青岛科创质量技术专家对《PDA技术报告第86号——药品包装完整性测试的行业挑战和当前技术》报告进行翻译整理，对技术报告内容进行倾情解读。

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密封性检测其他需要考虑的问题包括运输配送过程的密封性和商业化生产中密封性。在运输配送中需要考虑的各种物理因素对于密封性的影响，如高空运输的压力变化对于软袋和预灌封包材的密封性具有很大的挑战性。可依据ASTM和ISTA的相关法规进行运输模拟测试，确保样品在运输配送过程中的密封性。商业化生产的密封性检测可以依据风险评估的原则，制定检测方案，100%在线检测或者抽样检测。另外，密封性研究不仅仅是一个检测手段，更是一个控制策略，应对产品生命周期的各个阶段所面临的密封性风险进行评估，制定总体控制策略，使用针对性的方法，控制各个阶段的风险。

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Part

1

包装完整性评测的其他注意事项Additional Considerations for Package Integrity Profiling A robust package integrity profile for a given product-package system considers factors experienced throughout the product’slifecycle as required by USP <1207>. As such, a package integrity profile must consider anticipated or experienced stresses, including those resulting from transportation and distribution. Such stresses may include shock, vibration, compression, tempera-ture, pressure, and general package storage environment. 根据USP<1207>的要求，给定产品包装系统的稳健的包装完整性概要考虑了整个产品生命周期中所经历的因素。因此，包装完整性概况必须考虑预期或经验的压力，包括那些由运输和分销造成的。此类应力可能包括冲击、振动、压缩、温度、压力和一般包装储存环境。

Part

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运输和分销

Transportation and Distribution

A package integrity profile is unique to each product-package system, a concept that also applies to storage and distribution considerations. The types of stresses experienced in these lifecycle phases vary widely with dosage form, pack-out configuration, product require-ments, and distribution chain. Additiona-lly, the impact of any single stress factor, such as a temperature excursion, can vary with respect to product. An excursion critical to one product may be insubstantial to the quality of another. 每个产品包系统都有一个独特的包完整性概况，这一概念也适用于存储和分销考虑事项。在这些生命周期阶段经历的压力类型因剂型、包装配置、产品要求和分销链的不同而大不相同。此外，任何单一应力因素的影响（如温度偏移）可能因产品而异。对一种产品至关重要的偏差可能对另一种产品的质量没有实质性影响。 Given the potential impact to product quality and sterility, appropriate chall-enges and assessments should be made to ensure that product quality is not affected during the transportation and distribution circuit. The types of challenge conditions and subsequent assessments performed, however, reflect the properly assessed risks for the system in question. 考虑到对产品质量和无菌性的潜在影响，应进行适当的挑战和评估，以确保产品质量在运输和分销过程中不受影响。然而，挑战条件的类型和随后进行的评估反映了对相关系统进行的适当评估的风险。 As the intent of this report is to focus on package integrity, only those distribu-tion challenges impacting integrity are discussed here. Transportation and distribution challenges are not limited solely to integrity of the package, however. A fully integral package containing a proteinaceous product may experience vibration and shock that does not lead to integrity failure but, for example, may cause aggregation of protein. Thus, in addition to post-challenge CCIT, other assessments may be necessary to evaluate the impact of distribution on overall product quality. 由于本报告的目的是关注包的完整性，因此这里只讨论影响完整性的那些分销挑战。然而，运输和分销方面的挑战不仅限于包装的完整性。含有蛋白质产品的完整包装可能会经历不会导致完整性失效的振动和冲击，但可能会导致蛋白质聚集。因此，除了挑战后的CCIT外，还需要进行其他评估，以评估分销对整体产品质量的影响。

物理压力源

Physical StressorsPerhaps the most obvious challenges experienced during distribution are physical stresses such as shock, vibration, and compression. Often, these types of events result in gross leakage, for instance, a vial shattering. This type of gross defect is easily detected and generally prevents final use of the product. The formation of cracks, checks, chips, and other small defects, however, may result in leakage that negatively impacts product quality but is not readily detectable by the end user. Thus, these types of defects present a more latent and use-specific risk. Furthermore, such types of defects may result in more serious integrity concerns further along in the distribution chain, as a check may develop into a crack, or a crack may widen and permit liquid loss or microbial ingress. 也许在分销过程中遇到的最明显的挑战是物理应力，如冲击、振动和加压。通常，这些类型的事件会导致严重泄漏，例如，小瓶破碎。这种类型的严重缺陷很容易发现，通常会妨碍产品的最终使用。然而，裂缝、裂纹、缺口和其他小缺陷的形成可能会导致泄漏，从而对产品质量产生负面影响，但最终用户无法轻易检测到。因此，这些类型的缺陷呈现出更为潜在和特定的使用风险。此外，此类缺陷可能导致分销链中更严重的完整性问题，因为裂纹可能会发展为裂缝，或者裂缝可能会扩大，并允许液体损失或微生物进入。 Consequently, to evaluate and reduce risk associated with a shipment, not only the primary package, but the secondary and tertiary packaging should be considered. Numerous standards are available from such organizations as ASTM and the International Safe Transit Association (ISTA) to reliably and reproducibly subject package systems to physical stresses that replicate a variety of distribution chains, including via truck, rail, air, sea, or others. 因此，为了评估和降低与装运相关的风险，不仅应考虑初级包装，还应考虑二级和三级包装。ASTM和国际安全运输协会（ISTA）等组织提供了许多标准，以可靠且可重复地使包装系统承受物理应力，从而复制各种配送链，包括通过卡车、铁路、空运、海运或其他方式。

压力

PressureIn cases where a low-pressure environ-ment could present challenges to the package and product it contains, evaluation of the pressure differentials in a distribution chain could be critical. This is particularly relevant in cases of air shipment, where product may be stored in cargo areas with partial to nonexistent pressurization that, if left unevaluated, may result in unintended consequences. The ability of a sealed flexible container to resist creep or burst during air shipment is an example of risk that should be characterized. 在低压环境可能对包装及其所含产品构成挑战的情况下，评估分销链中的压差可能至关重要。在空运的情况下，这一点尤其重要，因为产品可能储存在部分或不存在增压的货物区域，如果不进行评估，可能会导致意外后果。在空运过程中，密封的柔性容器抵抗缓慢形变或爆裂的能力是一个应进行表征的风险示例。 Another example, one discussed with increasing frequency as the prevalence of prefilled syringes and prefilled syringe-based devices expands, is the concept of plunger movement. Although the degree to which plunger movement occurs is impacted by fill level, headspace volume, general package design, and pressure differentials experienced, how a low-pressure envir-onment may impact product sterility and quality in these types of systems must also be characterized. As a plunger moves backward, the seal, and possibly the product, may move into an unsterile area of the container. In extreme cases, the plunger may completely exit the barrel. 另一个例子是柱塞运动的概念，随着预灌封和基于预灌封器械的普及，讨论的频率越来越高。尽管柱塞移动的程度受到填充水平、顶空体积、一般包装设计和所经历的压差的影响，但还必须确定低压环境如何影响这些类型系统中的产品无菌性和质量。当柱塞向后移动时，密封件和产品可能会移动到容器的未灭菌区域。在极端情况下，柱塞可能会完全退出套筒。

测试方法

Testing ApproachesNumerous documents from internation-ally recognized organizations (e.g., ASTM, ISTA, ICH, ISO) are available for reference and provide reproducible ways of evaluating some of these stressors, including physical shock events, thermal cycling, and pressure cycling. However, the simulated distribution chain should reflect the anticipated stressors. Standards are meant to employ repro-ducible simulations but may not account for the variations and intricacies of specific distribution networks, such as iterative air shipments or a combination of different modes of transport. As with the application of many test methods and techniques, a proper assessment of the risks should inform decisions on evaluating such risks. 国际公认组织（如ASTM、ISTA、ICH、ISO）的大量文件可供参考，并提供了评估某些压力源的可重现的方法，包括物理冲击事件、热循环和压力循环。然而，模拟的分销链应反映预期的压力源。标准旨在采用可重现的模拟，但可能无法考虑特定分销网络的变化和复杂性，如反复空运或不同运输方式的组合。与许多测试方法和技术的应用一样，对风险的适当评估应为评估此类风险的决策提供信息。

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