Risk Assessment of Extractables and Leachables in Different Phases of Development.

In order to ensure the safety of patients, the toxicological risk assessment needs to thoroughly evaluate all potential risks which may be caused by any component present in a pharmaceutical drug product.
Components to be considered include active pharmaceutical ingredient(s), excipients, impurities as well as extractables and leachables (E&L).
E&L does not contribute to the efficacy of the pharmaceutical and therefore offers no benefit. But E&L may have a negative impact on the safety and/or quality of the drug product, and thereby can reduce the benefit/risk ratio.
In consequence, the entry of E&L into the pharmaceutical product needs to be controlled and assessed. Adequate control of E&L requires an understanding of the materials used in production as well as the manufacturing process.
As the knowledge on the manufacturing process evolves during the development of a drug product or medical device, it is advised to include learning cycles into the development program to avoid the existence of critical E&Ls. These learning cycles offer the opportunity to increase the knowledge on E&L associated with the product over its development time. Initially, chemical information should be collected on the materials used. First extraction studies will guide concerns, followed by simulation studies which are designed to mimic reality. In the end, the leachable study has to meet regulatory requirements and must cover real use conditions until the end of product shelf-life, and these leachables need to be covered by a thorough toxicological risk assessment.
Success factors for the preparation of a high quality E&L risk assessment are:
1) start early to avoid potential delays of the program
2) ensure continuous collaboration of CMC and toxicology functions throughout the entire development process.
Presented by Dr Clemens Günther, Senior Expert Nonclinical Safety, Director at Bayer AG, R&D Pharmaceuticals

Dr. Clemens Günther received his diploma in biology and doctorate for natural sciences from the Free University, Berlin-Germany.
He started his professional career in 1990 at Schering AG, Berlin-Germany. From 2000-2006 he became Head of Animal Pharmacokinetics where he also successfully supervised the generation of two doctoral theses.
From 2007 to 2013, Dr. Clemens Günther was Director and Head of Global Preclinical Development at Intendis GmbH, branded later on as Bayer Dermatology. In this position, he was responsible for Nonclinical Safety for the marketed product portfolio of Bayer Dermatology as well as the global preclinical development strategy including human DMPK for development and life cycle management projects.
After integration of Intendis GmbH into Bayer AG in 2013, he became Director Nonclinical Safety Consumer Care and later on Senior Expert Nonclinical Safety within the Division of Bayer Pharmaceuticals.
Meanwhile, Dr. Clemens Günther gained over 30 years of experience in drug development from drug discovery to clinical phase III. His expertise includes nonclinical development and regulatory toxicology of small molecules, biologics, medical devices, and drug device combination products including assessment of impurities, extractables, and leachables. His achievements comprise the successful registration of several pharmaceutical products in various medical indications.

Where N-Nitrosamine assessments for Drug Products meet Extractable / Leachable Qualifications for Pharmaceutical Primary Packaging

Recently there have been a number of drug product recalls due to the unexpected presence of N-Nitrosamines. While in most of those cases, N-Nitrosamine formation occurred at the level of the drug substance synthesis and stability, it is well known and documented that some materials, used in primary packaging can also be a source for N-Nitrosamine contamination of the packaged drug product (e.g. older grade elastomers and nitrocellulose laminated blister foils). The unanswered question is: do we know everything about the materials of construction of a container closure system and their ability to generate N-Nitrosamines? When looking at the formation mechanism of N-Nitrosamines, it are secondary amines (and potentially tertiary amines) that are a precursor to N-Nitrosamine formation, together with a nitrosating agent (such as e.g. nitrite/nitrous acid). When evaluating the extraction profile of materials of construction, it is clear that secondary amines are often encountered as an extractable being present in the material. Should this raise a “red flag” for those materials in a N-Nitrosamine risk mitigation strategy, as one precursor for N-Nitrosamine formation is obviously present in the material? And what could be the consequence of these findings, both for the design of extractable and leachable studies, as well as in the assessment of the E/L-results? This presentation will give more insights on how an integrated approach for both the E/L-qualification as well as the N-Nitrosamine risk evaluation for a pharmaceutical container closure system could look like. 

Because of recent product recalls due to the unexpected presence of N-Nitrosamines, it is important to take a look at the formation of these amines on materials prominently used in primary packaging of drug products. The unanswered question is: do we know everything about the materials of construction of a container closure system and their ability to generate N-Nitrosamines? It is commonly known that secondary amines (and potentially tertiary amines) are a precursor to N-Nitrosamine formation and that these are taken into consideration when evaluating the extraction profile of materials of construction. The question however remains: should this raise a ‘red flag’ in a N-Nitrosamine risk mitigation strategy?

All attention points, as well as the potential consequences of these findings for the design of extractable and leachable studies, will be presented in this live webinar. Also, a light will be shed on how this affects the assessment of the E/L-results. This presentation will give more insights on how an integrated approach for both the E/L-qualification as well as the N-Nitrosamine risk evaluation for a pharmaceutical container closure system could look like.

Presented by Ward d’Autry, Study Director E/L & Structural Elucidation, Nelson Labs Europe

Ward D’Autry received his Ph.D. from the Laboratory for Pharmaceutical Analysis, Faculty of Pharmaceutical Sciences of the University of Leuven (Belgium) in 2010. Since 2017 Mr. D’Autry works for Nelson Labs Europe as study director extractables & leachables. In this current role, he manages extractables & leachables studies with a focus on manufacturing components. In 2021 he will take up a new role as study director ofstructural elucidation, where he will manage second pass identification studies.
Sponsored by Nelson Labs

Nelson Labs, A Sotera Health company, is the leading, global provider of lab testing and expert consulting services. We perform microbiological and analytical laboratory tests across the medical device, pharmaceutical, and tissue industries. The company is regarded as a best-in-class partner with a strong track record of collaborating with customers to solve complex problems. We have over 700 scientists, technicians, and service specialists who diligently perform more than 700 rigorous tests in 13 global laboratory locations.
Based in Belgium, Nelson Labs Europe specializes in providing premium Extractables & Leachables testing services to the pharmaceutical and medical device industries. We also support pharmaceutical companies across the globe in developing worldwide compliance testing strategies to qualify container/closure applications and pharmaceutical production equipment from an Extractables & Leachables perspective.