2025年11?ECA?視檢查?作組發布《容器密封完整性測試指南》，為注射劑類藥品的容器密閉完整性（CCI）測試提供了最佳實踐建議。該?件旨在作為藥典各論的補充，同時體現當前藥品?產質量管理規范（GMP）的實踐要求，并界定了?套全?命周期的容器密閉完整性（CCI）控制策略，將確認 / 驗證、常規控制、供應商管理及穩定性研究納?統?框架。
除編輯優化外，3.0 新版本還包含以下變更。
附錄 1 容器密閉完整性（測試）要求的補充解讀
該新版本對附錄 1 第 8.22 ? 8.28 條條款提供了更詳盡的實?性解讀。其明確區分了兩類容器：?類是熔封容器（例如安瓿瓶、吹灌封 / 成型充填密封單元，即 BFS/FFS 單元），此類容器需進? 100% 完整性測試；另?類是機械密閉系統（例如西林瓶、預充式注射器），此類系統的完整性保障需通過經過驗證的?藝控制以及基于?險的容器密閉完整性測試（CCIT）取樣來實現。
依據第 8.23 條條款，該?件如今著重強調：取樣頻率與樣本量需具備科學依據，對于破壞性容器密閉完整性測試（CCIT）?法，通常應采?統計抽樣?案，例如 ISO 2859（S3/S4）標準中的方案。
包括預充式注射器
預充式注射器現已明確納?容器密閉完整性（CCI）概念及驗證框架中。第 4 章和第 4.1 章規定了?塞與尖端帽裝配驗證的要求、容器密閉完整性（CCI）性能確認（PPQ）取樣要求，以及相應的?藝控制要求——使注射器系統與基于西林瓶的 CCI 原則保持?致。
在穩定性測試中增加 CCI 驗證
新增章節（第 4.5 章）將容器密閉完整性（CCI）驗證界定為產品全?命周期控制策略的組成部分。該章節明確：對于西林瓶、預充式注射器等?熔封容器，應在穩定性試驗?案中采?經過驗證的 CCI 測試?法，以確認產品在整個有效期內的完整性；?若已建?完善的控制策略，在批次放?時則?需進? 100% 完整性測試。
1 Scope 范圍
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
本文旨在強調制藥行業中注射用藥品容器密封性測試的最佳實踐。本文應被視為對各藥典各論的補充與完善。為確保藥品在密封系統完整性方面保持穩定的產品質量，應對注射用藥品進行容器
密封性（CCI）測試。
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.
對本文中提出的操作流程及圖表進行修改，在任何時候都是可行的。然而，遵循本文提出的操作流程及圖表，或許能使容器密封性（CCI）測試過程更安全，還可能避免在藥品生產質量管理規范（GMP）審核與檢查中產生爭議 —— 因為文中所述方法既體現了當前的行業實踐，也在包含相關 GMP 檢查在內的多年工業應用過程中，充分證明了其具備滿足預期用途的適用性。
2 Regulatory Requirements 監管要求
2.1 European Commission and Annex 1 歐盟委員會與附件 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，有關容器密封性（CCI）的監管要求主要載于歐盟委員會《藥品生產質量管理規范》附件 1（詳見《歐盟藥品管理條例》第 4 卷 —— 人用及獸用藥品的藥品生產質量管理規范指南）。
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）要求匯總于 “無菌藥品最終處理” 章節的第 8.22 條、第 8.23 條、第 8.24 條、第 8.25 條及第 8.28 條中。
Conclusion/Interpretation: 結論 / 解讀
1. 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.”
參考文獻 8.22：“對于采用熔封方式密封的最終容器（例如吹灌封（BFS）容器、成型 - 充填- 密封（FFS）容器、小容量與大容量注射劑（SVP & LVP）袋、玻璃安瓿或塑料安瓿），在操作過程中，應評估、確定、有效控制并監測那些會影響密封完整性的關鍵參數與變量。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），應采用經驗證的方法進行 100% 密封性測試。對于采用熔封方式密封的大容量容器（>100 毫升），若有科學依據，且有數據證明現有工藝的一致性及工藝控制水平較高，則采用減量抽樣的方式可能是可接受的。需注意，目視檢查不被視為可接受的密封性測試方法。”
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.
解讀：因此，顯然采用熔封方式密封的容器（如安瓿）需進行 100% 容器密封性（CCI）測試。而非采用熔封方式密封的容器（西林瓶、注射器）則無需遵循 100% 容器密封性（CCI）測試要求。
2. 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.”
參考文獻 8.23：“對于采用非熔封密封系統的藥品，應抽取樣品并采用經驗證的方法進行密封性檢查。測試頻率應基于所使用容器與密封系統的相關認知及經驗來確定。應采用具備科學依據的抽樣方案，抽樣量則需根據供應商管理情況、包裝組件規格標準及工藝認知等信息來制定。”
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：
解讀：據此，對于安瓿和（注射劑）袋以外的容器，其密封性測試應基于產品認知及風險評估開展容器密封性測試（CCIT）評價。一旦內包裝材料組合的密封性在產品驗證中得到充分證實，常規批次的容器密封性測試（CCIT）可通過以下方式進行：
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).
采用具有合理依據的容器密封性測試（CCIT）頻率開展測試，例如在內包裝材料發生變更后，和 / 或按固定周期進行測試；同時，需在針對美國市場藥品推薦的貨架期穩定性試驗中，開展容器密封性測試（CCIT）評價（參見下文提及的美國食品藥品監督管理局（FDA）指導原則）。
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
采用統計抽樣法（例如依據 ISO 2859 中針對破壞性測試的特殊抽樣方案，選用特殊檢驗水平S3 或 S4），并通過染色滲透測試、真空衰減測試或高壓泄漏測試等密封性測試方法，對抽取的樣品進行容器密封性測試（CCIT）。不建議僅對單個單元進行測試。然而，受批次規模及其他因素（例如生物制品的情況）影響，可用于質量控制的抽樣量可能會受到限制。在多數情況下，抽樣量為 10-20 個單元。
Reference 8.24: “Containers sealed under vacuum should be tested for maintenance ofvacuum after an appropriate pre-determined period prior to certification/release andduring shelf life.”
參考文獻 8.24：“采用真空密封的容器，應在（藥品）合格證明出具 / 放行前，以及貨架期內，于預先確定的適當時間間隔后，對其真空度保持情況進行測試。
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-aidonly-circumstance when it can be shown that reconstitution under missing vacuum would lead to a product with adulterated product characteristics.
解讀：該要求在早期版本的附件 1（原第 123 條）中已存在。對于凍干制劑，生產商通常會使容器內部保持輕微負壓（通常比環境壓力低 100-300 毫巴，具體取決于西林瓶規格 / 密封件類型），這一設計有助于將稀釋液導入容器內，從而為制劑復溶提供便利，同時還能減少霧化 / 噴濺現象。若不存在這一負壓，使用者 / 醫護人員在注入稀釋液（復溶過程）時，可能需要對容器進行排氣操作（例如使用第二根針頭）以釋放壓力。因此，這種輕微負壓應被視為一種 “使用輔助手段”，而非 “強真空”。基于此，制劑放行前無需進行真空度百分比測試。僅當容器需要保持較高真空度（目的是維持產品特性，而非僅作為使用輔助手段）時，才需依據第 8.24 條的要求開展真空度測試。然而，在某些僅將負壓作為使用輔助手段的場景中，若能證明 “缺失負壓狀態下的復溶會導致產品特性不合格”，則同樣需遵守該真空度測試要求。
4. 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).”
參考文獻 8.25：“容器密封性驗證應考慮可能對容器完整性產生不利影響的所有運輸或航運要求（例如，因減壓或極端溫度造成的影響）。”
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.
解讀：因此，運輸 / 航運驗證應包含容器密封性（CCI）樣品測試，而該測試需基于運輸及航運環境對產品特性（尤其是對容器密封性（CCI））潛在影響的風險評估來開展。
5. 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.”
參考文獻 8.28：“對于無菌灌裝的無菌藥品，若其壓蓋操作在 A 級送風保護下的潔凈工藝環境中進行，則應在壓蓋前剔除無膠塞或膠塞移位的西林瓶。同時，應配備經適當驗證的膠塞高度自動檢測方法。”
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.
解讀：因此，經驗證合格的膠塞高度自動檢測是過程控制手段之一，有助于在常規生產中預防容器密封性（CCI）失效問題。需注意：僅通過膠塞高度控制，無法充分檢測出膠塞錯位和 / 或膠塞放置不當的情況。必須額外設置（其他）控制手段，以檢測這類與膠塞相關的缺陷。根據第8.28 條的要求，所有這些控制手段均需在壓蓋前部署到位。
Summary statement 總結陳述 / 概要說明
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.
一旦制定并實施經驗證的容器密封性（CCI）控制策略，即可初步滿足附件 1 中與容器密封性相關的要求。通過常規控制及穩定性研究過程中的持續驗證，能夠為藥品整個貨架期內的容器密封性（CCI）提供持續性保障。
2.2 American Market and USP <1207> and FDA Guidance Paper: 美國市場及《美國藥典》<1207> 與美國食品藥品監督管理局（FDA）指導原則：
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:
《美國藥典》<1207> 章節是具有支持作用的信息性章節，不具備法律約束力。根據該章節要求，容器密封性（CCI）測試通常應在以下三個階段進行：
1. the initial development of the product packaging system,
產品包裝系統的初期開發階段
2. routine manufacturing, and
常規生產階段，以及
3. shelf life stability assessments.
貨架期穩定性評估
The USP gives ideas and an overview of methods that can be used for the different drug products within different packaging systems.
《美國藥典》提供了相關思路及方法概述，這些方法可用于不同包裝系統中的各類藥品。
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發布的行業指導原則《無菌藥品穩定性方案中以容器密封系統完整性測試替代無菌測試》中規定：對于無菌藥品，應在穩定性方案中納入 “以容器密封系統完整性測試替代無菌測試” 的相關優勢說明。在此背景下，容器密封性（CCI）測試應作為藥品容器密封系統 “貨架期內” 評估的一項補充測試方法，而非取代穩定性方案評估中初始時間點（T0）和最終時間點（T 終）的無菌測試。
3 Recommendation for 100% CCI within Parenteral Drug Product Production 注射劑?產中 100% 容器密封性（CCI）測試的建議
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> .
根據附件 1 的要求，僅采用熔封密封和成型 - 填充 - 密封（簡稱 FFS）工藝密封的容器（如玻璃或塑料安瓿、注射劑袋）必須進行 100% 容器密封性（CCI）測試。
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.
在注射劑生產體系中，容器密封性（CCI）應被視為一項既定概念。該概念要求制定 CCI 方法概述，且在制定過程中需考量產品生產所采用的現有生產方式及技術。圖 1a 和圖 1b 列出了現行常規藥品生產質量管理規范（GMP）要求所涵蓋的 CCI 測試方法，這些方法可證明已灌裝產品無菌狀態的維持情況。CCI 概念包含多項 GMP 層面的措施，這些措施共同作用，確保包裝密封系統完整性的持續維持。
Figure 1a: CCI concept of Drug Product ?lled in vials
西林瓶灌裝藥品的容器密封性（CCI）概念
Figure 1b: CCI concept of Drug Product ?lled in syringes
注射器灌裝藥品的容器密封性（CCI）概念
Blue: Quali?cation/Validation
藍?：確認 / 驗證
Orange: sampling on batch level
橙?：批次層?的取樣
Green:100% control on batch level
綠?：批次層?的 100% 全檢控制
Purple: Monitoring of the primary packaging material supplier on a regular basis
紫?：對初級包裝材料供應商的定期監控
Black: CCI Veri?cation within stability testing
??：穩定性測試中的容器密封性（CCI）驗證
3.1 CCI performed during Quali?cation/Validation (blue Figure 1a and 1b) of a Drug Product/or a Filling Line在藥品或灌裝線的確認 / 驗證（圖 1a 和圖 1b 中藍色部分）過程中開展的容器密封性（CCI）測試
Shipping/Transport validation should include CCI samples to be tested.
運輸驗證應包含需檢測的容器密封性（CCI）樣品。
Microbiological Packaging Evaluation
微?物包裝評估
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 e?ective as microbial barrier when subjected to the Bacterial Ingress Test (BIT).
藥品初級包裝材料的評估。在此環節，通常會在藥品研發階段開展微?物容器密封性測試。該測 試旨在通過細菌侵?測試驗證?塞 / 西林瓶組合或?塞 / 尖端帽 / 注射器組合能否有效發揮微? 物屏障作?。
Media Fills (Aseptic Process Simulation)
培養基灌裝（?菌?藝模擬）
Media Fills show that microbiological contamination control is e?ective during the aseptic handling, preparation and ?lling of the drug product is under control from the inherent and environmental microbiological challenge (aseptic preparations). Successful (zero contaminated units) media ?lls (aseptic process simulations) are also demonstrating the e?ective CCI of ?lled units during manufacturing and handling of the units.
培養基灌裝表明在藥品的?菌操作、制備及灌裝過程中，微?物污染控制措施有效，能夠應對 來?固有環境及外部環境的微?物挑戰（即?菌制劑制備過程中的微?物?險）。此外，成功 的（零污染單位）培養基灌裝（?菌?藝模擬）還可證明，在產品的?產及操作過程中，已灌 裝產品的容器密封性（CCI）符合要求。
Crimping Validation (Vials)
壓塞驗證（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.
壓塞驗證應包含容器密封性（CCI）測試，以證明膠塞的放置位置和壓塞操作均符合要求，從而確保西林瓶包裝系統（包括膠塞、玻璃西林瓶和密封件）實現充分密封。藥品研發階段開展的 “失效邊界容器密封性（CCI）研究”，可用于確定生產過程中的公差范圍。
Syringe Requirements
注射器要求
For Drug Product ?lled in syringes, proper placement of the stoppers has to be validated using CCI sampling within the Process Performance Quali?cation (PPQ). It should be performed using worst case approaches. Herein, an appropriate statistically sound CCI sample size should be applied.
對于采用注射器灌裝的藥品，需在工藝性能確認（PPQ）過程中，通過容器密封性（CCI）取樣測試來驗證膠塞放置是否得當。該驗證需采用最差情況分析法，且應選用統計學上合理的容器密封性（CCI）取樣量。
Also in regard to TipCap setting validation, processes should include CCI samples to be tested.
在尖端帽（TipCap）安裝驗證方面，相關流程也應包含待檢測的容器密封性（CCI）樣品。
3.2 CCI Methods used for Batch Release on a Sampling Basis (orange Figure 1a and 1b)
?于批次放?的抽樣型容器密封性（CCI）測試?法（圖 1a 和圖 1b 中橙?部分）
Sterility Testing
?菌測試
On batch release level the sterility test performed for the batch release is also proof of correct CCI.
在批次放行層面，為批次放行而開展的無菌測試，同樣可作為容器密封性（CCI）合格的證明依據。
Release of Packaging Materials
包裝材料的放?
The packaging materials are monitored and released prior to their use. This includes speci?cations for the dimensions of the syringe barrel or vial and the closing system (stopper). With this the CCI is determined.
包裝材料在使用前需經過監控并完成放行。這其中包含對注射器針筒或西林瓶的尺寸規格，以及密封系統（膠塞）的規格要求。通過這些（監控與規格核驗），可確定容器密封性（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% ?視檢查、?于批次放?的容器密封性（CCI）測試?法（圖 1a 和圖 1b 中橙?部分）
Visual Inspection
?視檢查
The 100% visual inspection removes cracks, scratches and crimping defects. These identi?ed defects are detected by the optical control system based on the probabilistic nature of the likelihood of a defect being present and identi?ed. 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% 目視檢查可剔除裂紋、劃痕及壓塞缺陷。這些已識別的缺陷由光學控制系統依據缺陷存在及被識別的概率特性檢測得出。此處的 “光學系統” 既可為肉眼，也可為攝像頭。有鑒于此，應考慮到缺陷的檢測結果與缺陷尺寸相關。單純的目視檢查本身并非監控容器密封性（CCI）的適宜工具（另請參見附錄 1 相關章節）。
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 bedetected and rejected by the visual inspection in the knowledge that visual inspection is performed on
100% of ?lled units prior to release of the batch.
這是因為視覺系統無法評估容器密封件抵御微生物挑戰的可靠性。盡管如此，鑒于在批次放行前會對所有已灌裝產品進行 100% 目視檢查，仍可檢測到裂紋并剔除存在裂紋的產品。
Stopper Height Measurement (for Vials)
?塞?度測量（針對西林瓶）
It is essential to monitor the stopper height of products ?lled 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. Di?erent heights may be validated, but the crimping validation should include a de?nitive CCI statement. With this the CCI is evaluated in 100% of the batch prior to the release.
在生產過程中，對西林瓶灌裝產品的膠塞高度進行 100% 監控至關重要。膠塞安裝（及壓塞）工藝的驗證應包含容器密封性（CCI）測試。根據行業標準，膠塞高度低于 1 毫米時，可認為其具備微生物密封性。雖可對不同高度規格進行驗證，但壓塞驗證必須包含明確的容器密封性（CCI）結論。通過這種方式，可在批次放行前對整批產品的容器密封性（CCI）進行 100% 評估。
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.
所有有助于監控和控制容器密封性（CCI）的活動均應按照質量風險管理方法進行匯總和評估，以確保充分、適當地保障容器密封性（CCI）—— 即便未實施 100% 的容器密封性（CCI）測試。
When it is determined that the risk of the summarized established detection or remediationmethods 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.
當判定經匯總的既定檢測或補救方法在風險層面無法充分實現對容器密封性（CCI）的控制時，則 可 考 慮 建 立 100% 容 器 密 封 性 （ CCI ） 測 試 方 法 。 該 方 法 應 重 點 檢 測 最 大 允 許 泄 漏 率（MALR），而非僅關注樣品對象的整體完整性。
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 ?eld.
注：最大允許泄漏率（MALR）的完整性判定取決于所用方法的靈敏度，且需注意避免因檢測 /測試方法（本身的問題）引發爭議 —— 即該方法檢測出的 “問題” 在實際應用場景中并不會真正表現為容器完整性失效的情況。
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/ISO2859-1/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.
仍可通過采用適宜的產品流抽樣方式，從 100% 容器密封性（CCI）測試方法轉為破壞性容器密封性（CCI）測試方法。若將容器密封性（CCI）評估的樣品結果用于批次放行，則抽樣方案應基于統計學上適宜的抽樣計劃。其中一種可行方案是采用 DIN/ISO 2859-1/ANSI/ASQ 71.4 標準中的 S-3 或 S-4 水平。需注意，不宜僅依賴合格質量水平（AQL）數據進行批次放行。不建議僅對單個樣品進行測試。然而，受批次規模及其他因素（例如生物制品的情況）影響，可用于質量控制的樣品量可能有限。在許多情況下，樣品量為 10 至 20 個單位。
As an identi?ed CCI defect (leaking unit) it is also useful to use non-integral defect vials that are representative of normal production like real cracked vials.
作為已識別的容器密封性（CCI）缺陷（泄漏單元），使用能代表正常生產情況的非完整性缺陷西林瓶（例如真實的裂紋西林瓶）也十分有用。
3.4 Supplier Management for the primary Packaging Materials used (purple Figure 1)
所?初級包裝材料的供應商管理（圖 1 中紫?部分）
The Supplier of the primary packaging material should be monitored with regard to process changes and their in?uence on the CCI of the drug product packaging combination.
對于初級包裝材料的供應商，應就其工藝變更及其對藥品包裝組合的容器密封性（CCI）產生的影響進行監控。
3.5 CCI Veri?cation within Stability Testing (back Figure 1a and 1b)
穩定性測試中的容器密封性（CCI）驗證（圖 1a 和圖 1b 背?）
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 quali?ed container-closure system and e?ective 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).
容器密封性應被視為一項全生命周期控制策略，而非單一測試。如概述圖 1a 和圖 1b 所示，放行時的密封性通過以下兩方面實現：一是經過確認的容器密封系統，二是有效的受控過程監控（例如膠塞就位 / 高度、壓塞參數 / 密封質量、目視檢查以及組件 / 供應商管控）。在常規穩定性試驗方案中采用經驗證的容器密封性測試方法，可持續證明藥品在整個貨架期內始終保持密封性。若已建立完善的控制策略，通常無需在批次放行時執行 100% 容器密封性測試；密封性保障來源于各項控制措施的整體協同，再加上穩定性試驗中的容器密封性測試（除非風險評估或法規承諾有另行規定）。
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 e?ectively maintained, CCITresults from stability studies can be regarded as a veri?cation step of the overall CCI concept.
備注：穩定性研究中的容器密封性測試（CCIT）結果不應作為批次放行決策的依據。當圖 1a 和圖 1b 中 所 示 的 所 有 措 施 均 已 實 施 且 得 到 有 效 維 持 時 ， 穩 定 性 研 究 得 出 的 容 器 密 封 性 測 試（CCIT）結果可被視為對整體容器密封性（CCI）控制理念的驗證環節。
4 Recommendation for CCI Testing during the Shelf-Life Stability Assessment
貨架期穩定性評估期間的容器密封性（CCI）測試建議
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.
在貨架期穩定性評估中，需抽取樣品同步評估容器密封性（CCI）與無菌狀態。所采用的容器密封性（CCI）測試方法，其缺陷檢出能力應等于或優于微生物侵入測試。該檢出限可通過微生物侵入測試驗證確定，也可依據文獻中給出的限值設定。在產品開發階段或開發完成后確認該容器密封性（CCI）檢出能力或許十分有益，否則可能導致檢出的容器密封性（CCI）缺陷并非實際生產中可能出現的缺陷（即不具備生產代表性的缺陷）。
When investigating identi?ed CCI defects (leaking units), it is also useful to use non-integral defect vials that are representative of normal production like real cracked vials.
在調查已識別的容器密封性（CCI）缺陷（泄漏單元）時，使用能代表正常生產情況的非完整性缺陷西林瓶（例如真實的裂紋西林瓶）也十分有用。
注：關注公眾號了，回復“20251125”獲取原文，本公眾號已經有"藥研AI助手”了，將公眾號已發布的文章、各國GMP法規 、制藥行業相關書籍作為數據庫，以騰訊元寶作為基礎，DeepSeek-R1為模型。可在眾號內點擊“藥研AI”獲取二維碼，掃描進行提問呦