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Extractables and Leachables for Inhaled Medicines

How risk assessments can improve E&L strategies

Regulatory agencies such as the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) are encouraging a more structured approach to product development, such as using Quality by Design (QbD) principles.

The structured approaches encouraged by the FDA, EMA, and other regulatory bodies require additional upfront resources compared to a more traditional approach. Performing an initial assessment of materials used in the product and developing a more thorough understanding of products earlier in their development allows more appropriate experiments on the higher-risk aspects rather than generic approaches covering all materials.

Benefits of Performing a Risk Assessment

Extractables and leachables (E&L) risk assessments are valuable processes that can identify and highlight the risks of potential leachables from both the container closure system and the manufacturing processes. The risk assessments also include the level of risk that leachables might present to user safety and product quality.

By performing a risk assessment, manufacturers can better understand the product, whether a medical device or the container closure system, and the manufacturing processes. Identifying risks and scoring them based on that understanding allows for subsequent E&L studies to be more focused. Therefore, decisions around the E&L aspects of the project can be more appropriate.

Risk Assessment Lifecycle

Quality risk management is a systematic process. The lifecycle can be split into Assessment, Control, and Review stages, and there should be regular communication with stakeholders throughout the lifecycle. A typical quality risk management process is described in ICH Q9 with a flowchart, and it is a good place to start when designing a strategy. An initial assessment can be performed based on previously mentioned tables and decision trees from the FDA and EMA guidelines. This can inform stakeholders early in the assessment about the studies that might be required for the project.

The first step of the process is the Risk Assessment, which is further divided into a series of sections:

• Risk Identification involves identifying the parameters that might affect the leachables by reviewing and brainstorming processes and materials.

• Risk Analysis collates information to understand identified failure modes.

• Risk Evaluation uses information gathered during the Risk Analysis to score the failure modes. • Risk Control covers where the risks are either accepted or experimental studies are planned based on mitigating risk appropriately.

• A Risk Review reassesses the failure modes and re-scores them following any risk mitigations. Risk review can also be part of lifecycle management.