可提取文件中的常见缺陷 & 可滤取的测试

To ensure that plastic and rubber chemicals do not transfer into drug products at levels that present a risk to public health, 可萃取物和可浸出物(E&L) studies are a requirement for pharmaceutical product submissions.

Although regulatory guidance has been published by both the United States Pharmacopeia (USP) as well as the 产品 Quality Research Institute (PQRI), 这些研究没有规定的方法, 这在研究设计上有一定的灵活性. 然而, the customization of these studies also allows for some pitfalls in study design, 在审查时，哪些可能导致监管结果. With decades of experience successfully designing and delivering extractables and leachables studies, as well as providing regulatory and scientific support to clients who have relied upon im体育APP to address deficiencies in E&L study design, we have observed several common missteps which can be avoided, including:

没有选材阶段

Extractables and leachables studies often are carried out in the very late stages of drug development. At this time, 包装 has either been finalized, or is very near finalization. 在这些情况下, when extractables are observed above the safety concern threshold (SCT), the result is often taking an approach to justify raising the threshold limits based upon toxicology arguments. While this particular approach may or may not succeed and be accepted by the FDA, 无论如何, would have been unnecessary if extractable screening had been carried out during early drug development, 在最终的材料选择和供应链安排之前. 通过采用一种方法来实现E&L study design that incorporates extractables screening in early drug development, drug developers can easily pivot from problematic materials that require substantial toxicology arguments to obtain regulatory approval, 哪些可以批准，哪些不可以批准.

组件组合

Some sponsors choose to perform extractables screening on a combination of components with the goal of saving both development time and costs. 例如, 一个单一的研究是在混合的瓶子上进行的, 衬垫, 帽, 和标签, rather than carrying out extractables studies on each of the individual components. Sponsors who decide to pursue this approach will encounter two problems.

首先也是最重要的, it is significantly more difficult to determine both the source and identity of extractables that are found during the extractables screen.

第二个, baseline data on the individual components will not exist if a sponsor chooses not to perform a controlled extraction study on individual components. The lack of data for individual components presents a significant problem, as the Agency expects manufacturers to manage supply chain changes by performing controlled extraction studies on individual components as new lots are procured.

反向浸出策略

The “reversed leaching study” is another time and cost-saving strategy that some sponsors rely upon. Sponsors who choose to employ this strategy avoid extractable screening, 而是直接进行模拟浸出分析. 结果是, data will then be presented in filings to the Agency that no additional peaks were observed relative to the bulk product. 这种方法是有问题的，因为没有可提取的研究, one does not know where potential leachants may appear in the chromatography, 它们很可能被药品的特征所掩盖.

More correctly, leachables method development should be carried out based upon extractable findings. The leachables method should then be validated prior to examining end-of-life or stability samples.

缺乏对加工链材料的考虑

最近, the Agency has been dedicating higher levels of attention to manufacturing components that come into contact with drug product. 最初, 重点是注射药物, 但fda已经发布了关于口服解决方案的调查结果. The current expectation is that all materials which contact the drug product during manufacturing, 虽然接触可能是短暂的, 必须评估潜在的渗滤液. 十年前, clients would have been advised that the FDA is not concerned about leachants from stainless steel, 但这已不再成立. Therefore, even stainless steel holding tanks must be evaluated for metals leaching.

过于激进的安全问题阈值计算

When industry began addressing extractables from plastic 包装, 建立安全关注阈值(SCT), below which one did not need to be concerned with the impact to public safety from the carcinogenic or non-carcinogenic effects of leachants.

从食品包装接触指南来看，SCT为1.未知分析物5ug /天, assumed to be carcinogenic and assumed to be of average carcinogenicity, would raise the cancer rate in the population by one additional case in 100,000人. Early SCTs, developed for inhaled drug products, out of an abundance of caution, were set to be 0.15 ug/day, providing a risk-based approach for controlling leachants in drug products. 多年来，安全关注的门槛有所提高, particularly regarding low leaching risk/low risk of route of administration drug products, 导致一些赞助商主张sct高达20微克/天. The FDA stated at the June 2019 Smithers Rapra Extractables and Leachables Conference in Bethesda, MD, 在任何情况下，原子能机构都不会接受高于5微克/天的sct. 因此，超过这一水平将在审查时产生调查结果.

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