gmp php study,[技术干货] USP中文翻译连载 | 产品生命周期的包装密封性检查 (1、2之3)...

最近几次在客户GMP检查现场，充分感受到无菌产品包装密封性检查和验证的重要性，而国内又没有细致的无菌包装指南，USP<1207>这些年持续更新，完整细致且技术指导性较强，特此进行翻译，以饷洛施德GMP咨询公众号的读者。

无菌产品包装密封性是无菌保证的重要环节，其密封性保证方式也是无菌产品GMP检查的必然关注点。近年来随着包装密封性检测技术的快速提升，法规也同步保持更新。特别是USP<1207>及其附属章节为行业提供了系统化的参考指南。由于篇幅较长，我们选取技术性较强的<1207.1>部分，分次为大家提供中文翻译版本。

译注：本文“包装密封性”表述同于“包装完整性”。

第一章 介绍

Introduction

Package Integrity Evaluation—Sterile Products 1207 provides guidance in the integrity assurance of product packages. This chapter describes package integrity verification during three product lifecycle phases: 1) package development, package processing, and assembly validation; 2) product manufacturing; and 3) commercial product shelf-life stability assessments. Further, this chapter provides information on how to select, develop, and validate leak test methods.

无菌药品包装密封性评估<1207>提供了产品密封性保证的原则要求，本章节(1207.1)描述产品生命周期3个阶段过程中的包装密封性确认要求，分别是1)包装开发、生产和组装；2)产品生产；3)商业化产品货架期稳定性评估。除此之外，本章节亦介绍如何选择、开发和验证包装泄露的检测方法。

第二章 产品生命周期的包装密封性测试

PACKAGE INTEGRITYTESTING IN THE PRODUCT LIFE CYCLE

Appropriate packaging for a sterile product can be determined on the basis of aknowledge-gaining effort conducted during the product’s life cycle.

选择合适的无菌产品的包装，可以基于产品生命周期内持续的知识积累。

2.1 开发和验证

Development and Validation

2.1.1 包装开发

Package Development

Package development begins with the preparation of a product–package profile (e.g.,user requirements specification), which considers the product end use, stability requirements, and method of manufacture, as well as the anticipated storage, shipment, and distribution environments. This profile also defines the proper product–package quality requirements and the package’s maximum allowable leakage limit (see Package Integrity Evaluation Sterile Products ，<1207>, Product–Package Quality Requirements and the Maximum Allowable Leakage Limit). With this prospectively developed body of information, one can select each package component’s materials of construction, choose suitable component sources, and establish critical physical attributes and component dimensional tolerances. Each component material, with its critical dimensional tolerances, directly affects the integrity of the final packaged product. Assurance of package integrity originates from the use of appropriate materials, accurate and optimum closing properties, matching dimensional fit, appropriate multi-component stack heights and tolerances, and consistent control of processes used to assemble the closed package.

产品包装的选择基于一系列的产品包装信息(比如URS)，具体包括产品最终使用方式、稳定性需求、生产方式，以及存储、运输和分发环境。这些信息也界定了包装产品的质量需求，和包装最大允许泄露限度(见无菌产品包装密封性评估<1207>：包装产品的质量要求和包装最大允许泄露限度)。基于这些提前采集的信息，可以帮助确定包装部件的合适材料，决定合适的部件来源，并建立严格的物理指标和部件尺寸要求。每个具有严格尺寸限度的部件组成，直接影响到最终已包装产品的密封性。概括而言，包装密封性的可靠保障源于使用合适的材料，准确和适宜的包装特性，严格的尺寸，合适的多组件堆积高度与限值，和持续的组装工艺控制。

The manner in which the package is processed, formed, or assembled is an important consideration in package integrity assurance. A preliminary assessment of package integrity at the end of the development phase under conditions representative of the marketed product manufacturing system is prudent.

包装加工、制成和组装方式是密封性保证的重要方面。在产品开发末尾阶段，基于商业化生产体系的条件，进行包装密封性的初步评估就显得严谨而周到。

The second conditions include processes such as sealing operations and component sterilization. Where possible, processes are performed according to established and approved user requirement specifications. Establishing appropriate physical characteristic specifications for container materials, considering lot-to-lot variations, can ensure that the most extreme processing conditions anticipated (e.g., multiple sterilization cycles) do not physically damage materials in a manner that would adversely affect package integrity.

这些条件具体包括封口和部件灭菌处理工艺。如可能，相关工艺应尽可能依照URS进行。要建立合适的包装材料的物理指标，并考虑批间差异，这样有助于保证最严苛的工艺条件(比如，多次循环灭菌)也不会物理损坏包装材料，进而影响到密封性。

Finally, the robustness of the manufactured product–package system may be evaluated during the development phase by exposing a representative number of product samples to specified storage, shipment, distribution, and final product-use environments. These efforts may include studies that evaluate package integrity at the extremes of the finished product–package profile, not simply at optimal conditions. Given the complexity of some sterile packages, it may be useful for package integrity development studies to incorporate multi-point analyses of test packages manufactured within specified process parameters. Utilizing a common container–closure for which the producer has significant experience and process knowledge can supplement the overall development process and may help reduce the efforts needed. A battery of integrity and seal quality test methods may be employed during product–package development, starting with techniques able to measure the product’s inherent package integrity. Inherent package integrity of a viable package system conforms to the product’s maximum allowable leakage limit.

最后考虑已生产的包装产品耐受性，这点可以在开发过程中被评估到，评估方式是将一定数量的产品暴露在指定的存储、运输、分发和最终使用的环境中。这些研究活动可以涵盖一系列极端条件，而非简单的理想条件。考虑到一些无菌包装的复杂性，在指定工艺参数范围内，对生产的包装样品进行多点分析，进而将结果引入包装密封性研究计划中是有帮助的。采用普通的，生产商有丰富的经验和工艺知识的包装封闭系统，则有利于提升整个开发进程和节约开发所需的精力。从持续密封性开始，在包装开发过程中可能会用到一系列的包装产品密封性和封口质量测试方法。切实可行的持续密封性测试要满足最大允许泄露限度。

Test package quantities for inherent package integrity verification may vary on the basis of: 1) the complexity of the product–package, 2) the specifics of the user specification requirements, and 3) the prior experience of the producer. Test quantity choice is also influenced by the confidence that can be placed on the package integrity test results as well as the level of integrity assurance desired. In some cases inherent package integrity verification may be more readily and economically determined by using empty orplacebo-filled container–closure systems, thereby enabling larger sample quantities to be tested by the most sensitive and quantitative leak test methods without the risk of product formulation interference with the test method.

用于持续包装密封性测试的包装样品数量基于以下因素有所区别：1)包装产品的复杂性；2)URS所要求的特性，和3)生产商之前的经验积累。包装测试样品数量还受包装密封性测试结果可接受的置信限影响，以及受包装密封性所需达到的水平的影响。某些情况下，包装密封性确认可以通过空包装或填充剂填充的方式，以更快捷且经济的方式实现，从而保证可以有更多的样品应用到最灵敏且可定量的测试方法中，而不必担心产品组分对方法的干扰。

The outputs of the packaging development phase include the final user requirement specifications, which form the basis of production purchasing specifications for package components. Also during the development phase, the final equipment user requirement specifications are developed for package material cleaning, sterilization, and forming; sealing or assembly equipment; and allied materials supply and component feed systems. These user requirement specifications provide purchase specifications for the acquisition of equipment or for the vetting of potential contract manufacturers.

包装开发阶段的结果输出包括最终的URS，该URS形成最终销售的包装产品的质量基础。同时，开发阶段也形成包装材料清洁、灭菌和制成所需的仪器设备的URS；形成封口或组装的仪器设备URS；以及所需的材料和部件URS。这些URS将提供最终仪器设备采购的标准，或是为选择潜在的合作生产商提供参考。

2.1.2 包装加工和组装验证

PACKAGE PROCESSING AND ASSEMBLYVALIDATION

Final confirmation of acceptable inherent package integrity is generally part of a larger process validation activity for the overall production process. The scope depends upon the product type and whether the organization has previous experience with the container–closure system.

包装密封性的最终确认，通常是作为针对整个生产工艺进行的工艺验证的一部分。其范围取决于产品类型，以及组织在此之前对于包装系统是否有相关的经验。

All processes germane to the sterilization and formation of a package having integrity are to be evaluated against the user requirement specifications established in the package development phase, including likely process extremes. For example, inherent package integrity verification may consider extremes of package assembly variables such as line speed, heat-sealing temperature, screw-cap application torque, and vial-capping forces, as well as resterilization processes, labeling, and secondary and tertiary packaging processes. Validation test requirements and scope should fit the statistical requirements and capabilities of each process, taking into account both package and package line complexity, as well as prior experience with similar product packages.

具有密封属性的包装产品的灭菌和配制工序，都应基于包装开发阶段形成的URS，进行适当评估，包括在可能的极端工艺条件的评估。比如，持续的包装密封性可能需要考虑到极端的包装组装差异，如流水线速度、封口温度、旋盖扭转力和压盖力，还包括在灭菌工序、标签工序、二层和三层外包工序中存在的活动差异。验证测试的指标和范围应契合统计学要求和每步工序的工艺能力，同时也考虑到包装和包装线的复杂性，以及类似包装产品之前形成的经验。

Testing done during technical transfer from the product development site to the manufacturing sites will assist in determining whether the user requirement specification targets and the control ranges established in development require any modification when packages are made on a full manufacturing scale.

从开发场地向生产场地进行的技术转移中完成的相关测试，有利于决定大生产后相关URS内容和接受限度是否需要必要的调整。

Integrity test methods for package processing and assembly validation studies are meant to verify the packages’ continued conformance to the product’s maximum allowable leakage limit. For some product–packages, the most fitting integrity test methods for this life cycle phase may have a detection limit greater than the maximum allowable leakage limit. Methods able to reject largely leaking packages such as those caused by defective or out-of-specification  components, package damage, and/or package misassembly are appropriate. Seal quality tests suitable for use include those able to monitor package processing and/or assembly consistency.

包装加工和组装验证研究中所应用的密封