The term "PUPSIT", which stands for the Pre-Use Post-Sterilization Integrity Test, has been included in the revised Annex 1. While the term is new, the requirement to check the integrity of a sterilizing filter after it has been sterilized and before it is used for sterile filtration is not new. This has been included in Annex 1 since 1998.
术语“PUPSIT”代表灭菌后使用前的完整性测试，已包含在修订后的附录1 中。虽然该术语是新术语，但在除菌过滤器灭菌后和用于除菌过滤之前检查其完整性的要求并不新鲜。自1998年以来，该要求就已包含在附录1 中。

The background to this requirement and the explanation of its implementation were included in the EMA's Q&A section "Guidance on good manufacturing practice and good distribution practice: Questions and answers" already in 2007. In the Annex 1 version of 2008, the requirement was listed under No. 113.
该要求的背景及其实施的解释早在2007年就被纳入了EMA的问答部分“良好生产规范和良好分销规范指南：问答”。在2008年附录1版本中，该要求被列在第113号下。

What purpose does the PUPSIT serve? PUPSIT 的用途是什么？

The PUPSIT is performed to test the integrity of a sterilization filter and associated components after the filter has been sterilized but before it is used for sterile filtration. The test is designed to identify potential masking effects. The masking effect is a phenomenon in which a defect in a sterilization filter becomes clogged during the filtration process, for example by contaminants and/or components, resulting in a successfully passed integrity test after the filter has been used. A test after sterilization and before use of the filter should make it possible to detect such defects before using the filter and eliminate this risk.
PUPSIT 用于在过滤器灭菌后但用于除菌过滤之前测试除菌过滤器及其相关组件的完整性。该测试旨在识别潜在的掩蔽效应。掩蔽效应是一种现象，即除菌过滤器中的缺陷在过滤的过程中被堵塞，例如被污染物和/或成分堵塞，导致过滤器使用后完整性测试成功通过。在灭菌后和使用过滤器前进行的测试应该能够在使用过滤器之前检测到此类缺陷并消除这种风险。

Possible methods for testing the integrity of sterile filters are listed in the revised Annex 1 as examples such as the bubble test, water intrusion test, diffusion flow and pressure hold tests.
修订后的附录1列出了测试除菌过滤器完整性的可能方法，例如气泡测试、水侵入测试、扩散流和压力保持测试。

Why are the PUPSIT requirements so controversial? 为何PUPSIT要求如此有争议？

The necessity, practicability and risk-benefit relation of PUPSIT were controversially discussed during the revision of Annex 1. Among other things, concerns were expressed by experts and industry associations that the implementation of PUPSIT would entail additional risks, such as further interventions in the aseptic area, increased complexity of the filtration system, possible failure of PUPSIT components and stress on the sterilized filter during the test procedure. The probability of microbiological contamination due to a masking effect is considered to be very low.
在修订附录1时，对 PUPSIT 的必要性、实用性和风险收益关系进行了有争议的讨论。除其他事项外，专家和行业协会表示担心，实施PUPSIT会带来额外的风险，例如在无菌区域进行进一步干预、增加过滤系统的复杂性、PUPSIT组件可能出现故障以及在测试过程中对无菌过滤器施加压力。由于掩蔽效应而导致微生物污染的可能性被认为非常低。

As a result, the risk of contamination or impairment of product quality due to PUPSIT would outweigh the risk of product contamination due to a filter defect that is concealed during use of the filter and not detected afterwards.
因此，由于PUPSIT造成的污染或产品质量受损的风险将超过由于过滤器缺陷（在使用过程中隐藏且事后未被发现）造成的产品污染风险。

Last but not least, PUPSIT is a costly and time-consuming measure, the cost-effectiveness of which is being critically scrutinized in terms of the risk-benefit relationship.
最后但同样重要的一点是，PUPSIT是一项昂贵且耗时的措施，其成本效益正在从风险-收益关系的角度受到严格审查。

For which situations/processes/products is there a real risk?  哪些情况/工艺/产品存在真正的风险？

There is currently little data available on how likely the masking effect is to occur in a specific case and which circumstances enable or favor this. Current findings indicate that the masking effect actually occurs only rarely and depends, among other things, on the extent of the filter defect and the properties of the material to be filtered:
目前，关于掩蔽效应在特定情况下发生的可能性以及哪些情况会导致或有利于掩蔽效应的数据很少。目前的研究表明，掩蔽效应实际上很少发生，并且取决于过滤器缺陷的程度和要过滤的材料的性质等因素：

• The filter defect is large enough to allow microbial contamination to pass.
  过滤器缺陷足够大，可以让微生物污染通过。
• The filter defect is small enough to remain undetected when clogging occurs.
  过滤器缺陷足够小，当发生堵塞时无法检测到。
• A sufficient material or particle load is present to allow non-detectable blockage of defects.
  存在足够的材料或颗粒负载，以允许不可检测的缺陷阻塞。
• The product has a tendency to agglomerate.
  该产品有结块的趋势。

A general assessment of the masking effect appears difficult, as products and processes and subsequent combinations thereof are generally unique.
对掩蔽效应的总体评估似乎很困难，因为产品和工艺以及随后的组合通常都是独一无二的。

The studies "Test Process and Results of Potential Masking of Sterilizing Grade Filters" and "Datamining to Determine the Influence of Fluid Properties on the Integrity Test Values" published in 2020 can provide assistance for an individual assessment. These publications are the results of the Sterile Filtration Quality Risk Management (SFQRM) consortium, which was launched by the Parenteral Drug Association (PDA) and BioPhorum Organizations Group (BioPhorum) at the end of 2017.
2020 年发表的研究“除菌级过滤器潜在掩蔽的测试过程和结果”和“数据挖掘以确定流体特性对完整性测试值的影响”可以为个人评估提供帮助。这些出版物是无菌过滤质量风险管理(SFQRM) 联盟的成果，该联盟由肠外药物协会(PDA) 和BioPhorum 组织集团(BioPhorum) 于 2017 年底发起。

Who has to implement PUPSIT? 谁必须实施PUPSIT？

Although the requirement for PUPSIT was already present in the previous version of Annex 1 – as explained above – it has been significantly modified in the revised Annex 1. While the requirement is still considered mandatory, it is acknowledged that PUPSIT is not always feasible in certain cases due to process constraints (e.g. filtration of small volume products such as radiopharmaceuticals) and in such cases an alternative approach would be permissible under certain conditions.
尽管PUPSIT的要求在附录1的先前版本中已经存在（如上所述），但在修订后的附录1中已进行了重大修改。虽然该要求仍被视为强制性的，但人们承认，由于工艺限制（例如，过滤放射性药物等小体积产品），PUPSIT 在某些情况下并不总是可行的，在这种情况下，在某些条件下可以允许采用替代方法。

This means that PUPSIT is generally required for all processes involving sterile filtration of products that cannot be sterilized in their final container. Only in cases where PUPSIT is not possible an alternative approach can be considered.
这意味着，对于所有涉及无法在最终容器中灭菌的产品的除菌过滤工艺，通常都需要使用PUPSIT。只有在无法使用PUPSIT的情况下，才可以考虑采用替代方法。