Barry Cherney, Ph.D., Deputy Director DTP/OBP/CDER/ FDA Perspectives on Comparability of Biotechnology Derived Protein Products

Disclaimer The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to Drug Information Association, Inc. (“DIA”), its directors, officers, employees, volunteers, members, chapters, councils, Special Interest Area Communities or affiliates, or any organization with which the presenter is employed or affiliated. These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved. Drug Information Association, DIA and DIA logo are registered trademarks or trademarks of Drug Information Association Inc. All other trademarks are the property of their respective owners.

Overview High Level Concepts General Observations & Misconceptions Recent Trends in Comparability Determinations Lessons Learned

Concepts

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 identical - However, knowledge is sufficiently predictive to ensure any differences in quality attributes have no adverse impact on safety or efficacy

Categories of Testing Quality Studies (partial or comprehensive) –Physicochemical Tests –Functional Assays (Bioassays) Animal Studies –PK/PD/Biodistribution –Toxicity Clinical Studies –PK/PD –S & E Higher Lower Sensitivity to Detect changes

Product Life Cycle & Comparability Pre-INDPhase 1Phase 2Phase 3Pre-ApprovalPost Approval Toxicology Studies Short term Long term Dose Ranging S Dose Ranging S & E Information Transfer Scale/Facility Change Process Changes Manufacturing Continuous Improvement Full data set Low

General Observations

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 – Sometimes evaluation of bioavailability is performed or animal PD studies – Rarely clinical S or E (but is becoming more common)

Misconceptions 1.“ The product is comparable because it meets specifications ” a.Relevant tests may not be in specifications ─ Are the specifications sufficient indicators of product quality – you may need additional product characterization b. “ Results within limits but outside historical data may suggest important differences that warrant additional study ”

Hypothetical Example Manufacturing Change Lot number Potency units/ml Clinical lots Marketed

Historical Limits versus Specs Polyethylene gylcolated (PEG) protein Supplier of PEG was changed prior to licensure Requested PK study showed Pharmacokinetics changed significantly Lot chosen was out of trend in the distribution of Peg at site 1 (12% versus 15-17% historical range but was within spec 11%) Successful PK study was performed with a lot that was within historical limits

Misconceptions 2. Outcomes of Quality Evaluations When a product is determined not to be comparable by quality criteria…….. A. It’s a different, i.e., a new product or B.You need to perform non clinical and/or clinical testing to determine if the product is comparable Answer: A

Outcomes of Quality Evaluations Comparability is ultimately a clinical determination i.e., no impact on S & E According to Q5E Quality studies can tell you: 1. The products are comparable 2. There is insufficient info to make a determination 3. The pre and post-change products are not comparable i.e., they are not interchangeable

Trends in Comparability Studies

1.Greater Knowledge Knowledge in understanding what are the critical quality attributes changes the risk profile –Understanding the importance of tri and tetra antennary species in the interaction with the asialoglycoprotein receptor places more emphasis on similarity for these attributes and less on bi antennary species or total sialic acid content Better utilization of information obtained from clinical studies for establishing target ranges for comparability

Mining Clinical Data Manufacturing Change Lot number Potency units/ml Clinical lots How was this lot used?

2.Better Analytics MS applications particularly regarding carbohydrate structures AUC and FFF for protein aggregation CE instead of SDS PAGE Light scattering esp. couple to separation techniques

3.Evaluation of Lot Selected for Non clinical or Clinical Studies FDA is evaluating lots chosen for NC/C studies 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 lots that are most similar to the pre changed product may not be useful

“Cherry Picking” Lot number Manufacturing Change % tetra antennary Lots for PK Study Lower limit Upper limit

4.More Extensive Manufacturing Changes Changes in cell substrate and fermentation processes have become much more frequent Significant changes in the master cell banks or fermentation processes have historically required some clinical data including on occasion, clinical safety and/or efficacy data The need for clinical data in large part has been dependent on the inability to predict with a high degree of confidence that observed differences in critical quality attributes or bioavailability have no adverse impact upon safety or efficacy of the product

Clinical Comparability Outcomes Several different outcomes from clinical comparability studies have been observed: ─ Significant differences in clinical characteristics that adversely impact clinical performance ─ Differences in clinical characteristics that are unlikely to adversely impact clinical performance ─ Differences in clinical characteristics that show a benefit (decreased immunogenicity) ─ Insufficient information to conclude the product is comparable (Small clinical studies may not be informative, PD markers may have questionable relationship to efficacy)

5.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, more then one stress condition Measurable rate of degradation that allows a meaningful comparison

Hypothetical Example Time (in days) Potency units/ml Pre-Change Product 45 °C Post-Change Product 45 °C Pre-Change Product 60 °C

6.Global Harmonization Engagement with other regulatory authorities regarding reasons for the different regulatory outcomes is increasing. For example: A pre-licensed comparability study resulted in 3 distinct regulatory decisions from 3 regions One region only approved a 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 group, with the sponsor’s permission, why the specific approach was taken.

Lessons Learned

Lessons Learned Protein products can be exquisitely sensitive to minor impurities and seemingly minor process changes Changes within specification but out of trend with historical data may impact clinical performance Undetected differences in product attributes may have a potential impact on clinical parameters If you know what to look for you can find it, if it’s there Upstream process changes (i.e., impacting fermentation) have a greater risk to product quality Site or scale changes have been less problematic when other process changes are not included in the site or scale change

Lessons Learned Don’t make major process changes between the pivotal clinical studies and a marketing application – end of phase 2 is perhaps the best time When fixing a quality issue, implement the least significant change possible A different formulation is automatically different so the risk to product quality may be higher and could require higher categories of testing Physicochemical/biological characterizations are not a reliable predictor of immunological properties of a product