By Hanns-Christian Mahler, Alejandra Nieto, Klaus Wuchner, and Roman Mathaes
Container closure integrity (CCI) needs to be demonstrated for primary packaging of injectables prior to any human use for container closure system (CCS) qualification, as in-process control during manufacturing, and for quality control purposes to ensure microbiological quality (sterility) during storage, shipment, and use. It is a required test feature by health authorities and monographs, e.g., FDA guidance for industry, but current regulatory guidances do not provide much detail on how to assess CCI. The draft revision of USP <1207> aims to provide extensive and detailed guidance for CCI assessments by the pharmaceutical industry.
Consider these practical questions that are yet to be addressed by the pharmaceutical industry:
- Which CCI method should be chosen?
- Are deterministic methods (e.g., helium leak or headspace analysis) in general preferable over probabilistic (e.g., dye ingress) CCI methods?
- What considerations need to be made depending on primary packaging (e.g., vial, syringe, or device) and dosage form (e.g., liquid vs lyophilisate)?
- How to validate a physical CCI method and its cross-reference testing to microbial ingress testing the best way forward?
- What are the acceptance criteria for a CCI method? How many samples should be tested?
- What is the best way to introduce artificial leaks into CCS as positive controls for CCI assessments?
- How should the industry provide sufficient assurance for CCI during drug product manufacturing?
- Does the industry need to test CCI at intended shipment and storage conditions, especially if CCI could be different at these conditions (e.g., in frozen state)?
A group of European industry peers have met over the last two years to discuss these and other questions and will provide their perspectives and best practices on approaches to CCI in a manuscript. This group has agreed that flexibility toward CCI approaches is needed and that there is no gold standard of CCI test methods or generation of artificial leaks. The approach has to consider the intended use (e.g., container closure system qualification, manufacturing, or quality control), product design (e.g., primary packaging, liquid vs. dried dosage form), and phase.
There will be two sessions at the 2016 National Biotechnology Conference on this topic. First, Innovation in Container Closure Integrity Application, on Monday May 16 from 10:30 am–noon, will present recent advancements related to correlation of residual seal force testing and CCI for capping unit operations and CCI considerations for frozen products. On Tuesday, May 17 from 10:30 am–noon, there will be a talk on Industry Perspective on Current Draft Suggestions on CCI Testing in USP 1207 and Experience with Dye Ingress CCI Testing and Artificial Leak.
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