Comparability of Biotechnology Derived Protein Products: Lessons from the U.S Experience

Transcription

1 Comparability of Biotechnology Derived Protein Products: Lessons from the U.S Experience WCBP 2010, 14th Symposium on the Interface of Regulatory and Analytical Sciences for Biotechnology Health Products January 26, 2010, Washington, DC USA Barry Cherney, Ph.D., Deputy Director DTP/OBP/CDER/ FDA 1

2 Overview Background Lessons Learned Recent Trends in Comparability Evaluations 2

3 Defining Comparability A determination that a product is Comparable indicates that products are highly similar before and after a manufacturing change and that no adverse impact on the quality, safety or efficacy of the drug product occurred Does not mean pre- and post-change products are physico-chemically or biologically identical Existing knowledge is sufficiently predictive to ensure any differences in quality attributes have no adverse impact on safety or efficacy 3

4 General Observations The approaches to comparability have been very successful since formal implementation of this policy with the 1996 FDA Guidance document on comparability and ICH Guidance Q5E in 2005 Most post-marketing manufacturing changes are approved based on quality criteria alone without increases in post marketing adverse events Sometimes evaluation of bioavailability (PK/ bio distribution) is performed (animals or humans) PD studies (animals or humans) Rarely clinical S or E (but clinical info is becoming more common particularly in association with the transition to serum free processes 4

5 Lessons Learned Lessons derived primarily from manufacturing changes that lead to unexpected differences in product attributes ( bad outcomes ) These cases provide important information regarding our assumptions and can lead to better understanding of critical considerations when evaluating product comparability 5

6 1. Specifications Don t Define Comparability The product is comparable because it meets specifications is almost never sufficient for significant changes in manufacturing a. Relevant tests may not be in specifications Specifications confirm product quality based on a validated process but do not fully define Q so you may need additional product characterization b. Results within limits but outside historical data may suggest important differences that warrant additional study Q5E 6

7 60 Hypothetical Example Outside Historical Experience Phase 3 lots Potency units/mg P Marketed Manufacturing Change Lot number 7

8 Real Life Example Polyethylene gylcolated (PEG) protein PEG process was changed after phase 3 but prior to licensure FDA requested a PK study which showed PK changed significantly > 2 fold Pre-change lot chosen as the comparator, was used in an early clinical study and was out of trend in the distribution of Peg at 1 site (12%, versus 15-17% in pivotal studies) but was within spec (11%). Total PEG content seemed similar Successful PK study was performed with a lot that was better representative of pivotal clinical trial material and specs were revised 8

9 Real Life Example # 2 Fermentation process was changed post-approval to increase yield A critical attribute potentially impacting bioavailability was out of trend (30% less then expected) Related biological activities were altered consistent with expectations Product met spec and lower limit was represented in the clinical experience but product from that lot was administered at twice the dose recommended in the PI Clinical efficacy data were requested to support change submitted data did not support comparability 9

10 2. Biodistribution/ PD Measures are Often More Informative then PK Monitoring the amount of product in serum over time does not provide definitive evidence that the product is available at the site of action Some PK studies may not be sufficient to support comparability because multiple clearance mechanisms are involved. E.g.,. 10

11 Enzyme Replacement Therapies (ERTs) encounter competing pathways non-productive Therapeutic pathway non-productive Mannose R macrophage ASGR asialoglyoprotein R Liver Low receptor densities Target tissue Binding, uptake by cimpr 11

12 Other Lessons Learned Protein products can be exquisitely sensitive to minor impurities and seemingly minor process changes (trace metals - multiple examples in all phases of production, a change in the deionizer) Physicochemical/biological characterizations are not a reliable predictor of immunological properties of a product Undetected differences in product attributes may have a potential impact on clinical parameters (sample heterogeneity, reliance on averages may be misleading) If you don t know what to look for you can miss it When fixing a quality issue, implement the least significant change possible (don t fix leaching of heavy metals by a formulation change) A different formulation is automatically different so the risk to product quality may be higher and could require higher categories of testing 12

13 Other Lessons Learned Concerning stage of manufacture Upstream process changes (e.g., new MCB/fermentation components) have a greater risk to product quality and require very robust comparability studies Major changes (cell line, fermentation) are easier to implement pre phase 3 since critical clinical studies have not yet been performed Don t make major process changes between the pivotal clinical studies and a marketing application end of phase 2 is perhaps the best time Site or scale changes at licensure have been mostly successful when other process changes are not included in the change Adverse Event reporting is not a sensitive tool for assessment of clinical comparability Product attributes may act synergistically to impact clinical performance Mining clinical data can provide useful information to evaluate differences in product attributes 13

14 Recent Trends in Comparability Evaluations 14

15 1. Increased Understanding of Attributes and their Relationship to Clinical Performance Improvement in analytics and increased knowledge of how quality attributes may contribute to S & E has led to less focus on similarity of non critical attributes and increased focus those that may be critical. E.g., Subvisible particulates between 0.1 and 10 µm are not typically monitored but may impact immunogenicity The ability to characterize and quantitate complex N linked Glycans has led to a better understanding of their criticality 15

16 Complex N-linked Glycans Tetraantennary species appear to contribute more to overall bioavailability (increased half life) of a protein product then tri- antennary structures. > > Terminal Sialic Acid (SA) prevents binding to asialoglycoprotein R, enhancing availability at other sites Small changes in tetraantennary content and the presence or absence of terminal SA can have a significant impact on bioavailability and potentially on the safety or efficacy of a product, raising concerns when differences are observed 16

17 Complex N-linked Glycans N-acetyl-lactosamine repeats Repeating units of N-acetyl glucosamine and galactose Elongation of the oligosaccharide leading to greater hydrodynamic radius Associated with increase in in vivo potency presumably via increased bioavailability, raising concerns when differences are observed 17

18 2. Multidimensional Space Can Apply to Product Attributes Combinations of Product Characteristics may have Additive Effects on Clinical Performance, e.g., Small increase in lactosamine repeats associated with a small increase in the amount of tetra antennary structure may cause a significant increase in bioavailability Distribution of 3 Tetraantennary structures on the same molecule may have greater impact then when evenly distributed across 3 molecules Slight increase in specific activity coupled with slight increased in bioavailability may result in significant increase in potency 18

19 Attribute Space % Tetra Antennary Acceptable Range Bioactivity % Lactosamine Repeats Conclusion: Evaluate the significance of differences in quality attributes with potential interactions in mind 19

20 3. Better Utilization of Information Obtained from Clinical Studies for Establishing Comparability 60 Clinical lots Mining Clinical Data Potency units/ml How was this lot used? Manufacturing Change Lot number 20

21 4. Increased Scrutiny of Lots Selected for Nonclinical or Clinical Studies Lots chosen for NC/C studies should be evaluated to ensure that they provide meaningful information on any observed differences in CQAs Are differences in critical quality attributes appropriately addressed in non- clinical/clinical comparability studies Picking post-change lots that are most similar to the pre-changed product may not be useful 21

22 60 50 Cherry Picking Lots for PK Study Upper limit % tetra antennary Manufacturing Change Lot number Lower limit 22

23 4. Use of Comparative Stress Studies For comprehensive quality determinations, the Agency has asked for stress studies comparing the rates of degradation for the pre and post-change product Typically require more then one stress condition (e.g., light, temperature, agitation) Incremental rate of degradation that allows a meaningful comparison 23

24 Hypothetical Examples C Potency units/ml C Pre-Change Product Post-Change Product Time (in days) 24

25 5. Global Harmonization Engagement with other regulatory authorities is increasing. For example: A pre-license comparability study resulted in 3 distinct regulatory decisions from 3 regions One region only approved the small scale process based on differences in the API One region only approved a large scale process based on differences in impurities One region approved both FDA discussed with each region, with the sponsor s permission, why the specific approach was taken. Frank discussions were held and we all understood the rationale for each decision. FDA was comfortable with its decision. 25

26 6. Side by Side Analysis (SBS) Recent trend to eliminate side by side analysis in comparability exercises has been noted Comparison to historical data only Difficult to determine if differences are due to assay variability or product variability ICH Q5E is silent on the need for SBS analysis but FDA s April 1996 Guidance on Comparability of biotech products recommends this approach April 1996 Document was not withdrawn and is still relevant! 26

27 Acknowledgements Amy Rosenberg Steve Kozlowski Fred Mills 27