AUGUST 2022LIFE SCIENCES REVIEW9extractables analyses are focused on materials and systems.Leachables, as defined in USP <1664> Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery systems, are organic and inorganic chemical entities that are present in a packaged drug product because they have migrated into the packaged drug product from a packaging/delivery system, packaging component, or packaging material of construction under normal conditions of storage and use, or during drug product stability studies. Leachables analyses are focused on what has migrated into the drug product. USP Chapters <1663> and <1664> are informational chapters that provide guidance on a framework for extractables and leachables studies. As these guidelines are not prescriptive, it is important that pharmaceutical manufacturers have a strategy and an approach for extractables and leachables studies for their products early in drug product development. Container Closure Integrity (CCI) TestingContainer Closure Integrity (CCI) is another key area that needs to be evaluated in the development phase of drug products. CCI is defined as the ability of a device components to prevent product loss, to block the ingress of microorganisms, and to limit entry of detrimental gases, or other substances over the she lf life of the drug product ­thus ensuring that the drug product meets all necessary safety and quality standards. This terminology is synonymous with device integrity. CCI failures for devices include leakage, loss of product, increased concentration of product, contamination, sterility failure, critical headspace loss, over-pressurization, or loss of pressure.USP <1207> Package Integrity Evaluation ­Sterile Products addresses CCI and provides guidance on how to evaluate integrity of devices intended for sterile products.When considering techniques for CCI analysis, it is important to understand that there is no one test method that is appropriate for all product package systems. Method selection and validation should be based on what is best suited for the application, and the methods should target quantitative results (deterministic methods) versus qualitative results (probabilistic methods).Deterministic methods should be utilized when possible. Examples of deterministic methods include tracer gas, high voltage leak detection, vacuum decay and laser-based headspace analysis.Particle AnalysisAnother critical aspect of qualifying devices and related components is particles and the particle burden. Particles may be visible or subvisible, and categorized as intrinsic, extrinsic, or inherent. Intrinsic particles may come from processing or device materials, including stainless steel components, gaskets, glass container, rubber components, fluid transport tubing and others. Extrinsic particles are foreign to the manufacturing process, such as hair, non-process related fibers, and other foreign matter. Inherent particles are associated with specific drug product formulations such as suspensions, emulsions, aggregates, etc. Depending upon the drug product, there are different USP requirements and guidances that can be used in developing a particle testing strategy.Performance TestingThere are many aspects to consider when developing a sound approach to performance testing to qualify packaging and delivery systems, and combination products. These include assessing performance risks, establishing the testing strategy, and executing the testing plan. Identifying and assessing performance risks can help set the foundation for the product testing strategy. After assessing and understanding the performance risks, the next step is to establish the testing strategy. This step is an output of risk assessments, but also receives input from guidances from ISO, USP, and others. SummaryCombination products development has increased and is becoming even more complex due to advancements in drugs, technologies, and materials. Because the merging of device and drug is so complex, it is critical to have a multi-faceted testing strategy through every development phase of the combination product. Combination products development has increased and is becoming even more complex due to advancements in drugs, technologies, and materials
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