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 Molly Haan, Senior Technical Customer Support Scientist at NAMSA

Molly Haan is a Senior Technical Scientist at NAMSA. Her role includes navigating the complexities of regulatory inquiries, creating and managing intricate study designs, tracking regulatory trends, and delivering high-level technical guidance, particularly related to E&L testing. Prior to joining NAMSA, she served as a Senior Study Director for WuXi AppTec, an Application Specialist with Thermo Fisher Scientific and a Microbiologist and Chemist with Nestle. Based in Minneapolis, Molly holds a Bachelor’s degree in Microbiology from North Dakota State University, a Master’s in Biological Sciences from the University of Minnesota, and an MBA from Walden University.

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.  

Followed by a live Question and Answer Session

Sponsored by NAMSA and Cytiva

About NAMSA

Helping medical device Sponsors improve healthcare since 1967, NAMSA is the world’s leading MedTech Contract Research Organization (CRO) offering global end-to-end development services. Driven by its global regulatory expertise and in-depth therapeutic knowledge, NAMSA is dedicated to accelerating medical device product development, offering only the most proven solutions to move clients’ products through the development life cycle efficiently and cost-effectively. From medical device testing; regulatory, reimbursement and quality consulting; and clinical research services; NAMSA is the industry’s premier, trusted partner for successful development and commercialization outcomes. Web: namsa.com

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