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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.

Since the Technical Guideline on Compatibility Study of Chemicals and Elastomeric Closures was published by the National Medical Products Administration (NMPA, previously known as CFDA) in April 2018, it is essential for pharmaceutical companies to perform compatibility studies. However, for some domestic pharmaceutical companies that lack experience, it is unclear how to perform such a study. To address this, a series of trainings was planned by China National Pharmaceutical Packaging Association (CNPPA) – with the first held in December 2018. There were over 100 attendees from pharmaceutical companies, pharmaceutical packaging companies, NMPA-affiliated labs, and the third-party labs. The training received positive feedback from the participants.

Ophthalmic drug products (ODPs) present a special challenge for the measurement of extractables and leachables (E&L) due to the presence of multiple leachables sources. ODPs typically are packaged in labelled, semipermeable polymer (e.g., low density polyethylene) containers (i.e., primary container) and stored in cardboard containers (i.e., secondary container) along with instructions for use. The polymer, label, cardboard and paper are all possible sources of leachables.

Extractables and leachables (E&L) pose a potential risk to patient safety. Both pharmaceutical companies and regulatory agencies have rising concerns regarding E&L, which has led the Center for Drug Evaluation under the China Federal Drug Administration (CFDA) to release a new standard for public comment (December 30, 2016): Technical Guideline for Compatibility Study of Chemicals and Elastomer Closures. The compatibility study discussed therein focused on E&L.

Pharmaceutical industry focus on issues of extractables and leachables from packaging/delivery systems began during the mid-1990’s. Since then, regulatory agencies have become more educated, and drug product formulations have become more complex, which makes the need for a robust extractables and leachables program that much more critical. 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 question is – where to start?