Analytical Assessment of Leachables in Biological Drug Products: FDA’s Approach to Reviewing Information and Representative Review Cases

Biological drug products (biologics), such as therapeutic proteins, vaccines, and gene- and cell-based therapies, are produced through multi-step processes involving multiple materials that contact intermediates and introduce numerous leachables into the final drug product (DP). These steps include (i) purification of intermediates using chromatography, centrifugation, dialysis, filtration, and filling into final container closure systems; (ii) shelf-life storage; and (iii) in-use preparation of the DP. The respective materials include chromatography resins, filtration/dialysis membranes, tubing, collection bags/tanks, gaskets, valves, final container closure systems, and in-use preparation components. Consequently, assessing leachables risk in biologics is the most challenging compared to other types of DPs.

However, current guidances focus on assessing leachables only from single manufacturing components that are scored as high-risk for leachables and underestimate other components. Following these recommendations, manufacturers often design studies incorrectly by performing assessments only for selected components and not assessing the overall (cumulative) leachables in the final DP. Other issues involve using non-validated analytical methods that result in potentially high quantitation errors for compounds whose actual levels may exceed safety thresholds. Such issues usually cause multiple communications between the FDA and sponsors during application reviews, typically resulting in requirements to perform post-marketing assessments that burden both parties.

This presentation overviews the FDA’s approach and experience in reviewing information for leachables assessment and includes recent examples of representative review cases, aimed at facilitating proper leachables assessment. Our review experience has contributed to writing the ICH Q3E guidance draft, which is currently in the final stages of completion.

Presented by Andrey Sarafanov, PhD; Team Lead, Principal Investigator at Division of Hemostasis, Office of Plasma Protein Therapeutics, Office of Therapeutic Products, Center for Biologics Evaluation and Research at U.S. Food and Drug Administration

• 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 a live Question and Answer Session