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

04th September 2024 | 10:00am EDT / 7:00am PDT / 3:00pm BST / 4:00pm CEST | Andrey Sarafanov; PhD., Principal Investigator at U.S. FDA, Center for Biologics Evaluation and Research |BOOK FREE SEAT FOR THIS WEBINAR

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.

Sponsored by Nelson Labs

Nelson Labs is a global leader in microbiological and analytical chemistry testing and advisory services for the medical device and pharmaceutical industries. Nelson Labs serves over 3,000 customers across 13 facilities in the United States, Mexico, Asia, and Europe.  We provide our customers with mission-critical testing services, which assess the quality, effectiveness, and end-to-end sterility of products and, ultimately, the impact of the products on patient safety. These services are necessary for our customers’ regulatory approvals, product releases, and ongoing product performance evaluations.  We have over 900 laboratory tests supporting our customers from initial product development and sterilization validation, through regulatory approval and ongoing product testing for sterility, safety, and quality assurance.  Pharmaceutical lab testing services include microbiology, biocompatibility and toxicology assessments, extractables and leachables evaluations of pharmaceutical containers, sterilization validation, sterility assurance, packaging validation and distribution simulation, and facility and process validation.  We also provide expert advisory services to help customers navigate the regulatory requirements applicable throughout their product’s lifecycle. We are regarded as a best-in-class partner with a strong track record of collaborating with customers to solve complex issues.

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