USP1207 Package Integrity Evaluation-Sterile Products-Chinese

á1207ñ PACKAGE INTEGRITY EVALUATION—STERILE PRODUCTS

包装完整性评估 - 无菌产品

1. INTRODUCTION介绍

This chapter provides guidance on the integrity assurance of nonporouspackages intended for sterile pharmaceutical products. Background instructionis provided on the topics of leaks, leakage rate, and package sealing/closuremechanisms. Explanation is given as to how packages that conform to specifiedleakage limits help to ensure the contained product meets and maintainssterility and relevant physicochemical specifications. The integration ofpackage integrity assurance as a key component of the entire product life cycleis stressed. Guidance in the selection, validation, and use of leak testmethodologies as well as package seal quality tests is included. Detailedrecommendations are presented in three subchapters listed below:

本章为用于无菌药物产品的无孔包装的完整性保证提供指导。提供了关于泄漏、泄漏率和包装密封/闭合机制的背景说明。 解释了符合规定泄漏限值的包装如何帮助确保所含产品符合并保持无菌和相关的物理化学规格。强调了包装完整性保证作为整个产品生命周期关键组件的整合。 包括选择、验证和使用泄漏测试方法以及包装密封质量测试的指导。 详细建议见下列三个子章节：

•   Package Integrity Testing in theProduct Life Cycle—Test Method Selection and Validation á1207.1ñ

产品生命周期中的包装完整性测试 - 测试方法选择和验证á1207.1ñ

•   Package Integrity Leak TestTechnologies á1207.2ñ

封装完整性泄漏测试技术á1207.2ñ

•   Package Seal Quality TestTechnologies á1207.3ñ

包装密封质量测试技术á1207.3ñ

At the end of this chapter, the Glossary section defines terms asthey are used in the context of this set of four general information chapters.

在本章的最后，术语表部分定义了在这组四个一般信息章节的上下文中使用的术语。

The term product–package refers to the container–closure system plus theproduct contents. The container–closure system consists of the primarypackaging components, those components that are or may be in intimate contactwith the product, as well as secondary packaging components vital to ensuringcorrect package assembly, for example, the aluminum cap used to seal astoppered vial package.

术语产品包装是指容器封闭系统加上产品内容。容器封闭系统包括主要包装组件，与产品紧密接触或可能与产品紧密接触的那些组件，以及对确保正确的包装组装至关重要的二次包装组件，例如用于密封塞子的铝盖小瓶包装。

Suitable container–closure systems adequately store and protect thecontained pharmaceutical product. Thus, sterile product–package integrity isthe ability of a sterile product container–closure system to keep productcontents in, while keeping detrimental environmental contaminants out.Specifically, leaks of concern for sterile product–packages include thefollowing three categories described in Table 1. In other words, theleaks of concern for a given product–package are a function of the degree ofpackage protection demanded by the product to ensure that all relevant productphysicochemical and microbiological quality attributes are met through productexpiry and use.

合适的容器封闭系统充分地储存和保护所容纳的药物产品。因此，无菌产品包装的完整性是无菌产品容器 - 封闭系统保持产品内容物的能力，同时保持有害的环境污染物。 具体而言，无菌产品包装的泄漏问题包括表1中所述的以下三类。换句话说，对于给定产品包装的关注泄漏是产品要求的包装保护程度的函数，以确保 所有相关产品的物理化学和微生物质量属性都通过产品到期和使用来满足。

Table 1. Product Quality Risks Posed by Leaks of Concern

产品质量风险由关注的泄漏引起

Package integrity is synonymouswith container–closure integrity; these terms are used interchangeably throughout this chapter. In the past, to say a sterileproduct–package has container–closure integrity commonly meant that the packageeither had passed or was capable of passing a microbiological challenge test.This guidance chapter defines the concept of container–closure integrity morebroadly, encompassing the absence of all package leaks that risk productquality. By this definition, a package is considered to have integrity if itallows no leakage greater than the product–package maximum allowable leakagelimit. In other words, the largest and smallest leaks of concern are absent.

包装完整性与容器封闭完整性同义; 这一术语在本章中可互换使用。过去，无菌产品包装具有容器 - 封闭完整性通常意味着包装已通过或能够通过微生物挑战测试。本指导章节更广泛地定义了包含密封完整性的概念，包括没有任何可能影响产品质量的包装泄漏。根据这个定义，如果包装不允许泄漏大于产品包装最大允许泄漏限制，则认为包装具有完整性。换句话说，没有关注的最大和最小泄漏。

Leakage differs from permeation. Leakage is the unintentional entry orescape of matter (solids, liquids, or gases) through a breach in a package wallor through a gap between package components. Leakage can also refer to theleaking matter itself. Leakage flow rate is a function of the absolute and/orpartial pressure gradient of leaking matter that exists across the packagebarrier. In the context of this chapter, permeation is the passage of fluid(e.g., gas) into, through, and out of a nonporous package wall. Permeation, notleakage, occurs when only a small fraction of molecules is able to move througha barrier by way of any one hole. A nonporous package is able to permitpermeation, but not the volumetric flow of air. Package permeation testmethodologies fall outside of the chapter scope and are not described.

泄漏与渗透不同。泄漏是物质（固体，液体或气体）通过包装壁中的破口或包装组件之间的间隙无意进入或逃逸。泄漏也可以指泄漏物质本身。泄漏流速是跨越封装屏障存在的泄漏物质的绝对和/或分压梯度的函数。在本章的上下文中，渗透是流体（例如，气体）进入、通过和流出无孔包装壁的通道。当只有一小部分分子能够通过任何一个孔移动通过屏障时，就会发生渗透，而不是渗漏。无孔包装能够允许渗透，但不允许空气的体积流动。包装渗透测试方法不属于章节范围，因此不予描述。

Package integrity tests are leak test methods. A leak test is a methodthat detects the presence of (and in some cases, the magnitude or location of)a package breach or gap.

包装完整性测试是泄漏测试方法。泄漏测试是一种检测包装破裂或间隙的存在（以及在某些情况下，大小或位置）的方法。

Package seal quality tests are techniques used to characterize andmonitor the quality and consistency of a package seal or closure system parameter,which can influence the package’s ability to maintain integrity. An example isthe peel force test widely used to test seal strength. Seal quality tests arenot leak tests but can play a valuable role by monitoring a characteristic ofthe seal itself, the package materials, the package components, and/or theprocesses required to create the seal or closure mechanism.

包装密封质量测试是用于表征和监控包装密封或封闭系统参数的质量和一致性的技术，这可能影响包装保持完整性的能力。一个例子是广泛用于测试密封强度的剥离力测试。密封质量测试不是泄漏测试，但可以通过监测密封本身的特性，包装材料，包装组件和/或形成密封或闭合机构所需的过程来发挥有价值的作用。

Integrity test methods vary not only in their application and detectionlimit, but also in terms of detection range, precision, and specificity, forexample. No one test is appropriate for all packages or for all leak testingapplications. Selection criteria for package integrity test methods, as well asmethod comparison aids, are presented to guide the user in the selectionprocess.

完整性测试方法不仅在其应用和检测极限方面不同，而且在检测范围，精确度和特异性方面也不同。没有一种测试适用于所有包装或所有泄漏测试应用。提供包装完整性测试方法的选择标准以及方法比较辅助，以指导用户进行选择过程。

Leak tests, even many commonly recognizedindustry standard testing approaches, require optimization and validation foreach product–package application. A science- and risk-based approach may allowsome tests to be leveraged for broader ap-plication under certain circumstances.For example, small differences in product formulation or package design andmaterials may permit the use of one test for multiple product–packages. Packageintegrity verification plays an important role through-out the product lifecycle, starting with product development and continuing through marketedproduct stability studies.

泄漏测试，甚至许多公认的行业标准测试方法，都需要针对每个产品包应用进行优化和验证。基于科学和风险的方法可以允许在某些情况下利用一些测试来实现更广泛的应用。例如，产品配方或包装设计和材料的微小差异可允许对多个产品包装使用一个测试。包装完整性验证在整个产品生命周期中起着重要作用，从产品开发开始，并继续通过市场上的产品稳定性研究。

2. SCOPE范围

The package integrity leak tests and seal quality tests outlined in thischapter apply to the testing of both large and small volume container–closuresystems for sterile pharmaceutical dosage forms. Such package systems include,but are not limited to, the following examples.

本章概述的包装完整性泄漏测试和密封质量测试适用于无菌药物剂型的大容量和小容量容器封闭系统的测试。这种包装系统包括但不限于以下实施例。

• Vials or bottlesclosed with elastomeric closures or screw-thread caps

小瓶或瓶子用弹性封闭物或螺纹盖封闭

• Form-fill-sealplastic or glass ampules成型 - 填充 - 密封塑料或玻璃安瓿

• Syringes orcartridges注射器或药盒

• Flexible bags orpouches柔性袋子

• Packages for somedrug/device combination products (e.g., packages cased inside autoinjectors)

        某些药物/设备组合产品的包装（例如，自动注射器内的包装）

Outside the chapter scope are packaging systems and processing equipmentused in the preparation, storage, and manufacture of sterile pharmaceuticalproducts. Examples include containers for active pharmaceutical ingredients andcontainers for product intermediate or final bulk product.

本章范围之外是用于制备、储存和制造无菌药品的包装系统和加工设备。实例包括用于活性药物成分的容器和用于产品中间体或最终散装产品的容器。

Outside the chapter scope are packages used for sterile diagnosticproducts or medical devices, and some packages used for sterile drug/devicecombination products.

本章范围之外是用于无菌诊断产品或医疗设备的包装，以及用于无菌药物/设备组合产品的一些包装。

Outside the chapter scope are products having a primary package composedof porous barrier package materials, i.e., materials designed with pores oropenings to allow volumetric air flow while preventing airborne microbialcontamination.

在章节范围之外的是具有由多孔阻隔包装材料组成的初级包装的产品，即设计有孔或开口以允许体积空气流动同时防止空气传播的微生物污染的材料。

3. LEAKS AND LEAKAGE RATE泄漏和泄漏率

Leaks are commonly conceptualized as holes of a defined diameter, orchannels of distinctive diameter and length, although leaks that occurnaturally are generally complex, multicavity tortuous paths and are rarelyuniform in size or shape. Even artificially created leaks such as laser-drilleddefects (also called holes) used for leak-test method development andvalidation are irregular in size, shape, and depth. When stating the size of aleak, it is important to define the measurement approach. In some cases leaksare measured dimensionally, but quite often, leak size is determined based ongaseous leakage rate. For ex-ample, a package wall laser-drilled defect havinga nominal diameter of 5 ± 2 mm may have been size-certified by matching the airflow rate through thedrilled defect to that of a 5 ± 2 mm hole present in a thin metal plate referencestandard when pressurized with dry air at specified differential pressure andtemperature conditions.

泄漏通常被概念化为具有限定直径的孔，或具有独特直径和长度的通道，尽管自然发生的泄漏通常是复杂的多腔曲折路径并且在尺寸或形状上很少是均匀的。即使是人工创造的泄漏，例如用于泄漏测试方法开发和验证的激光钻孔缺陷（也称为孔），其尺寸、形状和深度都是不规则的。在说明泄漏的大小时，定义测量方法很重要。在某些情况下，泄漏是在尺寸上测量的，但通常，泄漏尺寸是基于气体泄漏率确定的。例如，标称直径为5±2μm的封装壁激光钻孔缺陷可以通过钻孔缺陷的气流速率与存在的5±2μm孔的气流速率相匹配来进行尺寸认证。在规定的压差和温度条件下用干燥空气加压时的薄金属板参考标准。

Gaseous leakage rate is a measure of the rate of gas flow (in mass orvolume units) that passes through a leak path under specific conditions oftemperature and the concentration or pressure differential across the barrierwall. Therefore, gaseous leakage rate has dimensions of pressure multiplied byvolume, divided by time. The international standard SI nomenclature is pascalcubic meter per second (Pa · m3 · s−1). These leakage measurement units referto the quantity of leaking gas (Pa · m3) per unit of time. When a leakage rateis described and no test conditions are noted, standard conditions of onestandard atmosphere differential pressure with dry air at 25° are assumed. Fora more complete discussion of gaseous leakage rates and units of measure referto reference 1.

气体泄漏率是在特定温度条件下穿过泄漏路径的气体流速（以质量或体积单位计）的量度，以及穿过阻挡壁的浓度或压差。因此，气体泄漏率具有压力乘以体积的尺寸除以时间。国际标准SI命名法是每秒帕斯卡立方米（Pa·m³/s）。这些泄漏测量单位是指每单位时间泄漏气体的量（Pa·m³）。当描述泄漏率并且没有注意到测试条件时，假设一个标准大气压差与25°干燥空气的标准条件。有关气体泄漏率和测量单位的更完整讨论，请参阅参考文献1。

Unintentional leaks in packages are often detected or sized using gas asa tracer element. Given a situation in which a tracer gas partial pressuredifference exists across the package barrier wall and no absolute pressuredifference exists, gaseous leakage is predominantly diffusional in nature asthe tracer gas moves from a region of higher concentration to a region of lowerconcentration. For example, the headspace in a vial package low in oxygenconcentration and at ambient pressure at time of closure will exhibit a rise inheadspace oxygen concentration over time as a function of diffusion rate(relative to package leak size) plus permeation rate (relative to permeabilitythrough the package). Such a change can be monitored instrumentally, as isdiscussed later in the chapter.

通常使用气体作为示踪元件来检测或确定包装中的无意泄漏。鉴于在整个封装隔离壁上存在示踪气体分压差并且不存在绝对压力差的情况，当示踪气体从较高浓度区域移动到较低浓度区域时，气体泄漏本质上主要是扩散的。例如，在氧气浓度低的环境包装中的顶部空间和在确定时的环境压力下，顶空氧气浓度随着时间的推移会随着扩散速率（相对于包装泄漏尺寸）加上渗透速率而增加（相对于通过包装的渗透性）。可以通过仪器监控这种变化，如本章后面所述。

Given the situation in which an absolute pressuredifference exists across the package barrier wall, gas leakage through pack-agegaps is more rapid (flux being primarily convective) as gas moves from thehigher pressure region to one of lower pressure. For most package materials,the permeation rate of the gas of concern through the package wall isinsignificant in comparison. In this example, the rate of leakage into thepackage is determined by monitoring the change in headspace absolute pressureas a function of time.

考虑到包装隔离壁上存在绝对压力差的情况，当气体从较高压力区域移动到较低压力区域时，通过包装间隙的气体泄漏更快（通量主要是对流）。对于大多数包装材料，通过包装壁的有关气体的渗透速率在比较中是微不足道的。在该示例中，通过监测作为时间的函数的顶空绝对压力的变化来确定泄漏到包装中的速率。

For many instrumental leak test methods described in this chapter, gasflow into or out of package leaks is induced by exerting a pressure gradientacross the package. In this way, a wide range of leak types and sizes can beidentified.

对于本章中描述的许多仪器泄漏测试方法，通过在包装上施加压力梯度来诱导流入或流出包装泄漏的气流。通过这种方式，可以识别各种泄漏类型和尺寸。

Liquid leakage rate is a measure of the volume of liquid that movesthrough a leak path as a function of time under specified conditions oftemperature and absolute differential pressure across the barrier wall. Liquidmovement through a leak path occurs only when leak size/shape, packagematerials of construction, the absence of leak obstruction, tracer liquidcomposition, and test parameters all work together. All sterileproduct–packages within the chapter scope are intended to prevent liquidleakage and block microbial entry, thus it is the absence of liquid leakageflow or the absence of liquid in the leak path, rather than the rate at whichliquid leakage occurs that is typically verified in relevant package leaktests. Liquid leakage rate measurements are only useful in measuring largersize leaks.

液体泄漏率是在特定的温度条件和穿过隔离壁的绝对压差下作为时间函数移动通过泄漏路径的液体体积的量度。只有当泄漏尺寸/形状、包装材料结构、没有泄漏障碍物、示踪剂液体成分和测试参数一起工作时，才会发生通过泄漏路径的液体运动。本章范围内的所有无菌产品包装都是为了防止液体泄漏和阻止微生物进入，因此没有液体泄漏流或泄漏路径中没有液体，而不是液体泄漏发生的速率。通常在相关的包装泄漏测试中验证。液体泄漏率测量仅适用于测量较大尺寸的泄漏。

4. CLOSURE TYPE AND MECHANICS闭合类型和结构

An understandingof closure mechanics makes it possible to better characterize, monitor, andtest packages for integrity.

对闭包机制的理解使得可以更好地表征，监视和测试包装的完整性。

This section discusses various closure systems and how each typefunctions to ensure package integrity.

本节讨论各种闭包系统以及每种类型如何起作用以确保包装完整性。

4.1 Physically Mated Closures物理配合闭合

Closure can be achieved by the close physical mating of two surfacesthat often are dissimilar in material composition. Examples include theinterference fit of a plunger inserted in a syringe barrel, the compression fitof an elastomeric closure cap-ped onto a vial finish surface, and theapplication force of a screw-cap torqued onto a bottle. Physically matedsurfaces are not bonded together; therefore, a tiny gap exists even betweenwell-closed components. Nevertheless, when properly designed and assembled,closure systems fit together such that liquid leakage (and microbial ingress)is prevented and gas migration is limited. Regarding screw-thread closures suchas those used for ophthalmic-product dropper bottles, the barrier to leakage isafforded by inner cap surfaces pressing against the package opening, in somecases aided by a secondary gasket or plug. The winding path afforded by thethreads of a screw-cap does not provide an optimal barrier to gas or liquid leakage,or to micro-bial ingress in the event of liquid presence in the cap threads.

闭合可以通过两个表面的紧密物理配合来实现，这两个表面通常在材料成分上不同。实例包括插入注射器筒中的柱塞的过盈配合，弹性体封闭帽的压缩配合到瓶子精加工表面上，以及拧紧到瓶子上的螺旋盖的施加力。物理匹配的表面不粘合在一起; 因此，即使在封闭良好的部件之间也存在微小的差距。然而，当正确设计和组装时，封闭系统配合在一起，从而防止液体泄漏（和微生物进入）并且气体迁移受到限制。关于螺纹封闭件，例如用于眼用产品滴管瓶的那些，通过压在封装开口上的内盖表面提供泄漏屏障，在某些情况下由辅助垫圈或插头辅助。由螺旋盖的螺纹提供的缠绕路径不会对气体或液体泄漏提供最佳屏障，或者在帽螺纹中存在液体的情况下提供微型进入。

4.2 Physicochemically Bonded Closures 物理化学成键关闭

Seals are formed when two similar or dissimilar surfaces arephysicochemically bonded together. One example is the formation and sealing ofcontiguous containers from a single material (e.g., glass or plastic ampules).In other form, fill, and seal systems, sheets of material are mated by means ofa heat or ultrasonic welding process. Two dissimilar materials may be joinedusing an intermediate bonding material. Fully fused seals inherently blockliquid leakage and microbial ingress; however, gaseous leakage and permeationmay occur.

当两个相似或不相似的表面物理化学键合在一起时形成密封。一个例子是由单一材料（例如，玻璃或塑料安瓿）形成和密封连续容器。在其他形式，填充和密封系统中，材料片通过热或超声波焊接工艺配合。可以使用中间粘合材料连接两种不同的材料。完全熔断的密封件固有地阻止液体泄漏和微生物进入; 但是，可能会发生气体泄漏和渗透。

4.3 Multiple-DosePackage Closures多剂量包装闭合

Multiple-dose package closures are designed to allow product accesswhile limiting microbial ingress and product leakage between doses. Forexample, elastomeric closures for parenteral products requiring needle-punctureaccess are designed to offer reseal protection against microbial ingress andproduct leakage. Some multiple-dose ophthalmic dosage form package closures aredesigned with filters, plugs, or other mechanical means that allow the productto be dispensed while restricting microbial ingress and product leakage. Forexample, ophthalmic product–package closure systems have been designed toautomatically pinch shut between intermittent dosing to limit microbial entryand product loss.

多剂量包装封口设计用于允许产品进入，同时限制剂量之间的微生物进入和产品泄漏。 例如，用于需要针刺穿通的注射用药物产品的弹性封闭物被设计成提供防止微生物侵入和产品泄漏的再密封保护。一些多剂量眼科剂型包装封口设计有过滤器，塞子或其他机械装置，其允许分配产品同时限制微生物进入和产品泄漏。 例如，眼科产品 - 包装封闭系统已设计成在间歇给药之间自动夹闭，以限制微生物进入和产品损失。

5. PRODUCT–PACKAGE QUALITY REQUIREMENTS AND THE MAXIMUM ALLOWABLE LEAKAGELIMIT

产品包装质量要求和最大允许泄漏限制

As noted in Introduction, package integrity is necessary tomaintain product critical quality attributes within physicochemical label-claimspecifications and to ensure product sterility until time of use. Detrimentalcontaminants include microorganisms and any substances that threaten patientsafety or product quality. Product leakage can cause a product to fail contentor potency specification limits. For certain products to maintain productphysicochemical stability, the package needs to maintain a headspace ofnonreactive gases and/or low water vapor content, sealed under atmospheric orreduced-pressure conditions. Headspace vacuum conditions may also be necessaryto facilitate product ease of use, e.g., product reconstitution using a diluentinjected into the container.

如引言中所述，包装完整性对于在物理化学标签声明规范中保持产品关键质量属性以及确保产品无菌直至使用时是必要的。有害污染物包括微生物和任何威胁患者安全或产品质量的物质。 产品泄漏可能导致产品内容或效力规格限制失败。 对于某些保持产品物理化学稳定性的产品，包装需要保持非反应性气体和/或低水蒸气含量的顶部空间，在大气压或减压条件下密封。 顶部真空条件也可能是必要的，以便于产品易于使用，例如使用注入容器中的稀释剂进行产品重构。

Most package types display very low but definite gaseous leakage flow throughthe gap that exists even between well-fitted closures. Therefore, it is notpractical to require that packages be absolutely leak-free. Rather, it is thesignificance of leakage in relation to product quality that needs to beconsidered. In other words, the package should not permit leakage beyond theproduct’s maximum allowable leakage limit. Such leaks of concern should beabsent.

大多数包装类型显示非常低但通过间隙存在明确的气体泄漏流量，即使在装配良好的封闭装置之间也存在。因此，要求包装绝对无泄漏是不实际的。相反，需要考虑的是与产品质量相关的泄漏的重要性。换句话说，包装不应允许泄漏超出产品的最大允许泄漏限制。应该没有这种关注的泄漏。

Identifying the maximum allowable leakage limit for a product–package isa science- and risk-based decision. The smaller the leak path, the less likelythe product can escape and the less likely microorganisms or other contaminantscan enter. Eventually, leak paths may be so small that only headspace gasexchange is realistically possible. Package construction and assembly, packagecontents, and the range of environments a given product–package may be exposedto during its life cycle are to be considered when specifying the maximumallowable leakage limit.

确定产品包装的最大允许泄漏限制是基于科学和风险的决策。泄漏路径越小，产品逃逸的可能性越小，微生物或其他污染物进入的可能性越小。最终，泄漏路径可能非常小，以至于只能进行顶空气体交换。在指定最大允许泄漏限制时，应考虑包装结构和组装，包装内容以及给定产品包装在其生命周期中可能暴露的环境范围。

There are two major product–package qualityrequirement categories used when specifying the maximum allowable leakage limitand one subcategory that applies only to multiple-dose packages. These arediscussed below.

在指定最大允许泄漏限制时使用两种主要的产品包质量要求类别，并且一个子类别仅适用于多剂量包装。这些将在下面讨论。

5.1 Sterility and ProductFormulation Content must be Preserved; Gas Headspace Content Preservation isnot Required

必须保存无菌和产品配方内容; 不需要气体顶空内容保存

This category includes product–packages for which the maximum allowableleakage limit correlates to the prevention of product formulation escape, orproduct contamination by external liquid or solid matter or by microorganisms,while gas headspace preservation (i.e., ambient pressure air) is of no concern.The smallest leak paths that allow only limited gas ex-change are irrelevant asthey pose no real risk to product quality.

此类别包括产品包装，其最大允许泄漏限制与防止产品配方逃逸或外部液体或固体物质或微生物对产品的污染相关，而气体顶空保存（即环境压力空气）则无关紧要。只允许有限气体交换的最小泄漏路径是无关紧要的，因为它们不会对产品质量构成真正的风险。

Considerable published research exists exploring rigid package leaks andtheir relationship to risk of aqueous solution leak-age and/or microbialingress. A key study series found orifice leaks of approximately 0.1 mm innominal diameter (using micro-pipettes) placed in rigid packages demonstrate asmall risk of aqueous liquid passage, while orifice leaks as small asapproximately 0.3 mm in nominal diameter first demonstrate some risk of microbial ingressby liquid challenge (2,3). For a summary of similar studies comparingrisks of microbial ingress and liquid leakage to leak size and type, the readermay refer to reference 4.

大量已发表的研究存在探索刚性包装泄漏及其与水溶液泄漏和/或微生物进入风险的关系。一项重要的研究系列发现，在刚性包装中，公称直径约为0.1μm的孔口泄漏（使用微型移液管）表明水性液体通过的风险很小，而孔口泄漏的公称直径小至约0.3μm，首先证明了一些液体攻击导致微生物进入的风险（2,3）。对于比较微生物进入和液体泄漏风险与泄漏尺寸和类型的类似研究的摘要，读者可参考参考文献4。

Given this body of evidence, a maximum allowable leakage limit of lessthan 6 × 10⁻⁶ mbar · L/s (measured by helium massspectrometry in the vacuum mode) can be adopted for products in this categorypackaged in rigid container–closure systems. This leakage rate equates to thepresence of an orifice of nominal diameter of between 0.1 and 0.3 mm. At thisleakage rate, the probability of microbial ingress was determined to be<0.10 (2). Selecting this conservative maximum allowable leakagelimit will ensure a low risk of microbial ingress and liquid leakage and caneliminate the need to perform additional microbial ingress or liquid challengestudies as a function of leak size.

鉴于这一证据，此类产品采用刚性容器封闭系统，可采用小于6×10^-6mbar·L /s的最大允许泄漏限值（在真空模式下通过氦质谱测量）。这种泄漏率相当于公称直径在0.1和0.3μm之间的孔的存在。在该泄漏速率下，微生物进入的概率被确定为<0.10（2）。选择这种保守的最大允许泄漏限制将确保微生物进入和液体泄漏的低风险，并且可以消除作为泄漏尺寸的函数执行额外的微生物进入或液体挑战研究的需要。

For other container systems such as those made using flexible materialsor those with complex, lengthy closure/seal interfaces, or those meant tocontain a product of markedly greater leakage potential, the risk of microbialingress or liquid passage through leak paths is not as widely publicized orperhaps understood. In such cases, where the relationship between defectsize/type to the risks of microbial ingress and/or liquid passage is lessprescriptive, a study exploring these relationships could be useful. Testresults can be used to establish a meaningful maximum allowable leakage limitfor the given product–package system, which can be employed for packageintegrity verification by other validated leak test methods of choice. Onceestablished, this maximum allowable leakage limit can be applied to similarproduct–packages with appropriate justification.

对于其他容器系统，例如使用柔性材料制造的容器系统或具有复杂，冗长的封闭/密封界面的容器系统，或者意味着包含具有显着更大泄漏潜力的产品的容器系统，微生物进入或液体通过泄漏路径的风险并不广泛公开或可能理解。在这种情况下，如果缺陷大小/类型与微生物进入和/或液体通过的风险之间的关系不那么规范，那么探索这些关系的研究可能是有用的。测试结果可用于为给定的产品 - 包装系统建立有意义的最大允许泄漏限制，该限制可用于通过其他经验证的选择的泄漏测试方法进行包装完整性验证。一旦建立，这个最大允许泄漏限制可以适用于类似的产品包，并有适当的理由。

Finally, before classifying a product–package in this category, one mayconsider the potential impact of product life cycle processing, storage,distribution and use scenarios on package integrity. For example, elastomericclosures have been found to shrink and lose their viscoelastic propertiesduring ultra-cold storage (<80°) to such an extent that gas influx intostoppered vial packages may occur. During warming, package closure is restored,trapping gases and notably raising internal package pressure. In such cases,gas headspace preservation may be a product quality concern, even if theproduct does not require specific headspace content or pressure for optimumstability.

最后，在对此类别的产品包进行分类之前，可以考虑产品生命周期处理，存储，分发和使用方案对包装完整性的潜在影响。例如，已发现弹性体封闭物在超冷存储（<80°）期间收缩并失去其粘弹性，使得可能发生气体流入带塞的小瓶包装中。在加热过程中，包装关闭恢复，捕获气体并显着提高内部包装压力。在这种情况下，即使产品不需要特定的顶空含量或压力以获得最佳稳定性，气体顶空保存也可能是产品质量问题。

5.2 Sterility, Product Formulation Content, and Gas Headspace Contentmust be Preserved

必须保留无菌、产品配方含量和气体顶空含量

The second category includes product–packages for which the packageshould prevent product formulation escape and product contamination by externalliquid or solid matter or by microorganisms, but in addition, the package mustpreserve the gas headspace content or absolute pressure. Preservation ofheadspace content and/or pressure is needed to maintain product stabilitywithin physicochemical specification limits, and/or to aid end-user productaccess. Thus, the maximum allow-able leakage limit for such products is likelymore stringent than that described in the first category. Although outside thechapter scope, the influence of gas permeation through the package itself mayalso need to be considered when establishing the maximum allowable leakagelimit as permeation plus leakage can impact package headspace content.

第二类包括产品包装，其包装应防止产品配方逃逸和产品被外部液体或固体物质或微生物污染，但此外，包装必须保持气体顶空含量或绝对压力。需要保持顶空含量和/或压力以保持产品在物理化学规格限制内的稳定性，和/或帮助最终用户产品进入。因此，这种产品的最大允许泄漏限制可能比第一类中描述的更严格。虽然在章节范围之外，但在确定最大允许泄漏限值时，也可能需要考虑气体渗透通过包装本身的影响，因为渗透加泄漏会影响包装顶空含量。

The maximum allowable leakage limit for products in this category may beexpressed in terms of the maximum allowable package headspace content orpressure change as a function of time. This limit, established for eachproduct–package system, may be applied to other similar product–packagessystems with appropriate justification.

此类产品的最大允许泄漏限值可以用最大允许包装顶空含量或作为时间函数的压力变化表示。为每个产品包装系统建立的此限制可以适用于具有适当理由的其他类似产品包装系统。

5.3 Sterility must bePreserved; Product Access is Required

必须保留无菌; 产品访问是必需的

This subcategory represents a quality requirement applicable only tomultiple-dose product–packages included in either of the above two categories.Once the product–package has reached the end-user and the closure has beenactivated or other-wise compromised to allow dosage access and delivery, themaximum allowable leakage limit at this life cycle phase (called the in-usemaximum allowable leakage limit) is defined in terms of microbial ingress andproduct loss prevention between and during dosage access. For example,elastomeric closures of multiple-dose vials or cartridges containingantimicrobial-preserved parenteral products are designed to afford resealprotection against microbial ingress and product formulation leakage as productis accessed via needle puncture as well as between doses.

该子类别表示仅适用于上述两类中包括的多剂量产品包的质量要求。一旦产品包装到达最终用户并且关闭已被激活或其他方式受损以允许剂量访问和交付，在该生命周期阶段的最大允许泄漏限制（称为使用中的最大允许泄漏限制）根据微生物进入和剂量访问期间和间隔内的产品损失预防来定义。例如，多剂量小瓶或含有抗微生物保存的注射用药物产品的药筒的弹性封闭物被设计成提供重新密封保护以防止微生物进入和产品制剂泄漏，因为通过针刺穿以及剂量之间获得产品。

To establish thein-use maximum allowable leakage limit for multiple-dose package closuresystems, a study will likely be required to explore the relationship betweenproduct access attempts, product loss risk and/or microbial ingress risk,versus leakage measurement by an alternative adequately sensitive leak testmethod of choice. These data can be used to establish a meaningful in-usemaximum allowable leakage limit expressed in units of measure reflective of thepreferred leak test method and that will assure that product loss and microbialingress risk during use is minimal. The in-use maximum allowable leakage limitestablished for a given product–package may be applied to other similarproduct–packages systems with appropriate justification.

为了确定多剂量包装封闭系统的使用中最大允许泄漏限值，可能需要进行一项研究，以探索产品获取尝试、产品损失风险和/或微生物进入风险与选择适当敏感的泄漏测试方法的替代泄漏测量之间的关系。这些数据可用于建立有意义的使用中最大允许泄漏限值，以反映优选泄漏测试方法的测量单位表示，并确保产品损失和微生物进入风险最小化。对于给定的产品包装，在使用中确定的最大允许泄漏极限可以应用于其他类似的产品包装系统，并有适当的理由。

6.     INHERENT PACKAGEINTEGRITY AND THE PACKAGE INTEGRITY PROFILE

固有的包装完整性和包装完整性简介

Inherent package integrity is the leakage characteristic of awell-assembled container–closure system using no-defect package components.Inherent package integrity is first determined during product–packagedevelopment and qualification and is a measure of the leak tightness of acontainer–closure system, given anticipated variables of material composition,dimension, processing, and assembly. Inherent package integrity may also bedetermined as a function of anticipated final product storage, distribution,and use. Acceptable inherent package integrity for a container–closure systemconforms to the specific product–package maximum allowable leakage limit.Inherent package integrity is expressed in terms that allow a meaningfulcomparison to the maximum allowable leakage limit.

固有的封装完整性是使用无缺陷封装元件的组装良好的容器封闭系统的泄漏特性。固有的包装完整性首先在产品包装开发和鉴定过程中确定，并且考虑到材料成分，尺寸，加工和装配的预期变量，是容器 - 封闭系统的密封性的量度。固有的包装完整性也可以根据预期的最终产品存储，分配和使用来确定。容器封闭系统可接受的固有包装完整性符合特定产品包装最大允许泄漏限制。固有封装完整性表示为允许与最大允许泄漏限制进行有意义的比较。

Confirmation that the inherent package integrity conforms to the maximumallowable leakage limit is the first step in product–package integrityverification. Verification of package integrity continues throughout theproduct life cycle. The package integrity profile is an ongoing database ofproduct life cycle package leak and seal quality test results. This profileprovides information regarding package integrity given operative variations inpackage component design and material; package assembly and processing; and productstorage, distribution, and stability. These concepts are more fully explored inPackage Integrity Testing in the Product Life Cycle—Test Method Selectionand Validation á1207.1ñ, Test Instrument Qualification, Method Development, and Method Validation.

确认固有封装完整性符合最大允许泄漏限制是产品封装完整性验证的第一步。包装完整性的验证在整个产品生命周期中持续进行。 包装完整性配置文件是产品生命周期包装泄漏和密封质量测试结果的持续数据库。 鉴于封装元件设计和材料的操作变化，该外形提供了有关封装完整性的信息; 包装组装和加工; 和产品的存储，分配和稳定性。 在产品生命周期 - 测试方法选择和验证(1207.1)，测试仪器认证、方法开发和方法验证中的包装完整性测试中更全面地探索了这些概念。

In summary, a product–package system havingintegrity is one in which the inherent package integrity conforms to therequired product–package maximum allowable leakage limit. Further, the packageintegrity profile database operates as a risk management tool to ensure thatfinished product container–closure systems are intact, able to block microbialingress, restrict loss of product contents including critical headspace gases,and prevent entry of detrimental gases or other substances, thus ensuring thatthe product meets all relevant physicochemical and microbiological label-claimspecifications through expiry and final end-use.

总之，具有完整性的产品包装系统是固有包装完整性符合所需产品包装最大允许泄漏限制的系统。此外，包装完整性概况数据库作为风险管理工具运行，以确保成品容器封闭系统完好无损，能够阻止微生物进入，限制产品内容物（包括关键顶空气体）的损失，并防止有害气体或其他物质进入，从而确保产品通过到期和最终用途满足所有相关的物理化学和微生物标签声明规范。

REFERENCES

1.Jackson CN, Sherlock CN, Moore PO, editors. In: Nondestructive testinghandbook. 3rd ed. Vol. 1. Leak testing. Columbus, OH: The American Society forNondestructive Testing; 1997.

2.Kirsch LE, Nguyen L, Moeckly CS, Gerth R. Pharmaceuticalcontainer/closure integrity. II: The relationship between microbial ingress andhelium leak rates in rubber-stoppered glass vials. PDA J Pharm Sci Technol.1997;51(5):195–202.

3.Kirsch LE. Pharmaceutical container/closure integrity. VI: A report onthe utility of the liquid tracer methods for evaluating the microbial barrierproperties of pharmaceutical packaging. PDA J Pharm Sci Technol.2000;54(4):305–314.

4.Guazzo DM, Singer DC, Stevens-Riley M, Walker D, Kirsch LE, Buus P, etal. Proposed revisions to general chapter sterile product packaging—integrityevaluation á1207ñ. Stimuli to the revision process. Pharmacopeial Forum.2014;40(5).

GLOSSARY术语

For definitions of container, materials of construction, packagingcomponent, packaging system, primary packaging component, and secondarypackaging component, see Packaging and Storage Requirements á659ñ. In thecontext of this chapter and its subchapters, the following definitions relevantto packaging and package integrity methods, seal and closure mechanisms apply.For definitions of specific leak test and seal quality test methods, refer to á1207.2ñ and á1207.3ñ,respectively.

有关容器，结构材料，包装组件，包装系统，主要包装组件和二次包装组件的定义，请参阅包装和储存要求á659ñ.在本章及其子章节的上下文中，以下与包装和包装完整性方法，密封和封闭机制相关的定义适用。有关具体泄漏测试和密封质量测试方法的定义，请分别参阅á1207.2ñ和á1207.3ñ.

Accuracy: The accuracy of aleak test method is a measure of the ability of the method to correctlydifferentiate packagesthat leak above the claimed detection limit fromthose that leak below this limit (do not leak); a measure of false positive andnegative occurrence. Alternatively, for those methods that deliver an outcomethat is a direct quantitative measure of gas leakage rate (or of gas content orpressure), accuracy is a measure of the method’s ability to produce an outcomecomparable to a true standard, such as a nationally recognized gas standard.

准确度：泄漏测试方法的准确性衡量方法是否能够正确区分泄漏超过要求检测限的包装与泄漏低于此限值的包装（不泄漏）; 衡量假阳性和阴性的情况。或者，对于那些提供气体泄漏率（或气体含量或压力）的直接定量测量结果的方法，准确度是衡量该方法产生与真实标准相当的结果的能力的指标，例如全国性公认的天然气标准

Container–closureintegrity: Container–closure integrityis the ability of a package to prevent product loss, to block microorganismingress, and to limit entry of detrimental gases or other substances, thusensuring that the product meets all necessary safety and quality standards.Synonymous with Package integrity.

容器密封完整性：容器密封完整性是指包装能够防止产品损失，阻止微生物进入，以及限制有害气体或其他物质的进入，从而确保产品符合所有必要的安全和质量标准。与包完整性同义。

Container–closureintegrity test: A container–closure integritytest is any package leak test (either physicochemical ormicrobiological)that detects the presence of a package breach or gap. Some tests may also beable to identify the leak magnitude and/or location. The term container–closureintegrity test is synonymous with package leak test or package integrity test.

容器密封完整性测试：容器密封完整性测试是检测包装破口或间隙存在的任何包装泄漏测试（物理化学或微生物学）。一些测试还可以识别泄漏量和/或位置。术语容器封闭完整性测试与包装泄漏测试或包装完整性测试同义。

Container–closure system: SeePackagingand Storage Requirementsá659ñ, General Definitions, Packaging System.

容器封闭系统：参见包装和储存要求á659ñ，一般定义，包装系统。

Detection limit: The leak testdetection limit is a measure of test method sensitivity. The detection limit isthe smallestleakage rate (or leak size) that a leak test method canreliably detect. Also called limit of detection.

检测限：泄漏测试检测限是测试方法灵敏度的度量。检测限是泄漏测试方法可以可靠检测的最小泄漏率（或泄漏量）。也称为检测限。

Deterministic leak test method: A deterministic leak test method is one in which the leakage event beingdetected ormeasured is based on phenomena that follow a predictablechain of events. In addition, the measure of leak detection is based onphysicochemical technologies that are readily controlled and monitored,yielding objective quantitative data.

确定性泄漏测试方法：确定性泄漏测试方法是其中检测或测量的泄漏事件基于可预测的事件链之后的现象的方法。此外，泄漏检测的测量基于易于控制和监测的物理化学技术，产生客观的定量数据。

In-use maximum allowable leakage limit: SeeMaximum allowable leaking limit.

使用中最大允许泄漏限制：请参阅最大允许泄漏限制。

Inherent package integrity: Inherent package integrity is the leakage rate (or leak size) of a well-assembled container–closuresystem using no-defect package components. Inherent package integrity is ameasure of the leak tightness of a container–closure system, given anticipatedvariables of material composition, dimension, processing, assembly; packagestorage, distribution and use.

固有封装完整性：固有封装完整性是使用无缺陷封装元件的组装良好的容器封闭系统的泄漏率（或泄漏尺寸）。鉴于材料成分，尺寸，加工，装配的预期变量，固有的包装完整性是容器 - 封闭系统的密封性的量度; 包装存储，分发和使用。

Leak: A leak is a breach in apackage wall or a gap between package components that is capable of permittingthe pas-sage of gas, liquid, or solid matter. Leak is synonymous with leakpath.

泄漏：泄漏是包装壁中的破裂或包装组件之间的间隙，其能够允许气体，液体或固体物质的通过。泄漏是泄漏路径的同义词。

Leakage: Leakage is the unintentionalescape or entry of matter (solid, liquid, or gas) through a breach in thepackagewall or through a gap between package components. Leakage canalso refer to the substance that enters or escapes from a compromised package.For example, “Leakage from the cracked container stained the package label.”

泄漏：泄漏是物质（固体，液体或气体）通过包装壁中的破裂或通过包装组件之间的间隙无意逃逸或进入。泄漏还可以指进入或逃离受损包装的物质。例如，“破裂容器的泄漏污染了包装标签。”

Leakage rate: Gaseous leakagerate is a measure of the rate of gas flow (in mass or volume units) that passesthrough aleak path under specific conditions of temperature andabsolute pressure or concentration differential. Leakage rate has dimensions ofpressure multiplied by volume, divided by time. For example, the internationalstandard SI nomenclature is pascal cubic meter per second (Pa · m3 · s−1). Othercommon units of measure include standard cubic centimeters per second (std ·cm3 · s−1 or sccs) and mbar liters per second (mbar · L · s−1). Liquid leakagerate is a measure of the volume of liquid that moves through a leak path as afunction of time under specified conditions of temperature and absolutedifferential pressure across the barrier wall. Liquid leakage rate measurement,possible for larger leak tests, requires that leak size, materials ofconstruction; absence of leak obstruction; tracer liquid composition; and testparameters work together to ensure liquid movement through the leak path.

泄漏率：气体泄漏率是在特定的温度和绝对压力或浓度差异条件下通过泄漏路径的气体流量（质量或体积单位）的量度。泄漏率的大小是压力乘以体积除以时间。例如，国际标准SI命名法是每秒帕斯卡立方米（Pa·m3·s-1）。

其他常见的测量单位包括每秒标准立方厘米（std·cm3·s-1或sccs）和每秒mbar升（mbar·L·s-1）。液体泄漏率是在特定的温度条件下穿过泄漏路径的液体体积随着时间的变化以及穿过阻隔壁的绝对差压的量度。液体泄漏率测量，可能进行较大的泄漏测试，需要泄漏尺寸，结构材料;没有泄漏阻塞;示踪液体成分;和测试参数一起工作以确保液体通过泄漏路径移动。

Linearity: Leak test methodlinearity is the ability of the method to elicit test results that aremathematically proportionalto leak path size or leakage rate.

线性：泄漏测试方法线性度是该方法引出测试结果的能力，该测试结果在数学上与泄漏路径大小或泄漏率成比例。

Master: A master is a packageprototype, model, or facsimile made to simulate an actual package in shape anddesign.Masters may be made of solid plastic or metal, or they may besimply a designated container–closure unit. Masters are designed to simulate ano-leaking package, and are often used in leak test system suitability tests toverify instrument performance.

Master：Master是一个包装原型，模型或传真，用于模拟形状和设计中的实际包装。主机可以由实心塑料或金属制成，或者它们可以简单地是指定的容器封闭单元。 Masters设计用于模拟无泄漏的包装，通常用于泄漏测试系统适用性测试以验证仪器性能。

Maximum allowable leakage limit: The maximum allowable leakage limit is the greatest leakage rate (orleak size) tolerable for a given product–package that poses no risk to productsafety and no or inconsequential impact on product quality. The maximumallowable leakage limit for a sterile pharmaceutical dosage form package willensure the content's sterility, preserve product contents, and prevent entry bydetrimental gases or other substances, thus ensuring that the product meetsrelevant physicochemical and microbiological specifications through expiry anduse. For multiple-dose product–packages, the in-use maximum allowable leakagelimit is defined as the degree of protection demanded of the closure to limitmicrobial ingress and product formulation leakage between and during dosageaccess.

最大允许泄漏限制：最大允许泄漏限制是给定产品包装可容忍的最大泄漏率（或泄漏尺寸），不会对产品安全造成任何风险，也不会对产品质量产生或无关紧要的影响。无菌药物剂型包装的最大允许泄漏限量将确保内容物的无菌性，保存产品内容物，并防止有害气体或其他物质进入，从而确保产品在到期和使用时符合相关的物理化学和微生物规格。对于多剂量产品包装，使用中的最大允许泄漏限度定义为封闭物要求的保护程度，以限制剂量进入之间和期间微生物进入和产品配方泄漏。

Microbiological challenge test: A microbiological challenge test is a package leak test whereby packageintegrity is evaluated by exposing containers filled with growth-supportivemedia to microorganisms suspended in submersion media (a liquid-borne challengetest). Leakage is evidenced by the subsequent growth of the challengemicroorganisms in the package contents. Synonymous with microbial challengetest.

微生物挑战测试：微生物挑战测试是包装泄漏测试，其中通过将填充有生长支持介质的容器暴露于悬浮在浸没介质中的微生物（液体传播的挑战测试）来评估包装完整性。随后的包装内容物中挑战微生物的生长证明了泄漏。与微生物挑战测试同义。

Negative control: A negativecontrol is a package with no known leak. Negative controls used for leak testmethod development and validation studies represent packages optimallyassembled using normally processed components. Negative controls shouldduplicate the container–closure system of the product under integrityinvestigation. For some methods, it may be necessary for negative controls tosimulate test product headspace and formulation content as well.

阴性对照：阴性对照是没有已知泄漏的包装。用于泄漏测试方法开发和验证研究的阴性对照表示使用正常处理组件最佳组装的包装。否定控制应在完整性调查下复制产品的容器封闭系统。对于某些方法，阴性对照可能也需要模拟测试产品顶空和配方内容。

Nonporous: Nonporous packaging does not have pores or openings to allow volumetricair flow. In other words, NMT asmall fraction of molecules is able topass through any one hole. Nonporous materials may be impermeable,semi-perme-able, or permeable to the passage of fluid through the packagebarrier wall.

无孔：无孔包装没有孔隙或开口以允许体积空气流动。 换句话说，NMT中的一小部分分子能够通过任何一个孔。 无孔材料可以是不可渗透的，半渗透的或可渗透的流体通过包装阻挡壁。

Nominal diameter: In the context ofthis chapter, nominal diameter is a means of expressing the size of a packageleak.Package leaks are typically irregular tortuous paths or matricesthat cross a package wall or barrier. Such leaks are difficult to size inaccurate or meaningful terms. The nominal diameter of a leak path is defined asthe width of an orifice of relatively short depth, through which gas (e.g., dryair) at equivalent airflow rate may pass when subject to one atmospheredifferential pressure at controlled temperature conditions.

公称直径：在本章的上下文中，公称直径是表示包装泄漏大小的一种方法。包装泄漏通常是不规则的曲折路径或穿过包装壁或屏障的基质。这种泄漏很难以准确或有意义的方式确定尺寸。泄漏路径的标称直径定义为相对较短深度的孔的宽度，当在受控温度条件下经受一个大气压差时，等效气流速率下的气体（例如，干燥空气）可以通过该孔。

Package integrity: SeeContainer–closureintegrity.

包装完整性：请参阅容器包装完整性。

Package integrity test: SeeContainer–closureintegrity test.

包装完整性测试：参见容器 - 封口完整性测试。

Package integrity profile: Thepackage integrity profile is a database of product life cycle package leak andseal qualitytest results that denotes product–package integrity givenoperative variations in package component design and material; package assemblyand processing; and product storage, distribution, and stability.

包装完整性简介：包装完整性简介是产品生命周期包装泄漏和密封质量测试结果的数据库，表示产品包装完整性，考虑到包装组件设计和材料的操作变化; 包装组装和加工; 和产品的存储，分配和稳定性。

Package leak test: SeeContainer–closureintegrity test.

包装泄漏测试：参见容器密封完整性测试。

Package seal quality: Package sealquality relates to the consistency of a package seal’s performance withinrequiredspecification limits. Examples of package seal qualityattributes include heat seal bond strength and capped vial package residualseal force.

包装密封质量：包装密封质量与包装密封在一定规格限度内的性能一致性有关。包装密封质量属性的实例包括热封粘合强度和加盖的小瓶包装残余密封力。

Package seal quality test: A packageseal quality test is used to characterize and monitor the quality of aproduct–pack-age seal or closure system to ensure that package assembly is consistentlykept within established limits. Package seal quality tests are not and cannotsubstitute for leak tests. However, they can provide some assurance of thepackage’s ability to maintain integrity by monitoring a characteristic of theseal itself, the package materials, the package components, and/or theprocesses required to create the seal or closure mechanism. Examples includethe seal peel force test and the capped vial package residual seal force test.

包装密封质量测试：包装密封质量测试用于表征和监控产品包装密封或封闭系统的质量，以确保包装组件始终保持在既定限度内。包装密封质量测试不能也不能代替泄漏测试。然而，它们可以通过监测密封件本身的特性，包装材料，包装组件和/或形成密封或闭合机构所需的过程来提供包装保持完整性的能力的一些保证。实例包括密封剥离力测试和加盖的小瓶包装残余密封力测试。

Permeation: Permeation is thepassage of fluid into, through, and out of a nonporous package wall.Permeation, notleakage, occurs when the package barrier has no holeslarge enough for more than a small fraction of molecules to pass through anyone hole.

渗透：渗透是流体进入，通过和流出无孔包装壁的通道。当封装屏障没有足够大的孔以使超过一小部分分子通过任何一个孔时，就会发生渗透，而不是泄漏。

Physicochemicalpackage integrity test: A physicochemicalpackage integrity test is a leak test that detects the presenceof apackage leak, or detects/measures package leakage rate, via physical orchemical means. All leak test methods that do not use microorganisms for leakdetection are physicochemical leak test methods.

物理化学包装完整性测试：物理化学包装完整性测试是一种泄漏测试，通过物理或化学方法检测包装泄漏的存在，或检测/测量包装泄漏率。所有不使用微生物进行泄漏检测的泄漏测试方法都是物理化学泄漏测试方法。

Porous: A porous package or packagematerial has pores or openings to allow volumetric air flow while stillblocking air-borne microbial passage. Examples include coated paper orspun-bonded polyolefin barrier materials that permit package penetration byethylene oxide gas or steam.

多孔：多孔包装或包装材料具有孔或开口以允许体积空气流动，同时仍然阻止空气传播的微生物通过。实例包括涂布纸或纺粘聚烯烃阻隔材料，其允许包装通过环氧乙烷气体或蒸汽渗透。

Positive control: A positivecontrol is a package with a known, intentional defect. Positive controls usedfor leak testmethod development and validation studies should duplicatestudy negative controls in terms of materials of construction, packageassembly, and component processing. Positive controls are used during leak testmethod development and validation. Some methods require the use of positivecontrols during routine testing as well.

阳性对照：阳性对照是具有已知的故意缺陷的包装。用于泄漏测试方法开发和验证研究的阳性对照应在构造材料，包装组装和组件处理方面重复研究阴性对照。在泄漏测试方法开发和验证期间使用阳性对照。一些方法也需要在常规测试期间使用阳性对照。

Precision: Leak test methodprecision is a measure of the method’s ability to yield reliable, repeatabledata. Precision includes repeatability (repeat testing of a single homogeneoustest sample population set), ruggedness (within laboratory tests performed bymultiple operators on multiple days, using multiple instruments; also known asintermediate precision), and reproducibility (tests among multiplelaboratories).

精度：泄漏测试方法精度是衡量方法产生可靠，可重复数据的能力的指标。精确度包括重复性（单个均质测试样本群体集的重复测试），坚固性（多个操作员在多天内进行的实验室测试，使用多种仪器;也称为中间精度）和再现性（多个实验室之间的测试）。

Probabilisticleak test method: A probabilisticleak test method is the converse of a deterministic leak test method, beingstochasticin nature. Probabilistic tests rely on a series of sequential and/orsimultaneous events, each associated with random outcomes described byprobability distributions. Thus, the findings are associated with uncertaintiesthat necessitate large sample sizes and rigorous test-condition controls toobtain meaningful results. Typically, sample size and test condition rigor areinversely related to leak size.

概率泄漏测试方法：概率泄漏测试方法与确定性泄漏测试方法相反，本质上是随机的。概率测试依赖于一系列顺序和/或同时发生的事件，每个事件都与概率分布描述的随机结果相关联。因此，这些发现与不确定性有关，这些不确定性需要大样本量和严格的测试条件控制才能获得有意义的结果。通常，样本大小和测试条件严格与泄漏大小成反比。

Product: The pharmaceutical product includes the pharmaceutical formulation aswell as the packaged headspace, whichmay consist of ambient air ornonreactive gases with specified water-vapor content under full orsub-atmospheric pressure conditions.

产品：药品包括药物配方以及包装的顶部空间，其可以由在完全或低于大气压的条件下具有特定水蒸气含量的环境空气或非反应性气体组成。

Product–package: Theproduct–package includes the primary package with critical secondary components(the container–closure system) plus the packaged product (the contents).

产品包装：产品包装包括带有关键辅助部件的主要包装（容器封闭系统）以及包装产品（内容物）。

Qualitative measure of analysis: A qualitative measure of analysis for leak testing is a measurementapproach based on asubjective evaluation of some quality, attribute, orcharacteristic of the test sample. Visual inspection is an example of aqualitative measure of analysis.

定性分析测量：泄漏测试分析的定性测量是基于对测试样品的某些质量，属性或特征的主观评估的测量方法。目视检查是分析的定性测量的一个例子。

Quantitation limit: The quantitationlimit is a leak test method characteristic defining the lowest leakage rate orleak sizethat can be differentiated with accuracy and precision underthe stated experimental conditions.

定量限制：定量限制是一种泄漏测试方法特征，定义了最低泄漏率或泄漏量，可以在所述实验条件下精确和精确地区分。

Quantitative measure of analysis: A quantitative measure of analysis for leak testing is a measurementapproach basedon objective, numeric data that either directly orindirectly correlates with leak presence, leak location, or leakage rate.Examples include the mass-of-gas-per-time reading generated by the helium massspectrometry tracer-gas leak test, or the pressure reading as a function oftest time measurement produced by the vacuum-decay method.

分析的定量测量：泄漏测试分析的定量测量是基于客观的数字数据的测量方法，其直接或间接地与泄漏存在，泄漏位置或泄漏率相关。实例包括由氦质谱示踪气体泄漏测试产生的每次气体质量读数，或作为由真空衰减方法产生的测试时间测量的函数的压力读数。

Range: The range of a leak testmethod is that interval between the smallest to largest leak size (or leakagerate) that canbe detected by a given leak test method with a suitablelevel of accuracy and precision.

范围：泄漏测试方法的范围是最小到最大泄漏尺寸（或泄漏率）之间的间隔，可通过给定的泄漏测试方法以适当的精度和精度检测。

Robustness: Robustness of aleak test method is the method’s ability to accurately identify leaking versusnonleakingpackages despite small but deliberate variations inprocedural parameters, providing an indication of the method’s suitabilityduring normal usage.

稳健性：泄漏测试方法的稳健性是该方法准确识别泄漏与非泄漏包装的能力，尽管程序参数有小但有意的变化，提供了方法在正常使用期间的适用性的指示。

Specificity: The specificityof a leak test method is the ability of the method to accurately differentiateleaking and non-leaking packages, despite interfering factors that may causefalse detection.

特异性：泄漏测试方法的特异性是该方法准确区分泄漏和非泄漏包装的能力，尽管可能导致错误检测的干扰因素。

System suitability: Systemsuitability is a manner of ensuring that the leak test method including all factors,which maybe subject to variability, that may impact test results (suchas instrumentation, analysts, test sample preparation steps, and the testenvironment) are adequately controlled and maintained in such a fashion thatthe method is rugged and robust.

系统适用性：系统适用性是一种确保包括可能影响测试结果的所有因素（包括可变性）的泄漏测试方法（如仪器，分析仪，测试样品制备步骤和测试环境）充分的方法以这种方式控制和维护，使得该方法坚固耐用。

System suitability test: A systemsuitability test is a test to verify that the leak test method and all keyfactors that mayimpact test results are correctly controlled and setprior to method performance.

系统适用性测试：系统适用性测试是一种测试，用于验证泄漏测试方法和可能影响测试结果的所有关键因素是否在方法性能之前被正确控制和设置。

Tortuous path: As applied toleaks, a tortuous path is a convoluted, complex leakage pathway. Most naturallyoccurringleaks, such as cracks and tears, are tortuous in nature,rather than pristine holes. As applied to sealing mechanisms, a sealingmaterial that has tortuous barrier qualities can block microbial entry.

[NOTE—The winding path afforded by the threads of a screw-cap (e.g., anophthalmic dropper bottle closure) does not provide an optimal barrier to gasor liquid leakage, nor does it provide an optimal barrier to microbial ingressin the event of a liquid presence in the cap threads.]

曲折路径：应用于泄漏，曲折的路径是一个复杂的，复杂的泄漏路径。大多数天然存在的泄漏，例如裂缝和撕裂，本质上是曲折的，而不是原始的洞。当应用于密封机构时，具有曲折屏障质量的密封材料可阻止微生物进入。

[注意 - 由螺旋盖螺纹（例如，滴眼液瓶盖）提供的缠绕路径不能提供对气体或液体泄漏的最佳屏障，也不会在微生物侵入时提供最佳屏障。在帽螺纹中存在液体。]

Type defect: A type defect isa positive-control package that represents realistic package flaws. Type-defectpositive controls may be included in leak test method feasibility anddevelopment studies before method validation. An example of a type defect is aheat seal wrinkle or a loose cap. Type defects are inherently irregular in sizeand shape and are often de-scribed qualitatively instead of being described interms of leak size or leakage rate.

类型缺陷：类型缺陷是一种阳性对照包，它代表了真实的包装缺陷。在方法验证之前，可以在泄漏测试方法可行性和开发研究中包括类型缺陷阳性对照。类型缺陷的一个例子是热封皱纹或松散的帽。类型缺陷在尺寸和形状上具有固有的不规则性，并且通常定性地描述，而不是根据泄漏尺寸或泄漏率来描述。