Extractables and Leachables

The FDA states: 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.*  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.

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.

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.

Synthetic rubber has replaced natural rubber in many fields over the past decades. Very notable are the synthetic halobutyl rubbers used as a base for pharmaceutical elastomer components. They are an excellent choice due to their attributes of low permeability to air and moisture, excellent aging resistance, and low level of extractables. Halobutyl rubbers are available in two types, chlorobutyl and bromobutyl; both can be manufactured by co-polymerization with halogenated monomer.

To ensure drug product efficacy, components of primary packaging and delivery systems must be evaluated for safety and performance. An essential aspect of this is an extractables and leachables (E&L) study. The purpose of an E&L study is to identify compounds (organic and inorganic) that may migrate from components into drug product formulations, in particular those that may put patient safety at risk.

The pharmaceutical industry’s focus on extractables and leachables from packaging/delivery systems began during the mid-1990’s. Today’s regulatory agencies are more educated about the process, and drug product formulations have become more complex, which makes the need for robust extractables and leachables programs more critical than ever. In fact, failure to properly evaluate extractables and leachables has had a negative impact on many pharmaceutical companies, e.g., late-stage stability failures, submission delays, and recalls. To avoid this, the first question to ask is – “where do I start?”