by Lukas Mogler
Principal Scientist, Forensic Chemistry, Drug Product Services
I have always had two passions in my life, cooking and science. Similar to professional chefs, scientists need to be equipped with deep insights into the quality of their dishes, ingredients, or even materials used during the cooking process. My passion for analysis, be it in the laboratory or the kitchen, later culminated in my studies. During my diploma thesis and PhD in pharmaceutical sciences, I focused on trace analysis and structural elucidation by mass spectrometry, so my analytical portfolio fitted well for impurity analysis in drugs. My current position at Lonza Drug Product Services is focused on performing extractables and leachables assessments and structure elucidation.
Understanding all factors that may have an impact on drug product purity, quality and safety represents a crucial part of the drug manufacturing process. When it comes to the latest stages of pharmaceutical manufacturing – filling the final drug product into its container or delivery system, the last thing we want is to discover a surprise in the form of impurity. Being able to detect any compounds that could have leaked from the processing and packaging equipment into the drug product is, therefore, crucial to ensure safer products for consumers and patients.
Defining extractables and leachables
Both terms, extractables and leachables (E&L), are used for chemical compounds migrating from plastic materials into the contact solution. The difference is that extractables are, per definition, extracted from a component of a process stream into an extraction solution, thus produced under laboratory conditions. On the other hand, leachables are chemical entities released under actual manufacturing and storage conditions from components into the process stream and might end up in the final drug substance or drug product.
Traditional biologics manufacturing continuously shifts from stainless steel equipment to single-use systems (SUS). These single-use systems, containing various plastic materials, consist of hundreds of components directly in contact with the process stream. To assess the potential of E&L for these components, risk-based E&L approaches are commonly applied and suggested by health and regulatory authorities.
From risk assessment to risk mitigation
The E&L evaluation for a given material begins with an in-sillico risk assessment. These assessments allow us to filter low-risk materials from medium and high-risk materials depending on their risk of introducing leachables into the process stream. According to their risk categorization, we mitigate the risk with an appropriate mitigation strategy.
If material is determined to have a high risk of introducing leachables into the process stream, we can follow different risk mitigation options. Most vendors can provide extractables data for their material tested according to generally accepted industry standards. This data is then evaluated specifically for each process and product. If the vendor extractables data is missing or is inadequate for the process or product, we have the capabilities to conduct in-house E&L testing in our laboratories at Lonza's Drug Product Services.
The setup of a conclusive study protocol is the basis for a proper E&L lab study. Sometimes, we simulate whole manufacturing processes on a small scale in our lab to generate realistic process samples. We use state-of-the-art mass spectrometry systems to screen for unknown E&L compounds at trace levels. As these compounds often do not match commercially available libraries, the following step is to perform structural elucidation. These compounds are then quantified and finally subjected to a toxicological assessment to ensure patients' safety.
The goal of an E&L assessment is to prove the safety of patients being treated with the product with regard to E&L compounds. For our customers, it is also to comply with health authorities' expectations. The European and US guidelines addressing the topic of E&L outline that manufacturing material and container closure systems shall not be reactive or absorptive to alter a drug's safety, quality or purity.
New challenges facing E&L assessments
The emerging portfolio of novel biologics, such as antibody-drug conjugates (ADCs) and cell and gene therapy (CGT) products, poses challenges to E&L assessments. The primary reason is that SUS systems are not always purchased off the shelf, but they are more and more customized as whole assemblies fitted for the individual process demand. New suppliers and components are entering the market and such components often miss conclusive extractables data that should be provided by the supplier.
Assessing E&L for traditional and emerging biologics is highly challenging, as it covers manufacturing processes with hundreds of different SUS components and screening for thousands of possible compounds through trace analysis. These requirements and challenges demand conclusive E&L strategies and strong analytical expertise to ensure our overall goal: bringing safe and efficient therapies to our patients. We in Lonza DPS – Forensic Chemistry have the in-house capabilities to support our customers with both tailored risk assessments and dedicated lab studies to solve these E&L challenges.
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Lonza Group Ltd has its headquarters in Basel, Switzerland, and is listed on the SIX Swiss Exchange. It has a secondary listing on the Singapore Exchange Securities Trading Limited (“SGX-ST”). Lonza Group Ltd is not subject to the SGX-ST’s continuing listing requirements but remains subject to Rules 217 and 751 of the SGX-ST Listing Manual.
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