Analytical Assessment of Leachables in Biological Drug Products: FDA Approach in Reviewing Information

Biological drug products (biologicals, such as therapeutic proteins, vaccine-, gene-, and cell therapy-based) are produced via multi-step processes involving multiple materials contacting intermediates and sourcing numerous leachables into final drug products (DP). Such steps involve (i) purification of intermediates using chromatography, centrifuging, dialysis, filtering, and filling in final container closure system, etc., (ii) shelf-life storage and (iii) in-use hold of DP. The respective contact materials involve chromatography resins, filtering/dialysis membranes, tubing, collecting bags/tanks, gaskets, valves, final container closure systems, etc. By these, the assessment of leachables risk in biologics is the most challenging compared to other types of DPs. However, current guidances are generally focused on assessment of the leachables only from single manufacturing components, scored to be high-risk for leachables, and by this, underestimate other components scored to have the lower risk. Following these directions, manufacturers typically perform the assessments only for the high-risk components and by this, underestimate the contribution of other materials to the overall (cumulative) leachables profile in final DP. Other typical issues involve (i) non-validation of analytical methods, resulting in ambiguity in Analytical Uncertainty Factor (AUF) used for calculation of the Analytical Evaluation Threshold (AET; reporting limit in an assay), (ii) missing the assessment of elemental (ionic) leachables, or (iii) incorrect leachables study design; altogether also resulting in potential underestimation of the leachables risk. These issues usually cause multiple back-and-forth communications between the FDA and Sponsor during the applications’ (BLAs and supplements) review, typically ending up with post-marketing requirements (PMR) and putting an unnecessary burden on both sides. This presentation overviews an FDA approach and experience in reviewing information for analytical assessment of leachables, including examples of the review cases and found issues, aimed to reduce the efforts of both sides in the review process and facilitate proper evaluation of the leachables risk and also used in preparation of the current ICH Q3E guidance draft.

Presented by Andrey Sarafanov, PhD., Principal Investigator at U.S. FDA, Center for Biologics Evaluation and Research

• Research interests: structure-function of blood coagulation factor VIII, mechanisms of FVIII clearance from the circulation, treatment of Hemophilia A, blood coagulation mechanisms.
• Regulatory work at FDA: review of information for drug products based on therapeutic proteins, for gene therapy, cell therapy and tissue-engineered products with additional focus on review of extractables and leachables assessment.
• J. H. Holland Laboratory of the American Red Cross (Rockville, MD), 1998-2004;
• University of Maryland School of Medicine (Baltimore, MD), 2004-2006;
• Armed Forces Institute of Pathology, Walter Reed Army Medical Center (Washington, DC), 2006-2008.
• BS/MS in Biochemistry – 1982, Moscow State University, USSR.
• PhD in Molecular Biology – 1998, Engelhard Institute of Molecular Biology, Russian Academy of Sciences, Moscow.

Followed by Sandi Schaible, Executive Director, Analytical Chemistry and Regulatory Toxicology at WuXi AppTec

Sandi Schaible joined WuXi AppTec in 2011 and is responsible for oversight and direction of WuXi AppTec’s Analytical Chemistry and Regulatory Toxicology departments in St. Paul, Minnesota, and our new lab in Munich, Germany, which is opening in late 2024. With over 30 years of experience, Ms. Schaible leads a team responsible for providing custom chemistry testing services, including extractables/leachables, materials characterization, and toxicological risk assessments. Ms. Schaible has worked in the pharmaceutical, medical device, environmental, and R&D industries, including over 20 years of analytical experience in GLP, GMP, FDA, and ISO regulated laboratories. She is actively involved in standards development and is an international and U.S. delegate for TC 194/WG14, the technical committee for ISO 10993-18.

James Hathcock, Sr. Director, Regulatory and Validation Strategy at Cytiva

James Hathcock, PhD is Director of Regulatory and Validation Strategy at Cytiva, responsible for the strategy to support safe and successful end-user implementation of technologies enabling pharmaceutical manufacturing.   He is currently an active supporting member to BioPhorum, BPSA, ASTM, ASME-BPE, PDA and ISO. He also leads the BPSA initiative on X-ray security of supply for single-use disposables, the BioPhorum Community of Practice for Extractables and leachables, and the ASME-BPE task group on single-use biocontainers; and has previously served as an expert manel member for USP <665> & <1665>.  Since joining Cytiva in 2008, James has led material and performance qualification strategies for medical and bioprocessing materials, coordinated relevant technical packages and briefings supporting regulatory filings, and supported business continuity and security of supply challenges.  Prior to his experienced with Cytiva, James served as professor of hematology at the Mt. Sinai School of Medicine in New York City, where he directed the protein purification laboratory related to drug characterization and discovery.  

Sponsored by WuXi AppTec and Cytiva

About WuXi AppTec

WuXi AppTec operates state-of-the-art analytical chemistry laboratories in both the US and Europe, located in St. Paul, Minnesota, and Munich, Germany. Our experienced scientists, chemists, and toxicologists are dedicated to providing high-quality analytical services. Our extractables/leachables team partners with our customers to support product safety with regulatory consulting, pre-clinical testing, and post-commercialization product testing support.  Our regulatory and technical experience with active participation and/or leadership on global committees allows us to anticipate regulatory trends.  Our chemistry program driving principle is complete chemical characterization.  This is our standard of practice as our chemists work closely with our toxicologists to provide the most mass-accurate data and virtually no unknowns in our chemistry reports.  Our technical and regulatory experts advise on test design and strategies for test plans while working closely to account for the product, indication, and patient population.  Furthermore, we stand behind our work – from test plans through clearance – responding to questions or other regulatory requests as part of the submission process.

About Cytiva

At Cytiva, our mission is to advance and accelerate the development of therapeutics. With 15 000 associates in more than 40 countries, we’re driven to use our expertise and talent to achieve better flexibility, capacity, and efficiency for our customers.  Our broad and deep portfolio of tools and technologies, global scale, and best-in-class service provides critical support from discovery to delivery, for customers spanning researchers, emerging biotech, large-scale biopharma, and contract manufacturers. Learn more at cytiva.com