Extractables and Leachables - Assessing Risk in a Complex Landscape

At West, we often get asked “What extractable compounds are present in your products?”, “What are the current requirements for Extractable and Leachable testing?” and “How do I make sense of all of this data and get the regulatory authorities what they want?”

It is not surprising that there is still confusion on the topic. Guidances, where available, do not give step by step instructions. In addition, drug products and other drug product contact materials are getting more and more complex. So, where should you start?

We know from ICH Q9 that, “The evaluation of the risk should be based on scientific knowledge and ultimately link to the protection of the patient.” Therefore, we should view all work done to characterize extractables and leachables in terms of patient risk.

Starting with component selection we can ask questions such as:

• What information am I able to obtain from my vendor as to material characteristics and safety?
• Does this material have inherent properties that are hazardous? If so, what are the main concerns and does data exist to confirm or deny presence?
• What is the drug product contact (time and temperature) and how can that increase or decrease patient risk?

With this information, you have a starting point in order to select the packaging materials that best fit your needs.

Now that you have selected the appropriate components, you can assess extractable information gaps and design fit for purpose analytical evaluations. The point here is not to do less testing, but rather, more focused testing in order to answer any outstanding questions.

Once all the pertinent extractable data has been obtained to understand your materials, you can further organize the information based on risk in order to decide which compounds should be monitored over the shelf life of the drug product and which should not (Leachables phase). Some questions to ask at this stage are:

• What is the toxicity of the analytes?
• What are the relative amounts, volatility and solubility of the compounds? How might that impact migration into your drug product?

After the organization of compounds is completed, you can use those justifications to define a leachables testing plan. Methods used to quantitate leachables should be validated and detection/quantitation levels should be meaningful in terms of patient safety. USP <1664> tells us that, “The completeness of an extractables assessment can only be judged against the overall goals of the assessment.” By defining your risks up front and developing thoughtful test plans, you can ensure that your decisions are both data-driven and patient-focused.