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The concept of Extractables and Leachables (E&L) is well known today, especially since the publication of United States Pharmacopeia (USP) monographs <1663>1 and <1664>2. USP <1663> defined extractables as “organic and inorganic chemical entities that are released from a pharmaceutical packaging/delivery system and into an extraction solvent under laboratory conditions.” Leachables are defined in USP <1664> as “foreign organic and inorganic chemical entities that are present in a packaged drug product because they have migrated into the packaged drug product from a packaging/delivery system, packaging component or packaging material of construction under normal conditions of storage and use or during drug product stability studies.”
Although USP <1663> and <1664> give detailed guidance and recommended best practices regarding assessment of extractables and leachables, respectively, associated with pharmaceutical packaging/delivery systems, they provide no specifications. This is because the safety of E&L levels needs to be assessed according to the specific drug application concerned. Therefore, E&L is still the hot topic for the pharmaceutical industry, especially for high-risk drug applications3 such as inhalation and injectable drug products.
One question often asked is when an E&L study should be initiated. The answer is, the earlier the better. Due to the potential adverse impact of leachables on product safety, it is prudent to initiate the extractables study at an early stage. In fact, even from the pre-planning and container closure system (CCS) selection phase, extractables from the CCS should be screened and used to support the CCS selection. In the E&L journey, West recommends that the first step be to collect supplier information on the components. A controlled extractables study is then performed to have a thorough understanding of the extractable profile of the chosen CCS for appropriate risk assessment. Finally, a leachables study is performed upon drug formulation finalization and through drug product shelf life to assure drug product safety and quality.
West understands that some drug manufacturers find such studies daunting as CCS evaluation is not conventionally within their core areas of expertise and there are always resource constraint considerations for companies, from large, established corporations to small, emerging companies. Therefore, to ease the first step in the process, West generated several readily-available extractables data and information on West’s rubber closures for our customers. Here, we will list and introduce each documentation we have currently for our customer’s reference:
TME lists (both as non-confidential and confidential versions) provide potential extractables derived theoretically based on the raw materials of the West rubber formulation, film or coating. The lists are provided to help customers in the determination of feasible targets, or identification of unknowns during customers’ E&L studies. As actual testing is not performed, TME lists are not intended for submission to regulatory agencies.
A compliance bulletin is a compilation of West declarations stating the potential presence of certain compounds of concern in the formulations such as Bisphenol A (BPA), heavy metals, nNitrosamines, etc. which are of potential safety/toxicological concerns. These bulletins typically rely on information provided by upstream suppliers. They can be submitted as supporting information to regulatory agencies. This information is offered in good faith and is not to be considered a warranty or quality specification, therefore, the information should not be substituted for customer’s studies in ensuring compliance and assurance that the packaging component is appropriate for use as final conditions for application are beyond our control.
EE data sheet contains extractable elements data generated from a one-time testing of West rubber formulation based on the Extractable Elements test previously proposed in a briefing for USP <381> in Pharmacopeial Forum (PF) 43(3). The proposed test is, however, removed from the USP chapter as per USP <381>, on the basis that “it is challenging to provide universally effective and efficient test methodologies, lists of target elements, and reporting requirements.” Therefore, the advice has been to leave it to the material user to establish and justify the testing required and typically considered as part of the extractables study. Nevertheless, West continued to provide the data sheet to serve as an information resource for our customers.
NA data sheets present results of nitrosamine extraction on certain West rubber formulations. Currently, there are no limits for elastomeric components used with injectable drug products. According to ICH M74, acceptable intake limits are defined based on drug products. It is understood that CCS is part of the final drug product and is therefore also a potential source of nitrosamines or nitrosamine precursors. As such, other than the compliance bulletin mentioned above, West also supports with this NA data for customer’s risk assessment in final drug product. Similar to an EE data sheet, this data is provided for informational purposes only and should not be submitted in any regulatory or other filings.
An MC package contains extractables screening data performed with target solvents. It serves as a starting point to identify potential compounds and elements with susceptibility to migrate into drug product and serves as a guide to risk assessment and an E&L testing program. It is not intended to be presented “as-is” in a regulatory submission since it is not based on the final drug product. To minimize risk, it is suggested to evaluate the guidances such as USP <1663>, USP <1664> and Product Quality Research Institute (PQRI)’s safety thresholds and best practices recommendation5 in order to determine the appropriate path forward.
The VeriSure®data package is an extractables technical package providing a comprehensive list of extractables of select rubber formulations with supporting data that was acquired based on sampling multiple lots of elastomeric components of various configurations, processing and cure conditions obtained from representative manufacturing sites. It is reviewed and updated as applicable throughout the lifespan of the elastomeric component. The Verisure® data package is intended to be used as a baseline to determine what compounds should be included in a leachables study, hence data can be pulled and used in risk assessment for regulatory submission.
The West E2L™ Risk Assessment is a tool for advancing the E&L process from extractables to leachables in an efficient way by providing a guideline, based on measurable criteria, to assist the client to determine the analytes to target for leachables method development. Criteria are associated with properties of extracted compounds, exposure, detection, and concern for package/product interaction, etc. The E2L™ risk assessment is provided solely for informational purposes and intended to assist the customer in making decisions regarding future leachable evaluation.
Leachables can and have led to problems with severe consequences for patients, therefore, a failure to understand and comply with requirements on E&L will cause regulatory bodies to delay or even deny approvals.
West has combined experience and expertise in elastomer technology and analytical chemistry by providing a holistic, risk-based approach to extractables and leachables evaluation. As a first step, these documents can help facilitate your Journey from Extractables to Leachables. The data should be evaluated based on your final system and correlated to intended use with appropriate risk assessment. In addition, West can offer analytical lab services at West’s GMP-and FDA-registered laboratory with technical consultation for customer E&L evaluations.
By integrating our knowledge and expertise of materials, components, packaging, and analytical testing, West can offer a more comprehensive approach. For more details on the documentation support available and West E&L analytical lab services click here or, contact a Technical Customer Service (TCS) representative, Account Manager.
VeriSure and E2L are trademarks or registered trademarks of West Pharmaceutical Services, Inc. in the United States and other jurisdictions.
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Demonstrating the compatibility of any material in contact with drug product throughout its lifecycle (manufacture, containment, and delivery) is a necessity for a regulatory submission. Defined as extractables and leachables, these assessments continue to evolve and expand due to consistently increasing regulatory agency expectations. Agency expectations require you to act sooner rather than later. Waiting until Phase III in drug development can lead to delays and additional costs due to poor assessments that are questioned by the reviewer, or incomplete submissions that require you to redo or execute additional work. You can start your Extractables and Leachables (E&L) assessment as soon as you have selected your packaging components.
The FDA states: <em>Drug product containers and closures shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality or purity of the drug beyond the official or established requirements.* </em>While they make this statement, there is no prescription offered in actually how to execute an extractables and leachables evaluation, which is, of course, an essential aspect of demonstrating suitability of containers and closures.
In view of patient safety and product quality, extractables and leachables assessments of pharmaceutical packaging and delivery systems have become an integral part of both development and regulatory submissions. Two crucial USP guidance chapters, USP <1663> “Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems” and USP <1664> “Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems” have been published to guide pharmaceutical companies on the practical and technical considerations required for extractables and leachables assessment programs.
Drug developers must understand and mitigate the risk of various chemical entities (leachables) migrating from any material that comes into contact with their drug product. Failure to execute an appropriate extractables and leachables assessment could lead to failures in meeting agency expectations and a delay in drug development timelines.
Focus on extractables and leachables (E&L) from packaging and delivery systems began in the mid-1990s but, since then, regulatory agencies have become more educated, and expectations of the pharmaceutical industry have increased. Examples of updated recommendations include USP<1663> and <1664> and injectable drug recommendations from Product Quality Research Institute (PQRI). Complex drug product formulations have become more common, so it is imperative to have a deeper knowledge of extractables to understand risks associated with potential interactions between packaging and drug product. <!--1664--><!--1663-->
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