elements Process Parameter Controls Process Qualification Input Material Control Elements Raw material testing Testing for the quality attribute Testing Strategy Testing Control Elements Stability testing Characterization In-process testing Release testing CQA Control Strategy 21 CMC Strategy Forum Europe 2014, Sorrento, Italy

22 Setting specifications for biosimilars ICH Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities as conditions of approval. Specifications are chosen to confirm the quality of the drug substance and drug product...and should focus on those molecular and biological characteristics found to be useful in ensuring the safety and efficacy of the product. Specification acceptance criteria (LL & UL) for biosimilars are initially defined by a combination of the originator range and process capability and later by process capability alone! 22 CMC Strategy Forum Europe 2014, Sorrento, Italy

23 Divergence a risk for biosimilars? After approval in EU a biosimilar is managed as an independent product Divergence = Different patterns of product drift and evolution (=shift) contributing, over time, to clinically meaningful differences Ramanan & Grampp BioDrugs Feb 2014 Does divergence between a biosimilar and its reference product pose a bigger risk than divergence between pre- and post-shift reference product or between interchangeably used originator products? Divergence between post- and pre-change product shown in PRCA Eprex case resulting in increased regulatory scrutiny regarding primary packaging and leachates However, to date not aware of data showing that divergence is an issue for biosimilars or interchangeably used originator products Quality systems of biologics manufacturers should ensure the detection and management of drift (unintended changes) via their control strategy, while evolution (intended changes) is well managed according to ICHQ5E guidance 23 CMC Strategy Forum Europe 2014, Sorrento, Italy

24 Conclusions The scientific principles behind the comparability exercise supporting manufacturing changes and assessment of biosimilarity are the same! The analytical comparability between the proposed biosimilar and reference product forms the foundation for establishing biosimilarity as very sensitive to differences! The QTPP, which includes ranges of QA s of the reference product, and the QA criticality assessment are key elements in directing biosimilar development! The closer the proposed biosimilar and its reference product are analytically, the less residual uncertainty and the more tailored the (non)clinical program should be! A good quality system should prevent divergence between pre- and post-change biologics, biosimilars and reference products, and interchangeably used biologics 24 CMC Strategy Forum Europe 2014, Sorrento, Italy