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.

Extractables & Leachables Qualification of the Primary packaging for Biological Products

In 2022, the final recommendations of the Product Quality Research Institute were published for Parenteral Drug Products. Apart from the wealth of information and considerations on design of extractable & leachable studies for parenteral drug products in general, it also contains valuable information on specific considerations for biological products. For biological products, not only the safety but also the quality of the product and related concerns about immunogenicity and leachables reactivity come into play. We will give an overview on the recommendations and how it affects the design of an extractable & leachable study for the primary packaging of biologics.

Presented by Sona Kovackova, PhD, Scientific Expert – E&L at Nelson Labs

Sona Kovackova earned her PhD in Organic Chemistry from the University of Chemistry and Technology in Prague, Czech Republic. She began her career as a Scientist at the Rega Institute for Medical Research, KU Leuven, Belgium, and later transitioned to Quality Control of medicines at the Belgian Institute of Public Health.

In 2017, Sona joined Nelson Labs Europe where she specializes in Extractables & Leachables studies, leveraging her extensive background in both analytical and organic chemistry. Sona’s primary focus lies in injectable applications, where understanding the interaction between drug products and their primary packaging is critical.

Selecting the Right Primary Packaging Materials for Biological Drug Products

Rubber components are an essential part of the primary packaging system of biological drugs, for example as stoppers for vials or plungers for prefilled syringes. To avoid drug compatibility issues, as well as complicated leachables and toxicological assessments, rubbers with high chemical purity are preferred. The presentation aims to demonstrate how the selection of the right compound, potentially complemented with a coating, can help prevent issues when packaging biological drugs. Additionally, it is shown how the availability of good extractables data can further alleviate the E&L process. To provide some background, the different types of rubber ingredients are discussed first, together with the type of extractables that are to be expected.

Presented by by Tine Hardeman, Manager Material Development bij at Datwyler

Tine Hardeman studied Polymer Chemistry at the University of Leuven and received her MSc in 2013. She acquired a PhD for her dissertation on the controlled synthesis of conjugated polymers in 2017.After gaining R&D experience at Kaneka Belgium, Tine started her career at Datwyler in 2018 as Manager Material Development. In this role, she is working on the development of new rubber formulations, raw material management, and helping customers with rubber compound-related questions, among other things. Additionally, she has been focusing on the field of Extractables & Leachables.

This webinar ends with a live Q&A session

Sponsored by Nelson Labs and Datwyler

About 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.

About Datwyler

Datwyler is a leading specialist for system-critical elastomer components and a key player in the global healthcare market. Our state-of-the-art solutions for drug packaging and medical devices, build on over 100 years of experience. Within our healthcare offering, we provide a unique range of products and services, including the most advanced elastomer formulations, coatings, aluminum seals, and processing technologies. With our global production footprint, we make an important contribution to our customers’ reliable supply chain. Partnering with the world’s top pharmaceutical and medical companies, we are a vital link and stand by our mission to improve patients’ lives.