4031/45 Ready Methods Reduce E&L Program Timelines 

In 21 CFR 211.94 it is stated that “Drug product containers and closures shall not be reactive, additive, or absorptive to alter the safety, identity, strength, quality or purity of the drug beyond the official or established requirements.” While the code makes this statement, and if expanded on in the related FDA Guidance for Industry Container Closure Systems for Packaging Human Drugs and Biologics (May 1999), there is no prescription offered in how to execute an extractables and leachables evaluation, which is, of course, an essential aspect of demonstrating suitability of container closure systems.

Working groups like Product Quality Research Institute (PQRI) and guidance chapters like USP <1663> Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems and <1664> Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems provide direction. For small molecule drug products, manufacturers must understand these guidelines and determine how to apply them for extractables and leachables evaluations of individual drug products.

With expertise in both materials’ science and extractables and leachables evaluations for pharmaceutical packaging components and delivery devices West’s analytical labs has an established approach for executing extractables and leachables evaluations for individual drug products. This approach is composed of understanding risks, developing, and validating targeted leachables studies, and supporting drug products through stability testing. Through knowledge and experience, West subject matter experts partner with customers to reduce the risk to their drug product by designing and performing the studies that identify leachables from the primary packaging components.

Industry best practices ask drug product manufacturers to gain data on extractables first, then evaluate those extractables via a risk assessment to identify target leachables, and lastly develop and validate methods at appropriate levels to quantitate leachables levels in the drug product. The process of performing these studies can be time intensive. This is a challenge given the nature of market demands for drug product manufacturers, who need to move quickly to help ensure that drugs reach the market safely and efficiently. To meet this need, 4031/45 Ready Methods are already qualified for observing potential 4031/45 Gray related leachables, thereby expediting the process for validating leachables for a particular drug product.

In addition to understanding the guidelines mentioned above, the industry faces challenges of quickly getting a therapeutic or life-saving drugs to market, and the potential lack of knowledge and resources needed to meet regulatory expectations. To address these challenges, West Services and Solutions has developed the 4031/45 Ready Methods. The 4031/45 Ready Methods qualified leachables methods for detecting leachable compounds from this rubber formulation. These methods were developed using drug product simulants such as water-based formulations, buffer solutions, and formulations containing benzyl alcohol. These drug product simulants were used as models based on an understanding of their typical use in small molecule injectable drug products. Customers can perform a risk assessment with the 4031/45 Gray extractables profile to determine if the available extractables data is sufficient for their use case. If the assessment concludes that additional extractables testing is not needed, they can move directly to next steps: (a) toxicological risk assessment; (b) identification of target extractables for leachables and their reporting thresholds; and (c) determination of feasibility of the chosen extractables in their small molecule drug product and drug specific validation. This can help reduce the overall testing time. After the completed validation work, the result is a set of leachables methods that are specific to their drug product and that can be used for stability testing.

West is also able support customers with two additional services:

1. E2L Assessment: This service provides a paper-based risk assessment on the extractables data in the 4031/45 Gray extractables profiles. This risk assessment uses nine different categories to rank the extractable compounds that take into consideration aspects of the intended drug product. The purpose is to assist in the customer's assessment of the extractables package, as well as their selection of compounds to target during a leachables study. It does not specify specific compounds to target; the E2L service does not take the place of the need to perform a toxicological risk assessment for leachables specific to their drug product.


2. Simulation Study: This study generates data using exaggerated storage conditions to provide customers a first glimpse as to what extractable compounds may actually migrate into their drug product. Drug product, placebo, or appropriate simulant is exposed to the exaggerated storage conditions and evaluated using screening methods to determine what, if any, extractable compounds might be observed using “actual-use extraction conditions”. A reporting threshold is calculated based on the dosage of the drug product and used as the reporting threshold for these extractables.

The goal of both is to aid in the customer’s assessment of the extractables data to, ultimately, pick the appropriate 4031 Ready Methods and reporting requirements.

West’s analytical labs have been performing extractables and leachables evaluations for 25 years, providing a holistic approach for customers’ container closure systems, devices, and combination products. We deliver tailored extractables and leachables solutions based on the stage of development of the product to address the challenges faced by the customer and the industry. By integrating our knowledge and expertise of materials, components, packaging, and analytical testing, West offers a more comprehensive approach and timely delivery of generics manufacturers' packaging and regulatory needs through the with the 4031/45 Ready Methods. Visit our Services pages or Contact us for more information.