重磅！！ECA发布《容器密封完整性测试指南 Version 3.0 2025 》
2025年11月ECA目视检查工作组发布《容器密封完整性测试指南》，为注射剂类药品的容器密闭完整性（CCI）测试提供了最佳实践建议。该文件旨在作为药典各论的补充，同时体现当前药品生产质量管理规范（GMP）的实践要求，并界定了一套全生命周期的容器密闭完整性（CCI）控制策略，将确认 / 验证、常规控制、供应商管理及稳定性研究纳入统一框架。
除编辑优化外，3.0 新版本还包含以下变更。
附录 1 容器密闭完整性（测试）要求的补充解读
该新版本对附录 1 第 8.22 至 8.28 条条款提供了更详尽的实用性解读。其明确区分了两类容器：一类是熔封容器（例如安瓿瓶、吹灌封 / 成型充填密封单元，即 BFS/FFS 单元），此类容器需进行 100% 完整性测试；另一类是机械密闭系统（例如西林瓶、预充式注射器），此类系统的完整性保障需通过经过验证的工艺控制以及基于风险的容器密闭完整性测试（CCIT）取样来实现。
依据第 8.23 条条款，该文件如今着重强调：取样频率与样本量需具备科学依据，对于破坏性容器密闭完整性测试（CCIT）方法，通常应采用统计抽样方案，例如 ISO 2859（S3/S4）标准中的方案。
包括预充式注射器
预充式注射器现已明确纳入容器密闭完整性（CCI）概念及验证框架中。第 4 章和第 4.1 章规定了胶塞与尖端帽装配验证的要求、容器密闭完整性（CCI）性能确认（PPQ）取样要求，以及相应的工艺控制要求 —— 使注射器系统与基于西林瓶的 CCI 原则保持一致。
在稳定性测试中增加 CCI 验证
新增章节（第 4.5 章）将容器密闭完整性（CCI）验证界定为产品全生命周期控制策略的组成部分。该章节明确：对于西林瓶、预充式注射器等非熔封容器，应在稳定性试验方案中采用经过验证的 CCI 测试方法，以确认产品在整个有效期内的完整性；而若已建立完善的控制策略，在批次放行时则无需进行 100% 完整性测试。
1 Scope 范围
This paper aims to highlight best practice for Container Closure Integrity (CCI) testing of medicinal products for parenteral use in the pharmaceutical industry. It should be seen as addition and complementary to the monographs of the different Pharmacopoeias. CCI testing of medicinal products for parenteral use should be used in order to ensure consistent product quality with regards to closure system integrity.
本文旨在强调制药行业中注射用药品容器密封性测试的最佳实践。本文应被视为对各药典各论的补充与完善。为确保药品在密封系统完整性方面保持稳定的产品质量，应对注射用药品进行容器密封性（CCI）测试。
Modifications from the procedures and figures proposed in this paper are possible at any time. However, following the proposed procedures and figures may lead to safer CCI processes and may avoid discussions in GMP audits and inspections, as the described approach reflects current practice and has previously demonstrated its suitability for purpose during many years of industrial operation which includes referring GMP inspections.
对本文中提出的操作流程及图表进行修改，在任何时候都是可行的。然而，遵循本文提出的操作流程及图表，或许能使容器密封性（CCI）测试过程更安全，还可能避免在药品生产质量管理规范（GMP）审核与检查中产生争议 —— 因为文中所述方法既体现了当前的行业实践，也在包含相关 GMP 检查在内的多年工业应用过程中，充分证明了其具备满足预期用途的适用性。
2 Regulatory Requirements 监管要求
2.1 European Commission and Annex 1 欧盟委员会与附件 1
Currently, the regulatory requirements regarding CCI are stated mainly in Annex <1> of the European Commission (Rules Governing Medicinal Products in the European Union, Vol. 4, EU Guideline to Good Manufacturing Practice, Medicinal Products for Human and Veterinary Use)
目前，有关容器密封性（CCI）的监管要求主要载于欧盟委员会《药品生产质量管理规范》附件 1（详见《欧盟药品管理条例》第 4 卷 —— 人用及兽用药品的药品生产质量管理规范指南）。
CCI Requirements are summarized in section “Finishing of sterile products” in clauses 8.22, 8.23, 8.24, 8.25 and 8.28.
容器密封性（CCI）要求汇总于 “无菌药品最终处理” 章节的第 8.22 条、第 8.23 条、第 8.24 条、第 8.25 条及第 8.28 条中。
Conclusion/Interpretation: 结论 / 解读
Reference 8.22: “Where final containers are closed by fusion, e.g. Blow-Fill-Seal (BFS), Form-Fill-Seal (FFS), Small and Large Volume Parenteral (SVP & LVP) bags, glass or plastic ampoules, the critical parameters and variables that affect seal integrity should be evaluated, determined, effectively controlled and monitored during operations. Glass ampoules, BFS units and small volume containers ( ≤100 ml) closed by fusion should be subject to 100% integrity testing using validated methods. For large volume containers ( >100 ml) closed by fusion, reduced sampling may be acceptable where scientifically justified and based on data demonstrating the consistency of the existing process, and a high level of process control. It should be noted that visual inspection is not considered as an acceptable integrity test method.” 参考文献 8.22：“对于采用熔封方式密封的最终容器（例如吹灌封（BFS）容器、成型 - 充填 - 密封（FFS）容器、小容量与大容量注射剂（SVP & LVP）袋、玻璃安瓿或塑料安瓿），在操作过程中，应评估、确定、有效控制并监测那些会影响密封完整性的关键参数与变量。采用熔封方式密封的玻璃安瓿、吹灌封（BFS）容器以及小容量容器（≤100 毫升），应采用经验证的方法进行 100% 密封性测试。对于采用熔封方式密封的大容量容器（>100 毫升），若有科学依据，且有数据证明现有工艺的一致性及工艺控制水平较高，则采用减量抽样的方式可能是可接受的。需注意，目视检查不被视为可接受的密封性测试方法。”
Interpretation: Thus, it is clear that objects sealed via fusion, e.g. ampoules, are required to undergo 100% CCI testing. Objects not sealed under fusion (vials and syringes) do not require a 100% CCI testing regime.
解读：因此，显然采用熔封方式密封的容器（如安瓿）需进行 100% 容器密封性（CCI）测试。而非采用熔封方式密封的容器（西林瓶、注射器）则无需遵循 100% 容器密封性（CCI）测试要求。
Reference 8.23: “Samples of products using systems other than fusion should be taken and checked for integrity using validated methods. The frequency of testing should be based on the knowledge and experience of the container and closure systems being used. A scientifically justified sampling plan should be used. The sample size should be based on information such as supplier management, packaging component specifications and process knowledge.” 参考文献 8.23：“对于采用非熔封密封系统的药品，应抽取样品并采用经验证的方法进行密封性检查。测试频率应基于所使用容器与密封系统的相关认知及经验来确定。应采用具备科学依据的抽样方案，抽样量则需根据供应商管理情况、包装组件规格标准及工艺认知等信息来制定。”
Interpretation: With this, the integrity testing of containers other than ampoules and bags should undergo a product knowledge and risk based CCIT evaluation. Once integrity of the combination of primary packaging materials has been thoroughly proven in product validation, CCIT of routine batches may be performed by:
解读：据此，对于安瓿和（注射剂）袋以外的容器，其密封性测试应基于产品认知及风险评估开展容器密封性测试（CCIT）评价。一旦内包装材料组合的密封性在产品验证中得到充分证实，常规批次的容器密封性测试（CCIT）可通过以下方式进行：
Utilizing a justifiable frequency of CCIT e.g. after changes of the primary packaging material and/or on a regular basis, performing an evaluation of the CCIT within shelf life stability tests recommended for US products (see FDA Guidance Paper, see below).
采用具有合理依据的容器密封性测试（CCIT）频率开展测试，例如在内包装材料发生变更后，和 / 或按固定周期进行测试；同时，需在针对美国市场药品推荐的货架期稳定性试验中，开展容器密封性测试（CCIT）评价（参见下文提及的美国食品药品监督管理局（FDA）指导原则）。
Utilizing statistical sampling, e.g. according to special sampling plans for destructive testing from ISO 2859 (special inspection level S3 or S4), and performing CCIT of this sample by integrity test methods like dye ingress testing, vacuum decay or high voltage leak testing. Testing single units only is not recommended. However, the sample size available for quality control may be limited due to the size of the batches and other considerations, for instance in the case of biological products. In many cases, the sample size is 10-20 units.
采用统计抽样法（例如依据 ISO 2859 中针对破坏性测试的特殊抽样方案，选用特殊检验水平 S3 或 S4），并通过染色渗透测试、真空衰减测试或高压泄漏测试等密封性测试方法，对抽取的样品进行容器密封性测试（CCIT）。不建议仅对单个单元进行测试。然而，受批次规模及其他因素（例如生物制品的情况）影响，可用于质量控制的抽样量可能会受到限制。在多数情况下，抽样量为 10-20 个单元。
Reference 8.24: “Containers sealed under vacuum should be tested for maintenance of vacuum after an appropriate pre-determined period prior to certification/release and during shelf life.” 参考文献 8.24：“采用真空密封的容器，应在（药品）合格证明出具 / 放行前，以及货架期内，于预先确定的适当时间间隔后，对其真空度保持情况进行测试。”
Interpretation: This requirement was already present in the earlier Annex 1 version (former clause 123). For lyophilized products, manufacturers commonly target a slight negative pressure inside the containers (typically about 100-300 mbar below ambient pressure, depending on vial size/closure) to facilitate reconstitution by helping transfer the diluent into the container and with it reducing aerosolization/splash. Without this negative pressure, users/healthcare professionals may need to vent the container (e.g., with a second needle) to release pressure during diluent injection (reconstitution). Thus, this slight negative pressure can be viewed as an application aid rather than a strong vacuum. As a consequence, there is no need for a % vacuum test before release. Vacuum testing according to section 8.24 is to be applied for those containers where a considerable vacuum is required in order to maintain product characteristics other than only an application aid. However, this testing requirement would also apply for the application-aid-only-circumstance when it can be shown that reconstitution under missing vacuum would lead to a product with adulterated product characteristics.
解读：该要求在早期版本的附件 1（原第 123 条）中已存在。对于冻干制剂，生产商通常会使容器内部保持轻微负压（通常比环境压力低 100-300 毫巴，具体取决于西林瓶规格 / 密封件类型），这一设计有助于将稀释液导入容器内，从而为制剂复溶提供便利，同时还能减少雾化 / 喷溅现象。若不存在这一负压，使用者 / 医护人员在注入稀释液（复溶过程）时，可能需要对容器进行排气操作（例如使用第二根针头）以释放压力。因此，这种轻微负压应被视为一种 “使用辅助手段”，而非 “强真空”。基于此，制剂放行前无需进行真空度百分比测试。仅当容器需要保持较高真空度（目的是维持产品特性，而非仅作为使用辅助手段）时，才需依据第 8.24 条的要求开展真空度测试。然而，在某些仅将负压作为使用辅助手段的场景中，若能证明 “缺失负压状态下的复溶会导致产品特性不合格”，则同样需遵守该真空度测试要求。
Reference 8.25: “The container closure integrity validation should take into consideration any transportation or shipping requirements that may negatively impact the integrity of the container (e.g. by decompression or extreme temperatures).” 参考文献 8.25：“容器密封性验证应考虑可能对容器完整性产生不利影响的所有运输或航运要求（例如，因减压或极端温度造成的影响）。”
Interpretation: Thus, a shipping/transport validation should include CCI samples to be tested based on a risk assessment of the potential impact of transport and shipping environment on the product characteristics, especially on the CCI.
解读：因此，运输 / 航运验证应包含容器密封性（CCI）样品测试，而该测试需基于运输及航运环境对产品特性（尤其是对容器密封性（CCI））潜在影响的风险评估来开展。
Reference 8.28: “Where capping of aseptically filled sterile product is conducted as a clean process with grade A air supply protection, vials with missing or displaced stoppers should be rejected prior to capping. Appropriately qualified, automated methods for stopper height detection should be in place.” 参考文献 8.28：“对于无菌灌装的无菌药品，若其压盖操作在 A 级送风保护下的洁净工艺环境中进行，则应在压盖前剔除无胶塞或胶塞移位的西林瓶。同时，应配备经适当验证的胶塞高度自动检测方法。”
Interpretation: Thus, qualified automated stopper-height detection is one of the in-process controls that helps to prevent CCI failures during routine production. Note: stopper height control alone does not lead to proper detection of misplaced and/or not correctly set stoppers. There must be (further) controls in place which also detect these stopper related defects. According to 8.28, all these controls have to be in place before capping.
解读：因此，经验证合格的胶塞高度自动检测是过程控制手段之一，有助于在常规生产中预防容器密封性（CCI）失效问题。需注意：仅通过胶塞高度控制，无法充分检测出胶塞错位和 / 或胶塞放置不当的情况。必须额外设置（其他）控制手段，以检测这类与胶塞相关的缺陷。根据第 8.28 条的要求，所有这些控制手段均需在压盖前部署到位。
Summary statement 总结陈述 / 概要说明
Once a validated CCI control strategy is in place, the Annex 1 expectations related to container-closure integrity are met initially. Ongoing verification via routine controls and during stability studies provides continued assurance of CCI over the entire shelf life.
一旦制定并实施经验证的容器密封性（CCI）控制策略，即可初步满足附件 1 中与容器密封性相关的要求。通过常规控制及稳定性研究过程中的持续验证，能够为药品整个货架期内的容器密封性（CCI）提供持续性保障。
2.2 American Market and USP <1207> and FDA Guidance Paper: 美国市场及《美国药典》<1207> 与美国食品药品监督管理局（FDA）指导原则：
The USP<1207> is a supportive, not legally binding, US Pharmacopeia informational chapter. According to this chapter, CCI testing should generally occur during the following three phases:
《美国药典》<1207> 章节是具有支持作用的信息性章节，不具备法律约束力。根据该章节要求，容器密封性（CCI）测试通常应在以下三个阶段进行：
the initial development of the product packaging system, 产品包装系统的初期开发阶段 routine manufacturing, and 常规生产阶段，以及 shelf life stability assessments. 货架期稳定性评估
The USP gives ideas and an overview of methods that can be used for the different drug products within different packaging systems.
《美国药典》提供了相关思路及方法概述，这些方法可用于不同包装系统中的各类药品。
In FDA’s guidance for industry (Container and closure system integrity testing in lieu of sterility testing as a component of the stability protocol for sterile products) is stated that the advantages of using container and closure system integrity tests in lieu of sterility tests within the stability protocol should be included for sterile products. Herein the CCI testing should be an additional method during the “in shelf-life” assessment of the product container closure system. It does not replace the sterility testing at the starting (T-zero) and final (T-final) stability program assessments.
在FDA发布的行业指导原则《无菌药品稳定性方案中以容器密封系统完整性测试替代无菌测试》中规定：对于无菌药品，应在稳定性方案中纳入 “以容器密封系统完整性测试替代无菌测试” 的相关优势说明。在此背景下，容器密封性（CCI）测试应作为药品容器密封系统 “货架期内” 评估的一项补充测试方法，而非取代稳定性方案评估中初始时间点（T0）和最终时间点（T 终）的无菌测试。
3 Recommendation for 100% CCI within Parenteral Drug Product Production 注射剂生产中 100% 容器密封性（CCI）测试的建议
Only containers closed by fusion and Form-Fill-Seal such as glass or plastic ampoules and bags must be tested 100% according to Annex <1> .
根据附件 1 的要求，仅采用熔封密封和成型 - 填充 - 密封（简称 FFS）工艺密封的容器（如玻璃或塑料安瓿、注射剂袋）必须进行 100% 容器密封性（CCI）测试。
CCI should be seen as a concept established within the parenteral drug product production system where there is a need for a CCI method overview, considering manufacturing methods and technologies already in place for the manufacture of the product. CCI testing methods covered by already-in-place routine GMP requirements which demonstrate maintenance of sterility of the filled product, are shown in figure 1a and 1b. The CCI concept consists of several measures at the GMP level, which collectively ensure the maintenance of integrity of the packaging closure system.
在注射剂生产体系中，容器密封性（CCI）应被视为一项既定概念。该概念要求制定 CCI 方法概述，且在制定过程中需考量产品生产所采用的现有生产方式及技术。图 1a 和图 1b 列出了现行常规药品生产质量管理规范（GMP）要求所涵盖的 CCI 测试方法，这些方法可证明已灌装产品无菌状态的维持情况。CCI 概念包含多项 GMP 层面的措施，这些措施共同作用，确保包装密封系统完整性的持续维持。
Figure 1a: CCI concept of Drug Product filled in vials
西林瓶灌装药品的容器密封性（CCI）概念
Figure 1b: CCI concept of Drug Product filled in syringes
注射器灌装药品的容器密封性（CCI）概念
Blue: Qualification/Validation 蓝色：确认 / 验证
Orange: sampling on batch level 橙色：批次层面的取样
Green: 100% control on batch level 绿色：批次层面的 100% 全检控制
Purple: Monitoring of the primary packaging material supplier on a regular basis 紫色：对初级包装材料供应商的定期监控
Black: CCI Verification within stability testing
黑色：稳定性测试中的容器密封性（CCI）验证
3.1 CCI performed during Qualification/Validation (blue Figure 1a and 1b) of a Drug Product/or a Filling Line
在药品或灌装线的确认 / 验证（图 1a 和图 1b 中蓝色部分）过程中开展的容器密封性（CCI）测试
Shipping/Transport validation should include CCI samples to be tested. 运输验证应包含需检测的容器密封性（CCI）样品。 Microbiological Packaging Evaluation 微生物包装评估
Evaluation of the drug product primary packaging material. Here a mCCI (Microbiological CCI) is normally performed during the development of a drug product showing that the combination of stopper/vial or stopper/tip-cap/syringe is effective as microbial barrier when subjected to the Bacterial Ingress Test (BIT).
药品初级包装材料的评估。在此环节，通常会在药品研发阶段开展微生物容器密封性测试。该测试旨在通过细菌侵入测试验证胶塞 / 西林瓶组合或胶塞 / 尖端帽 / 注射器组合能否有效发挥微生物屏障作用。
Media Fills (Aseptic Process Simulation) 培养基灌装（无菌工艺模拟）
Media Fills show that microbiological contamination control is effective during the aseptic handling, preparation and filling of the drug product is under control from the inherent and environmental microbiological challenge (aseptic preparations). Successful (zero contaminated units) media fills (aseptic process simulations) are also demonstrating the effective CCI of filled units during manufacturing and handling of the units.
培养基灌装表明在药品的无菌操作、制备及灌装过程中，微生物污染控制措施有效，能够应对来自固有环境及外部环境的微生物挑战（即无菌制剂制备过程中的微生物风险）。此外，成功的（零污染单位）培养基灌装（无菌工艺模拟）还可证明，在产品的生产及操作过程中，已灌装产品的容器密封性（CCI）符合要求。
Crimping Validation (Vials) 压塞验证（西林瓶）
The crimping validation should include CCI tests in order to show that the stopper setting and the crimping are appropriate to ensure adequate closure of the vial system (stopper, glass vial and seal). The Edge of failure CCI studies during development may be used to determine manufacturing tolerance levels.
压塞验证应包含容器密封性（CCI）测试，以证明胶塞的放置位置和压塞操作均符合要求，从而确保西林瓶包装系统（包括胶塞、玻璃西林瓶和密封件）实现充分密封。药品研发阶段开展的 “失效边界容器密封性（CCI）研究”，可用于确定生产过程中的公差范围。
Syringe Requirements 注射器要求
For Drug Product filled in syringes, proper placement of the stoppers has to be validated using CCI sampling within the Process Performance Qualification (PPQ). It should be performed using worst case approaches. Herein, an appropriate statistically sound CCI sample size should be applied.
对于采用注射器灌装的药品，需在工艺性能确认（PPQ）过程中，通过容器密封性（CCI）取样测试来验证胶塞放置是否得当。该验证需采用最差情况分析法，且应选用统计学上合理的容器密封性（CCI）取样量。
Also in regard to TipCap setting validation, processes should include CCI samples to be tested.
在尖端帽（TipCap）安装验证方面，相关流程也应包含待检测的容器密封性（CCI）样品。
3.2 CCI Methods used for Batch Release on a Sampling Basis (orange Figure 1a and 1b)
用于批次放行的抽样型容器密封性（CCI）测试方法（图 1a 和图 1b 中橙色部分）
Sterility Testing 无菌测试
On batch release level the sterility test performed for the batch release is also proof of correct CCI.
在批次放行层面，为批次放行而开展的无菌测试，同样可作为容器密封性（CCI）合格的证明依据。
Release of Packaging Materials 包装材料的放行
The packaging materials are monitored and released prior to their use. This includes specifications for the dimensions of the syringe barrel or vial and the closing system (stopper). With this the CCI is determined.
包装材料在使用前需经过监控并完成放行。这其中包含对注射器针筒或西林瓶的尺寸规格，以及密封系统（胶塞）的规格要求。通过这些（监控与规格核验），可确定容器密封性（CCI）是否合格。
3.3 CCI Methods used for Batch Release based on 100% Visual Inspection (orange Figure 1a and 1b)
基于 100% 目视检查、用于批次放行的容器密封性（CCI）测试方法（图 1a 和图 1b 中橙色部分）
Visual Inspection 目视检查
The 100% visual inspection removes cracks, scratches and crimping defects. These identified defects are detected by the optical control system based on the probabilistic nature of the likelihood of a defect being present and identified. The “optical system” may be either the human eye or a camera. With this in mind, it should be considered that the detection is relative to the dimension of the defect. A purely visual inspection is not an appropriate tool by itself to monitor CCI (see referring section also Annex 1).
100% 目视检查可剔除裂纹、划痕及压塞缺陷。这些已识别的缺陷由光学控制系统依据缺陷存在及被识别的概率特性检测得出。此处的 “光学系统” 既可为肉眼，也可为摄像头。有鉴于此，应考虑到缺陷的检测结果与缺陷尺寸相关。单纯的目视检查本身并非监控容器密封性（CCI）的适宜工具（另请参见附录 1 相关章节）。
This is due to the fact that the vision system cannot evaluate the robustness of the container closure relative to the microbiological challenge. Nevertheless, cracks can be detected and rejected by the visual inspection in the knowledge that visual inspection is performed on 100% of filled units prior to release of the batch.
这是因为视觉系统无法评估容器密封件抵御微生物挑战的可靠性。尽管如此，鉴于在批次放行前会对所有已灌装产品进行 100% 目视检查，仍可检测到裂纹并剔除存在裂纹的产品。
Stopper Height Measurement (for Vials) 胶塞高度测量（针对西林瓶）
It is essential to monitor the stopper height of products filled in vials 100% during production. The validation of the stopper setting (and crimping) should include CCI tests. As an industry standard a stopper height of less than 1mm is considered to be microbiologically tight. Different heights may be validated, but the crimping validation should include a definitive CCI statement. With this the CCI is evaluated in 100% of the batch prior to the release.
在生产过程中，对西林瓶灌装产品的胶塞高度进行 100% 监控至关重要。胶塞安装（及压塞）工艺的验证应包含容器密封性（CCI）测试。根据行业标准，胶塞高度低于 1 毫米时，可认为其具备微生物密封性。虽可对不同高度规格进行验证，但压塞验证必须包含明确的容器密封性（CCI）结论。通过这种方式，可在批次放行前对整批产品的容器密封性（CCI）进行 100% 评估。
All activities contributing to monitor and control CCI should be summarized and evaluated following a Quality Risk Management approach to ensure CCI is adequately and appropriately ensured - even without implementing a 100% CCI testing.
所有有助于监控和控制容器密封性（CCI）的活动均应按照质量风险管理方法进行汇总和评估，以确保充分、适当地保障容器密封性（CCI）—— 即便未实施 100% 的容器密封性（CCI）测试。
When it is determined that the risk of the summarized established detection or remediation methods do not adequately address the control of CCI of the container, then there may be the possibility of establishing a 100% CCI testing method which focuses on detecting a maximum allowable leak rate (MALR) and not merely the total integrity of the sample objects.
当判定经汇总的既定检测或补救方法在风险层面无法充分实现对容器密封性（CCI）的控制时，则可考虑建立 100% 容器密封性（CCI）测试方法。该方法应重点检测最大允许泄漏率（MALR），而非仅关注样品对象的整体完整性。
Note: The integrity determinations of MALR are dependent on the sensitivity of the methods used and one should take care not to create an issue by detection/testing method that does do not actually manifest itself as non-integral units in the field.
注：最大允许泄漏率（MALR）的完整性判定取决于所用方法的灵敏度，且需注意避免因检测 / 测试方法（本身的问题）引发争议 —— 即该方法检测出的 “问题” 在实际应用场景中并不会真正表现为容器完整性失效的情况。
There remains the possibility to move from a 100% CCI method to a destructive CCI method using appropriate product stream sampling. If the results of the samples assessed for CCI are used for batch release, then the sampling plan should be based on a statistically appropriate sampling plan. One of the possibilities is the S-3 or S-4 level of the DIN/ISO 2859-1/ANSI/ASQ 71.4. One should take care in relying on AQL data alone for batch release. Testing single units only is not recommended. However, the sample size available for quality control may be limited due to the size of the batches and other considerations, for instance, in the case of biological products. In many cases, the sample size is 10-20 units.
仍可通过采用适宜的产品流抽样方式，从 100% 容器密封性（CCI）测试方法转为破坏性容器密封性（CCI）测试方法。若将容器密封性（CCI）评估的样品结果用于批次放行，则抽样方案应基于统计学上适宜的抽样计划。其中一种可行方案是采用 DIN/ISO 2859-1/ANSI/ASQ 71.4 标准中的 S-3 或 S-4 水平。需注意，不宜仅依赖合格质量水平（AQL）数据进行批次放行。不建议仅对单个样品进行测试。然而，受批次规模及其他因素（例如生物制品的情况）影响，可用于质量控制的样品量可能有限。在许多情况下，样品量为 10 至 20 个单位。
As an identified CCI defect (leaking unit) it is also useful to use non-integral defect vials that are representative of normal production like real cracked vials.
作为已识别的容器密封性（CCI）缺陷（泄漏单元），使用能代表正常生产情况的非完整性缺陷西林瓶（例如真实的裂纹西林瓶）也十分有用。
3.4 Supplier Management for the primary Packaging Materials used (purple Figure 1) 所用初级包装材料的供应商管理（图 1 中紫色部分）
The Supplier of the primary packaging material should be monitored with regard to process changes and their influence on the CCI of the drug product packaging combination.
对于初级包装材料的供应商，应就其工艺变更及其对药品包装组合的容器密封性（CCI）产生的影响进行监控。
3.5 CCI Verification within Stability Testing (back Figure 1a and 1b)
稳定性测试中的容器密封性（CCI）验证（图 1a 和图 1b 背面）
Container-closure integrity (CCI) is considered to be a lifecycle control strategy, rather than a single test. As outlined in Figures 1a and 1b, integrity at release is established by a qualified container-closure system and effective monitored process controls (e.g., stopper seating/height, crimp parameters/seal quality, visual inspection, and component/supplier controls). A validated CCIT method, applied within the routine stability program, provides ongoing evidence that CCI is maintained through shelf-life. Where a robust control strategy is in place, 100% CCIT at batch release is generally not required; assurance derives from the totality of controls plus stability CCIT (unless a risk assessment or regulatory commitment dictates otherwise).
容器密封性应被视为一项全生命周期控制策略，而非单一测试。如概述图 1a 和图 1b 所示，放行时的密封性通过以下两方面实现：一是经过确认的容器密封系统，二是有效的受控过程监控（例如胶塞就位 / 高度、压塞参数 / 密封质量、目视检查以及组件 / 供应商管控）。在常规稳定性试验方案中采用经验证的容器密封性测试方法，可持续证明药品在整个货架期内始终保持密封性。若已建立完善的控制策略，通常无需在批次放行时执行 100% 容器密封性测试；密封性保障来源于各项控制措施的整体协同，再加上稳定性试验中的容器密封性测试（除非风险评估或法规承诺有另行规定）。
Remark: stability study CCIT results should not be part of a release decision. When all measures shown in Figures 1a and 1b are implemented and effectively maintained, CCIT results from stability studies can be regarded as a verification step of the overall CCI concept.
备注：稳定性研究中的容器密封性测试（CCIT）结果不应作为批次放行决策的依据。当图 1a 和图 1b 中所示的所有措施均已实施且得到有效维持时，稳定性研究得出的容器密封性测试（CCIT）结果可被视为对整体容器密封性（CCI）控制理念的验证环节。
4 Recommendation for CCI Testing during the Shelf-Life Stability Assessment 货架期稳定性评估期间的容器密封性（CCI）测试建议
For the shelf-life stability assessment, samples are taken to evaluate the CCI in parallel to the sterility assessment. The defect detection capability of the CCI testing method used should be based equal or better than microbial ingress testing. This limit can be validated using a microbiological ingress test or can be based on limits given in the literature. It may be useful to ensure this CCI after or during product development, otherwise it might lead into the detection of CCI defects of non-realistic/non-production representative defects.
在货架期稳定性评估中，需抽取样品同步评估容器密封性（CCI）与无菌状态。所采用的容器密封性（CCI）测试方法，其缺陷检出能力应等于或优于微生物侵入测试。该检出限可通过微生物侵入测试验证确定，也可依据文献中给出的限值设定。在产品开发阶段或开发完成后确认该容器密封性（CCI）检出能力或许十分有益，否则可能导致检出的容器密封性（CCI）缺陷并非实际生产中可能出现的缺陷（即不具备生产代表性的缺陷）。