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在制藥科學(xué)領(lǐng)域，確保注射用容器密封完整性對于維持產(chǎn)品的無菌性和安全性至關(guān)重要。

 

The methods employed for container–closure integrity (CCI) testing play a crucial role in this process, influencing regulatory compliance and product quality assurance. At its core, CCI testing aims to prevent the contamination ingress into pharmaceutical products, particularly in parenteral formats where sterility is non-negotiable. Microbial-ingress testing was a practical mode for evaluating a container’s ability to maintain sterility. The integrity of a closure directly impacts the product's shelf life, efficacy and, overall, patient safety. Historically, the evaluation of sterility and CCI were tightly intertwined, and microbial-ingress testing was the gold standard to establish CCI and product sterility.
用于容器密封完整性（CCI）測試的方法在這個過程中起著關(guān)鍵作用，影響著法規(guī)符合性和產(chǎn)品質(zhì)量保證。從核心來看，CCI 測試旨在防止污染物進(jìn)入藥品，尤其是在無菌性要求不可協(xié)商的注射劑中。微生物侵入測試是評估容器維持無菌能力的一種實用模式。密封的完整性直接影響產(chǎn)品的保質(zhì)期、功效，以及患者的整體安全。從歷史角度看，無菌性和 CCI 的評估緊密相連，微生物侵入測試是確定 CCI 和產(chǎn)品無菌性的黃金標(biāo)準(zhǔn)。

 

With the advent of new drug products, delivery systems and inspection technologies, the microbial-ingress test method has lost scientific relevance for CCI.
隨著新藥品、給藥系統(tǒng)和檢測技術(shù)的出現(xiàn)，微生物侵入測試方法在 CCI 方面已失去科學(xué)相關(guān)性。

 

 

The Kirsch Study
基爾希研究

 

The study by Kirsch et al. (1997), often hailed as a benchmark in microbial-ingress testing, underscores the impact of submicron defects on sterility assurance. It demonstrates convincingly that even small defects can compromise the integrity of container closures, potentially leading to microbial ingress under specific conditions. This study was the first and only peer-reviewed article that took up the challenge of answering the question: What is the critical defect size for sterile products? (1)
基爾希等人（1997 年）的研究常被譽為微生物侵入測試的基準(zhǔn)，強調(diào)了亞微米缺陷對無菌保證的影響。該研究令人信服地表明，即使是微小的缺陷也會損害容器密封的完整性，在特定條件下可能導(dǎo)致微生物侵入。這是第一篇也是唯一一篇經(jīng)過同行評審的文章，承擔(dān)起回答這個問題的挑戰(zhàn)：無菌產(chǎn)品的關(guān)鍵缺陷尺寸是多少？（1）

 

 

One of the significant criticisms of microbial-ingress testing lies in its probabilistic nature and the lack of a globally standardized methodology. Unlike deterministic methods that provide clear, pass/fail outcomes based on measurable parameters, microbial-ingress tests can vary significantly depending on testing conditions and interpretations. This variability raises concerns about the consistency and reliability of results across different testing laboratories and scenarios.
對微生物侵入測試的一個重大批評在于其概率性質(zhì)以及缺乏全球標(biāo)準(zhǔn)化方法。與基于可測量參數(shù)提供明確的通過 / 不通過結(jié)果的確定性方法不同，微生物侵入測試會因測試條件和解釋的不同而有顯著差異。這種可變性引發(fā)了對不同測試實驗室和場景下結(jié)果的一致性和可靠性的擔(dān)憂。

 

 

Kirsch et al. established several important considerations related to CCI and the microbial ingress test. It established that defects below 1 micron in size can still present a risk for microbial ingress. It also established that the risk of microbial ingress was almost certain as the defect size increased to the 10-micron mark. This microbial-ingress study was always thought to be a gold standard to assess a container’s ability to maintain sterility. Additionally, one of the most profound yet overlooked findings of the Kirsch study were these two simple takeaways:
基爾希等人確立了一些與 CCI 和微生物侵入測試相關(guān)的重要考量因素。研究確定，尺寸小于 1 微米的缺陷仍然可能存在微生物侵入的風(fēng)險。同時還確定，當(dāng)缺陷尺寸大至 10 微米時，微生物侵入的風(fēng)險幾乎是必然的。這項微生物侵入研究一直被認(rèn)為是評估容器維持無菌能力的金標(biāo)準(zhǔn)。此外，基爾希研究中一個極其重要但被忽視的發(fā)現(xiàn)有以下兩點：

 

Microbial ingress can occur with defects of sizes between 1 and 10 microns.
微生物侵入可能發(fā)生在尺寸在 1 到 10 微米之間的缺陷處。
 

Microbial ingress is not able to reliably detect defects of sizes between 1 and 10 microns.
微生物侵入測試無法可靠地檢測出尺寸在 1 到 10 微米之間的缺陷。
 

The Kirsch study brought to light the variable method performance. If sterility was a golden standard for sterile products, but the method to establish that characteristic is highly probabilistic, that method itself is not reliable for evaluating CCI. The Kirsch study showed what microbes can achieve and the probabilistic nature of microbial-ingress test results. The microbial-ingress method has provided general clarity around the risk of ingress but does not provide the tools to mitigate that risk.
基爾希研究揭示了方法性能的可變性。如果無菌性是無菌產(chǎn)品的金標(biāo)準(zhǔn)，但確定該特性的方法具有高度的概率性，那么該方法本身在評估 CCI 方面并不可靠。基爾希研究展示了微生物可能造成的情況以及微生物侵入測試結(jié)果的概率性質(zhì)。微生物侵入方法提供了關(guān)于侵入風(fēng)險的大致情況，但沒有提供減輕該風(fēng)險的工具。

 

Despite the general clarity microbial ingress provides around the risk of ingress, the methodology behind creating the test procedure is still unclear. The industry is left without guidance for rigid parenteral products, with the only standardized method relating to single-use systems. ASTM E3251-23 Standard Test Method for Microbial Ingress Testing on Single-Use Systems, which focuses on the methodology used to establish the microbial integrity of a single-use system or to determine the maximum allowable leakage limit, directly focuses on CCI. The standard heavily weighs on arbitrary “Relevant Conditions” to create the parameters and specifications for the method and explicitly states that:
盡管微生物侵入測試在侵入風(fēng)險方面提供了大致的情況，但創(chuàng)建測試程序背后的方法仍不明確。對于剛性注射產(chǎn)品，行業(yè)缺乏相關(guān)指導(dǎo)，唯一的標(biāo)準(zhǔn)化方法與一次性使用系統(tǒng)相關(guān)。ASTM E3251-23《一次性使用系統(tǒng)微生物侵入測試的標(biāo)準(zhǔn)測試方法》直接關(guān)注 CCI，該標(biāo)準(zhǔn)側(cè)重于用于確定一次性使用系統(tǒng)微生物完整性或確定最大允許泄漏極限的方法。該標(biāo)準(zhǔn)嚴(yán)重依賴任意的 “相關(guān)條件” 來創(chuàng)建方法的參數(shù)和規(guī)格，并明確指出：

 

Any size defect may be forced to fail under sufficiently aggressive conditions (including a large enough sample size, high differential pressure, or high hydrostatic pressure, for example) that would not ordinarily reflect normal use conditions (2).
在足夠嚴(yán)格的條件下（例如，足夠大的樣本量、高壓差或高靜水壓），任何尺寸的缺陷都可能被強制判定為不合格，而這些條件通常不能反映正常使用條件（2）。

 

 

If a method can be forced to fail under certain conditions, it can also be forced to pass. The results of microbial-ingress testing can be influenced by operators and test-method developer bias. Although E3251 can be used for alternative containers, such as rigid parenterals (4.4.4), the limitations and bias remain.
如果一種方法在某些條件下可能被強制判定為不合格，那么它也可能被強制判定為合格。微生物侵入測試的結(jié)果可能受到操作人員和測試方法開發(fā)者偏見的影響。盡管 E3251 可用于替代容器，如剛性注射產(chǎn)品（4.4.4），但局限性和偏見仍然存在。

 

In other life-science spaces, guidance is provided by the U.S. Food and Drug Administration (FDA), where the agency recommends microbial-ingress testing for Intravascular Administration Sets Premarket Notification Submissions, but no guidance is provided on a standard procedure (3). Some laboratories have taken the lack of industry guidance into their own hands and created elaborate test procedures to challenge new packages after deeming common practices unfit for current sterility and stability requirements (4).
在其他生命科學(xué)領(lǐng)域，美國食品藥品監(jiān)督管理局（FDA）提供了相關(guān)指導(dǎo)，該機構(gòu)建議對血管內(nèi)給藥裝置的上市前通知提交進(jìn)行微生物侵入測試，但沒有提供關(guān)于標(biāo)準(zhǔn)程序的指導(dǎo)（3）。一些實驗室自行處理行業(yè)指導(dǎo)缺失的問題，認(rèn)為常見做法不符合當(dāng)前的無菌性和穩(wěn)定性要求后，創(chuàng)建了精心設(shè)計的測試程序來對新包裝進(jìn)行挑戰(zhàn)（4）。

 

 

Position
立場

 

The concept of CCI and microbial ingress were once synonymous. Microbial ingress and sterility testing were the determining measures of CCI. Despite more deterministic CCI methods being developed for industry, there remains a comfort in using physical methods such as microbial ingress. While microbial ingress remains unevolved in the ability to detect defects, technology and regulation have evolved significantly.
CCI 和微生物侵入的概念曾經(jīng)是同義詞。微生物侵入和無菌性測試是確定 CCI 的決定性措施。盡管為行業(yè)開發(fā)了更多確定性的 CCI 方法，但使用微生物侵入等物理方法仍然存在一定的合理性。雖然微生物侵入在檢測缺陷的能力方面沒有發(fā)展，但技術(shù)和法規(guī)已經(jīng)發(fā)生了顯著變化。

 

The scope of CCI has evolved well beyond the protection of sterility. Parenterals need to be equally evaluated for risk of oxygen, moisture or bacterial ingress to the drug product. Today, CCI stands alone as an evaluation of the container performance, of which acting as a microbial barrier is a performance characteristic.
CCI 的范圍已經(jīng)遠(yuǎn)遠(yuǎn)超出了對無菌性的保護(hù)。對于注射劑，需要同樣評估氧氣、水分或細(xì)菌進(jìn)入藥品的風(fēng)險。如今，CCI 獨立作為對容器性能的評估，其中作為微生物屏障是其性能特征之一。

 

Since 1997, no further studies beyond Kirsch et al. have addressed the test method’s performance. There is no global standard for microbial-ingress testing for the performance of CCI, nor is there a unified or recommended approach. USP General Chapter <1207> Package Integrity Evaluation—Sterile Products discourages using microbial-ingress methods over deterministic alternatives for establishing CCI (5).
自 1997 年以來，除了基爾希等人的研究外，沒有進(jìn)一步的研究涉及該測試方法的性能。對于 CCI 性能的微生物侵入測試，沒有全球標(biāo)準(zhǔn)，也沒有統(tǒng)一或推薦的方法。美國藥典通用章節(jié) < 1207>《包裝完整性評估 —— 無菌產(chǎn)品》不鼓勵使用微生物侵入方法，而推薦使用確定性方法來確定 CCI（5）。

 

 

In 2008, the FDA published Guidance for Industry: Container and Closure System Integrity Testing in Lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products. At that time, only a few technologies existed to support deterministic CCI, and the technical importance of sterility still held regulatory prominence over other environmental contaminants. The 2008 guidance document established a regulatory position in which sterility and CCI are two separate evaluations, sterility focusing only on the sterile nature of the process and not CCI. The guidance document provides the industry with the open pathway to properly address CCI independently of microbial ingress (6).
2008 年，F(xiàn)DA 發(fā)布了《行業(yè)指南：容器和密封系統(tǒng)完整性測試，以替代無菌測試作為無菌產(chǎn)品穩(wěn)定性方案的一部分》。當(dāng)時，支持確定性 CCI 的技術(shù)很少，無菌性的技術(shù)重要性在法規(guī)方面仍高于其他環(huán)境污染物。2008 年的指導(dǎo)文件確立了法規(guī)立場，即無菌性和 CCI 是兩個獨立的評估，無菌性僅關(guān)注生產(chǎn)過程的無菌性質(zhì)，而不涉及 CCI。該指導(dǎo)文件為行業(yè)提供了獨立于微生物侵入來正確處理 CCI 的明確途徑（6）。

 

 

Path Forward
前進(jìn)方向

 

More than 15 years after the publication of the 2008 guidance document on CCI, the debate on how best to identify and mitigate risks is still vibrant. The concept of holistic CCI has broadened the focus for CCI through space and time to capture container–closure performance for the full life cycle of a product. The technologies and methods available for both CCI and sterility testing have evolved to improve reliability and accuracy. The products and delivery systems are more complex and have varying requirements. One thing that has not evolved is the fundamentals of biology and physics, the factors that would improve the microbial-ingress test method. Test method standards associated with microbial ingress have also not advanced from the position of being little more than a probabilistic biological indicator.
在關(guān)于 CCI 的 2008 年指導(dǎo)文件發(fā)布 15 年多后，關(guān)于如何最好地識別和減輕風(fēng)險的爭論仍然激烈。整體 CCI 的概念通過時間和空間拓寬了對 CCI 的關(guān)注范圍，以捕捉產(chǎn)品整個生命周期的容器密封性能。用于 CCI 和無菌性測試的技術(shù)和方法已經(jīng)發(fā)展，以提高可靠性和準(zhǔn)確性。產(chǎn)品和給藥系統(tǒng)更加復(fù)雜，且有不同的要求。沒有發(fā)展的是生物學(xué)和物理學(xué)的基本原理，而這些因素本可以改進(jìn)微生物侵入測試方法。與微生物侵入相關(guān)的測試方法標(biāo)準(zhǔn)也沒有從僅僅作為概率性生物指示劑的地位取得進(jìn)展。

 

 

Next-generation CCI solutions are detailed out in USP’s Chapter <1207> Packaging Integrity Evaluation-Sterile Products. The chapter outlines deterministic methods that follow a predictable, controlled process that produces a measurable result. Methods such as vacuum or pressure decay, high voltage leak detection (HVLD), helium leak detection and headspace analysis (HSA) are foundational solutions within the deterministic CCI space. These methods vary in scope and capability. Helium leak detection is highly sensitive to small leaks but requires greater sample preparation. Figure 1 highlights the risk of environmental contaminants and the associated level of leak detection by foundational CCI methods. The other methods mentioned vary in practicality, non-destructive nature, smallest detectable leak size and overall test method speed, among other characteristics. Ultimately, each method applies scientific principles to provide the most accurate and reliable measure of container closure integrity.
美國藥典的 < 1207 > 章節(jié)《包裝完整性評估 —— 無菌產(chǎn)品》詳細(xì)介紹了下一代 CCI 解決方案。該章節(jié)概述了遵循可預(yù)測、可控過程并產(chǎn)生可測量結(jié)果的確定性方法。諸如真空或壓力衰減、高壓泄漏檢測（HVLD）、氦泄漏檢測和頂空分析（HSA）等方法是確定性 CCI 領(lǐng)域的基礎(chǔ)解決方案。這些方法在范圍和能力上有所不同。氦泄漏檢測對小泄漏高度敏感，但需要更多的樣品制備。圖 1 突出了環(huán)境污染物的風(fēng)險以及基礎(chǔ) CCI 方法的相關(guān)泄漏檢測水平。提到的其他方法在實用性、非破壞性、可檢測的最小泄漏尺寸和整體測試方法速度等方面存在差異。最終，每種方法都應(yīng)用科學(xué)原理來提供關(guān)于容器密封完整性的最準(zhǔn)確和可靠的測量。

 

Figure 1 CCI Risk and Detection Method
圖 1 容器密封完整性（CCI）風(fēng)險與檢測方法
 

There was a time and place when the microbial-ingress method belonged in the conversation of CCI. While the concern for sterility remains part of the CCI discussion, the advent of new technologies that are more capable of CCI has effectively replaced microbial ingress. The conversation on CCI was once encompassed within the evaluation of microbial-ingress testing.
曾幾何時，微生物侵入方法在容器密封完整性（CCI）的討論中占據(jù)一席之地。雖然對無菌性的關(guān)注仍是 CCI 討論的一部分，但更能檢測 CCI 的新技術(shù)的出現(xiàn)，已經(jīng)有效地取代了微生物侵入方法。曾經(jīng)關(guān)于 CCI 的討論包含在微生物侵入測試的評估之中。

 

 

As with all pharmaceutical risk management, mitigating risk begins with fully understanding the risk. CCI is an interdisciplinary and dynamic space. Each application will present different risks, challenges and opportunities. From a regulatory standpoint, deterministic CCI test methods are gaining favor due to their robustness and ability to promptly provide actionable data.
與所有藥品風(fēng)險管理一樣，降低風(fēng)險始于充分了解風(fēng)險。CCI 是一個跨學(xué)科且充滿動態(tài)變化的領(lǐng)域。每種應(yīng)用都會帶來不同的風(fēng)險、挑戰(zhàn)和機遇。從監(jiān)管的角度來看，確定性的 CCI 測試方法因其穩(wěn)健性和能夠迅速提供可采取行動的數(shù)據(jù)的能力而受到青睞。

 

 

Regulatory bodies recognize the limitations of microbial-ingress testing and increasingly emphasize the importance of deterministic testing approaches that align with current good manufacturing practices and international standards. This shift reflects a broader industry acknowledgment of the limitations of probabilistic tests in ensuring consistent product quality and safety.
監(jiān)管機構(gòu)認(rèn)識到微生物侵入測試的局限性，并越來越強調(diào)與現(xiàn)行良好生產(chǎn)規(guī)范和國際標(biāo)準(zhǔn)一致的確定性測試方法的重要性。這種轉(zhuǎn)變反映了整個行業(yè)對概率性測試在確保產(chǎn)品質(zhì)量和安全一致性方面的局限性的更廣泛認(rèn)可。

 

Summary
總結(jié)
 

The industry has developed a wide variety of deterministic test methods that evaluate CCI with greater accuracy and sensitivity than ever before. Today's test methods available in the marketplace can capture defects in the microbial-ingress range with much greater reliability and accuracy. Provided the context of the microbial-ingress performance and CCI technology capability, it is difficult to argue any future for the microbial-ingress test method.
行業(yè)已經(jīng)開發(fā)出了各種各樣的確定性測試方法，這些方法比以往任何時候都更準(zhǔn)確、更靈敏地評估 CCI。如今市場上可用的測試方法能夠以更高的可靠性和準(zhǔn)確性檢測出微生物侵入范圍內(nèi)的缺陷。鑒于微生物侵入測試的性能和 CCI 技術(shù)能力的背景，微生物侵入測試方法很難有前景。

 

 

In contrast, deterministic CCI Test methods offer a more reliable and standardized approach to assessing container closure integrity. These methods, which include technologies such as Microcurrent high-voltage leak detection (HVLD), vacuum decay, and laser-based headspace analysis, provide quantitative data that directly correlate with the absence of leaks above a defined threshold. Such deterministic outcomes are crucial for regulatory compliance and provide pharmaceutical manufacturers with clear indications of product safety and quality.
相比之下，確定性的 CCI 測試方法為評估容器密封完整性提供了更可靠和標(biāo)準(zhǔn)化的方法。這些方法包括微電流高壓泄漏檢測（HVLD）、真空衰減和基于激光的頂空分析等技術(shù)，提供與在規(guī)定閾值以上無泄漏情況直接相關(guān)的定量數(shù)據(jù)。這樣的確定性結(jié)果對于法規(guī)合規(guī)性至關(guān)重要，并為藥品制造商提供了產(chǎn)品安全和質(zhì)量的明確指示。

 

 

In conclusion, while microbial ingress testing has historically served as a benchmark for container–closure integrity assessment, its probabilistic nature and lack of standardization present significant challenges. Deterministic CCI test methods offer a compelling alternative, providing pharmaceutical scientists and manufacturers with reliable, consistent and actionable data to safeguard product integrity. As the industry continues to evolve, embracing deterministic testing approaches promises to enhance regulatory compliance, streamline quality assurance processes, and, ultimately, bolster patient safety in the realm of parenteral packaging.
總之，雖然微生物侵入測試在歷史上一直是容器密封完整性評估的基準(zhǔn)，但其概率性質(zhì)和缺乏標(biāo)準(zhǔn)化帶來了重大挑戰(zhàn)。確定性的 CCI 測試方法提供了一個有吸引力的替代方案，為藥品科學(xué)家和制造商提供可靠、一致且可采取行動的數(shù)據(jù)，以保障產(chǎn)品完整性。隨著行業(yè)的不斷發(fā)展，采用確定性測試方法有望提高法規(guī)合規(guī)性，簡化質(zhì)量保證流程，并最終在注射用包裝領(lǐng)域增強患者安全。