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嘉峪檢測(cè)網(wǎng) 2022-08-12 22:07
藥品包裝完整性測(cè)試的行業(yè)挑戰(zhàn)和當(dāng)前技術(shù)
2021年5月美國(guó)PDA更新技術(shù)報(bào)告TR 86，此前，TR27是PDA在1998年4月發(fā)布的，距今已有20多年時(shí)間，在這20多年的時(shí)間中，隨著CCIT應(yīng)用實(shí)踐的深入和CCIT技術(shù)的升級(jí)換代，國(guó)際上對(duì)CCIT有了新的認(rèn)識(shí)?；谶@些新的認(rèn)識(shí)、新的技術(shù)和實(shí)踐總結(jié)，PDA整理了一份長(zhǎng)達(dá)57頁(yè)的技術(shù)報(bào)告TR 86。
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密封性檢測(cè)其他需要考慮的問(wèn)題包括運(yùn)輸配送過(guò)程的密封性和商業(yè)化生產(chǎn)中密封性。在運(yùn)輸配送中需要考慮的各種物理因素對(duì)于密封性的影響，如高空運(yùn)輸?shù)膲毫ψ兓瘜?duì)于軟袋和預(yù)灌封包材的密封性具有很大的挑戰(zhàn)性。可依據(jù)ASTM和ISTA的相關(guān)法規(guī)進(jìn)行運(yùn)輸模擬測(cè)試，確保樣品在運(yùn)輸配送過(guò)程中的密封性。商業(yè)化生產(chǎn)的密封性檢測(cè)可以依據(jù)風(fēng)險(xiǎn)評(píng)估的原則，制定檢測(cè)方案，100%在線檢測(cè)或者抽樣檢測(cè)。另外，密封性研究不僅僅是一個(gè)檢測(cè)手段，更是一個(gè)控制策略，應(yīng)對(duì)產(chǎn)品生命周期的各個(gè)階段所面臨的密封性風(fēng)險(xiǎn)進(jìn)行評(píng)估，制定總體控制策略，使用針對(duì)性的方法，控制各個(gè)階段的風(fēng)險(xiǎn)。
Part1包裝完整性評(píng)測(cè)的其他注意事項(xiàng)
Additional Considerations for Package Integrity Profiling
A robust package integrity profile for a given product-package system considers factors experienced throughout the product’s lifecycle as required by USP <1207>. As such, a package integrity profile must consider anticipated or experienced stresses, including those resulting from transportation and distribution. Such stresses may include shock, vibration, compression, tempera-ture, pressure, and general package storage environment.
根據(jù)USP<1207>的要求，給定產(chǎn)品包裝系統(tǒng)的穩(wěn)健的包裝完整性概要考慮了整個(gè)產(chǎn)品生命周期中所經(jīng)歷的因素。因此，包裝完整性概況必須考慮預(yù)期或經(jīng)驗(yàn)的壓力，包括那些由運(yùn)輸和分銷造成的。此類應(yīng)力可能包括沖擊、振動(dòng)、壓縮、溫度、壓力和一般包裝儲(chǔ)存環(huán)境。
Part2運(yùn)輸和分銷
Transportation and Distribution
A package integrity profile is unique to each product-package system, a concept that also applies to storage and distribution considerations. The types of stresses experienced in these lifecycle phases vary widely with dosage form, pack-out configuration, product require-ments, and distribution chain. Additiona-lly, the impact of any single stress factor, such as a temperature excursion, can vary with respect to product. An excursion critical to one product may be insubstantial to the quality of another.
每個(gè)產(chǎn)品包系統(tǒng)都有一個(gè)獨(dú)特的包完整性概況，這一概念也適用于存儲(chǔ)和分銷考慮事項(xiàng)。在這些生命周期階段經(jīng)歷的壓力類型因劑型、包裝配置、產(chǎn)品要求和分銷鏈的不同而大不相同。此外，任何單一應(yīng)力因素的影響（如溫度偏移）可能因產(chǎn)品而異。對(duì)一種產(chǎn)品至關(guān)重要的偏差可能對(duì)另一種產(chǎn)品的質(zhì)量沒(méi)有實(shí)質(zhì)性影響。
Given the potential impact to product quality and sterility, appropriate chall-enges and assessments should be made to ensure that product quality is not affected during the transportation and distribution circuit. The types of challenge conditions and subsequent assessments performed, however, reflect the properly assessed risks for the system in question.
考慮到對(duì)產(chǎn)品質(zhì)量和無(wú)菌性的潛在影響，應(yīng)進(jìn)行適當(dāng)?shù)奶魬?zhàn)和評(píng)估，以確保產(chǎn)品質(zhì)量在運(yùn)輸和分銷過(guò)程中不受影響。然而，挑戰(zhàn)條件的類型和隨后進(jìn)行的評(píng)估反映了對(duì)相關(guān)系統(tǒng)進(jìn)行的適當(dāng)評(píng)估的風(fēng)險(xiǎn)。
As the intent of this report is to focus on package integrity, only those distribu-tion challenges impacting integrity are discussed here. Transportation and distribution challenges are not limited solely to integrity of the package, however. A fully integral package containing a proteinaceous product may experience vibration and shock that does not lead to integrity failure but, for example, may cause aggregation of protein. Thus, in addition to post-challenge CCIT, other assessments may be necessary to evaluate the impact of distribution on overall product quality.
由于本報(bào)告的目的是關(guān)注包的完整性，因此這里只討論影響完整性的那些分銷挑戰(zhàn)。然而，運(yùn)輸和分銷方面的挑戰(zhàn)不僅限于包裝的完整性。含有蛋白質(zhì)產(chǎn)品的完整包裝可能會(huì)經(jīng)歷不會(huì)導(dǎo)致完整性失效的振動(dòng)和沖擊，但可能會(huì)導(dǎo)致蛋白質(zhì)聚集。因此，除了挑戰(zhàn)后的CCIT外，還需要進(jìn)行其他評(píng)估，以評(píng)估分銷對(duì)整體產(chǎn)品質(zhì)量的影響。
物理壓力源
Physical Stressors
Perhaps the most obvious challenges experienced during distribution are physical stresses such as shock, vibration, and compression. Often, these types of events result in gross leakage, for instance, a vial shattering. This type of gross defect is easily detected and generally prevents final use of the product. The formation of cracks, checks, chips, and other small defects, however, may result in leakage that negatively impacts product quality but is not readily detectable by the end user. Thus, these types of defects present a more latent and use-specific risk. Furthermore, such types of defects may result in more serious integrity concerns further along in the distribution chain, as a check may develop into a crack, or a crack may widen and permit liquid loss or microbial ingress.
也許在分銷過(guò)程中遇到的最明顯的挑戰(zhàn)是物理應(yīng)力，如沖擊、振動(dòng)和加壓。通常，這些類型的事件會(huì)導(dǎo)致嚴(yán)重泄漏，例如，小瓶破碎。這種類型的嚴(yán)重缺陷很容易發(fā)現(xiàn)，通常會(huì)妨礙產(chǎn)品的最終使用。然而，裂縫、裂紋、缺口和其他小缺陷的形成可能會(huì)導(dǎo)致泄漏，從而對(duì)產(chǎn)品質(zhì)量產(chǎn)生負(fù)面影響，但最終用戶無(wú)法輕易檢測(cè)到。因此，這些類型的缺陷呈現(xiàn)出更為潛在和特定的使用風(fēng)險(xiǎn)。此外，此類缺陷可能導(dǎo)致分銷鏈中更嚴(yán)重的完整性問(wèn)題，因?yàn)榱鸭y可能會(huì)發(fā)展為裂縫，或者裂縫可能會(huì)擴(kuò)大，并允許液體損失或微生物進(jìn)入。
Consequently, to evaluate and reduce risk associated with a shipment, not only the primary package, but the secondary and tertiary packaging should be considered. Numerous standards are available from such organizations as ASTM and the International Safe Transit Association (ISTA) to reliably and reproducibly subject package systems to physical stresses that replicate a variety of distribution chains, including via truck, rail, air, sea, or others.
因此，為了評(píng)估和降低與裝運(yùn)相關(guān)的風(fēng)險(xiǎn)，不僅應(yīng)考慮初級(jí)包裝，還應(yīng)考慮二級(jí)和三級(jí)包裝。ASTM和國(guó)際安全運(yùn)輸協(xié)會(huì)（ISTA）等組織提供了許多標(biāo)準(zhǔn)，以可靠且可重復(fù)地使包裝系統(tǒng)承受物理應(yīng)力，從而復(fù)制各種配送鏈，包括通過(guò)卡車、鐵路、空運(yùn)、海運(yùn)或其他方式。
壓力
Pressure
In cases where a low-pressure environ-ment could present challenges to the package and product it contains, evaluation of the pressure differentials in a distribution chain could be critical. This is particularly relevant in cases of air shipment, where product may be stored in cargo areas with partial to nonexistent pressurization that, if left unevaluated, may result in unintended consequences. The ability of a sealed flexible container to resist creep or burst during air shipment is an example of risk that should be characterized.
在低壓環(huán)境可能對(duì)包裝及其所含產(chǎn)品構(gòu)成挑戰(zhàn)的情況下，評(píng)估分銷鏈中的壓差可能至關(guān)重要。在空運(yùn)的情況下，這一點(diǎn)尤其重要，因?yàn)楫a(chǎn)品可能儲(chǔ)存在部分或不存在增壓的貨物區(qū)域，如果不進(jìn)行評(píng)估，可能會(huì)導(dǎo)致意外后果。在空運(yùn)過(guò)程中，密封的柔性容器抵抗緩慢形變或爆裂的能力是一個(gè)應(yīng)進(jìn)行表征的風(fēng)險(xiǎn)示例。
Another example, one discussed with increasing frequency as the prevalence of prefilled syringes and prefilled syringe-based devices expands, is the concept of plunger movement. Although the degree to which plunger movement occurs is impacted by fill level, headspace volume, general package design, and pressure differentials experienced, how a low-pressure envir-onment may impact product sterility and quality in these types of systems must also be characterized. As a plunger moves backward, the seal, and possibly the product, may move into an unsterile area of the container. In extreme cases, the plunger may completely exit the barrel.
另一個(gè)例子是柱塞運(yùn)動(dòng)的概念，隨著預(yù)灌封和基于預(yù)灌封器械的普及，討論的頻率越來(lái)越高。盡管柱塞移動(dòng)的程度受到填充水平、頂空體積、一般包裝設(shè)計(jì)和所經(jīng)歷的壓差的影響，但還必須確定低壓環(huán)境如何影響這些類型系統(tǒng)中的產(chǎn)品無(wú)菌性和質(zhì)量。當(dāng)柱塞向后移動(dòng)時(shí)，密封件和產(chǎn)品可能會(huì)移動(dòng)到容器的未滅菌區(qū)域。在極端情況下，柱塞可能會(huì)完全退出套筒。
測(cè)試方法
Testing Approaches
Numerous documents from internation-ally recognized organizations (e.g., ASTM, ISTA, ICH, ISO) are available for reference and provide reproducible ways of evaluating some of these stressors, including physical shock events, thermal cycling, and pressure cycling. However, the simulated distribution chain should reflect the anticipated stressors. Standards are meant to employ repro-ducible simulations but may not account for the variations and intricacies of specific distribution networks, such as iterative air shipments or a combination of different modes of transport. As with the application of many test methods and techniques, a proper assessment of the risks should inform decisions on evaluating such risks.
國(guó)際公認(rèn)組織（如ASTM、ISTA、ICH、ISO）的大量文件可供參考，并提供了評(píng)估某些壓力源的可重現(xiàn)的方法，包括物理沖擊事件、熱循環(huán)和壓力循環(huán)。然而，模擬的分銷鏈應(yīng)反映預(yù)期的壓力源。標(biāo)準(zhǔn)旨在采用可重現(xiàn)的模擬，但可能無(wú)法考慮特定分銷網(wǎng)絡(luò)的變化和復(fù)雜性，如反復(fù)空運(yùn)或不同運(yùn)輸方式的組合。與許多測(cè)試方法和技術(shù)的應(yīng)用一樣，對(duì)風(fēng)險(xiǎn)的適當(dāng)評(píng)估應(yīng)為評(píng)估此類風(fēng)險(xiǎn)的決策提供信息。
Part3100%在線檢測(cè)
100% Online Testing
A holistic approach to controlling CCI should be taken to ensure package integrity at the time of manufacture as well as over the shelf life of the product (17). This holistic approach includes consideration of:
應(yīng)采取整體方法控制CCI，以確保生產(chǎn)時(shí)以及產(chǎn)品保質(zhì)期內(nèi)的包裝完整性（17）。這種整體方法包括考慮：
• CCIT method (in-line, near-line, off-line)
•CCIT方法（在線、近線、離線）
• Quality of primary package compon-ents
•主要包裝組件的質(zhì)量
• Primary package design
•初級(jí)包裝設(shè)計(jì)
• Manufacturing process qualification
•生產(chǎn)工藝鑒定
• Product manufacturing process
•產(chǎn)品生產(chǎn)工藝
• Change control process
•變更控制流程
• Shelf-life assessment
•貨架期評(píng)估
The CCIT method is a critical part of the control strategy, and an in-line test can make the overall approach more robust. However, the in-line test should not be the sole point of control.
CCIT方法是控制策略的關(guān)鍵部分，在線測(cè)試可以使整個(gè)方法更加堅(jiān)固。然而，在線測(cè)試不應(yīng)是唯一的控制點(diǎn)。
In-line testing is defined as 100% testing of all filled and sealed primary packages for CCI during the production process, after the final sealing operation.
在線測(cè)試是指在生產(chǎn)過(guò)程中，在最終密封操作后，對(duì)所有灌裝的和密封的初級(jí)包裝進(jìn)行100%的包裝密封完整性測(cè)試。
Currently, some regulatory requirements state that all container types fused and filled on the filling line (e.g., ampules, blow-fill-seal containers) must be 100% inspected (19). For other products, no current regulatory requirement exists for 100% in-line testing. The decision to conduct 100% in-line testing for other products should be based on risk assessment, as part of a holistic approach. A package that is accepted at the in-line test station is not guaranteed to maintain its CCI during the shelf life and use of the product. Conversely, a package that is rejected by the in-line test station is guaranteed not to meet the product’s CCI requirements. Therefore, the in-line test station acts as a filter for rejected packages, reducing the risk of CCI failures due to random process failure modes.
目前，一些監(jiān)管要求規(guī)定，在灌裝線上熔封和灌裝的所有容器類型（例如安瓿、吹填密封容器）必須進(jìn)行100%檢查（19）。對(duì)于其他產(chǎn)品，目前沒(méi)有關(guān)于100%在線測(cè)試的法規(guī)要求。對(duì)其他產(chǎn)品進(jìn)行100%在線測(cè)試的決定應(yīng)基于風(fēng)險(xiǎn)評(píng)估，作為整體方法的一部分。在線測(cè)試通過(guò)的包裝不能保證在產(chǎn)品的貨架期和使用期間保持其包裝密封完整性。相反，在線測(cè)試沒(méi)有通過(guò)的包裝肯定不符合產(chǎn)品的包裝密封完整性要求。因此，在線測(cè)試充當(dāng)不合格包裝的過(guò)濾器，降低隨機(jī)工藝故障模式導(dǎo)致包裝密封完整性缺失的風(fēng)險(xiǎn)。
Consistent failure modes that are due to equipment malfunctioning or setup can be detected by other means, such as off-line quality control testing. A particular advantage of in-line CCIT compared to off-line quality control testing is the elimination (and cost savings) of handling suspect lots of products due to sample rejection at the off-line test station.
由設(shè)備故障或設(shè)置引起的連續(xù)故障模式可通過(guò)其他方式檢測(cè)，如離線質(zhì)量控制測(cè)試。與離線質(zhì)量控制測(cè)試相比，在線CCIT的一個(gè)特殊優(yōu)勢(shì)是，消除了在離線測(cè)試因樣品不合格而處理可疑批次產(chǎn)品的問(wèn)題（并節(jié)約了成本）。
For high-speed lines, current technolog-ies cannot test for the small-sized defects that off-line test methods can. However, since most process failure modes result in medium to large defects in the package, widening the reject limit for in-line testing is a reasonable and low-risk decision. For each product, its process failure modes are examined to ensure that the in-line test station LoD does indeed present a low risk for that specific product based on its compon-ents, parameters, and requirements.
對(duì)于高速線路，現(xiàn)有技術(shù)無(wú)法測(cè)試離線測(cè)試方法可以測(cè)試的小尺寸缺陷。然而，由于大多數(shù)工藝缺陷模式會(huì)導(dǎo)致包裝中出現(xiàn)中大型缺陷，因此擴(kuò)大在線測(cè)試的不合格限值是一個(gè)合理且低風(fēng)險(xiǎn)的決定。對(duì)于每種產(chǎn)品，檢查其工藝故障模式，以確保在線測(cè)試檢測(cè)限LoD確實(shí)根據(jù)其組件、參數(shù)和要求為特定產(chǎn)品提供低風(fēng)險(xiǎn)保障。
While it can add value in some situations, technology is not currently available to enable 100% in-line testing for all CCS and product types. Where feasible, regulations and quality risk management principles identified in ICH Quality Guideline Q9: Quality Risk Management should be used to determine if 100% in-line testing should be implemented (3).
雖然在某些情況下密封性檢測(cè)可以增加價(jià)值，但目前還沒(méi)有技術(shù)能夠?qū)λ邪b密封系統(tǒng)和產(chǎn)品類型進(jìn)行100%在線測(cè)試。在可行的情況下，應(yīng)使用ICH質(zhì)量指南Q9：質(zhì)量風(fēng)險(xiǎn)管理中確定的法規(guī)和質(zhì)量風(fēng)險(xiǎn)管理原則來(lái)確定是否應(yīng)實(shí)施100%在線測(cè)試（3）。
Integrating 100% in-line testing into the manufacturing process requires a strong commitment. The inline test station requires capital investment and the operational cost of the equipment, which adds to the cost of the product. Multiple test stations may be required on each filling line to overcome differences between line speeds and test station throughput. Furthermore, the equipment requires the manufacturer to provide skilled resources to qualify, operate, and support this type of equipment, which is inherently much more complicated than an off-line quality control test station using the same measurement techno-logy.
將100%在線測(cè)試集成到生產(chǎn)工藝中需要巨大的投入。在線測(cè)試站需要資本投資和設(shè)備的運(yùn)營(yíng)成本，這增加了產(chǎn)品的成本。每條灌裝線上可能需要多個(gè)測(cè)試站，以克服線速度和測(cè)試站吞吐量之間的差異。此外，設(shè)備要求制造商提供熟練的資源，以鑒定、操作和支持此類設(shè)備，這比使用相同測(cè)試技術(shù)的離線質(zhì)量控制測(cè)試站復(fù)雜得多。
No one test method fits all products. In-line test methods must be nondestruc-tive for the specific product to be tested.
沒(méi)有一種測(cè)試方法適用于所有產(chǎn)品。在線測(cè)試方法必須對(duì)待測(cè)試的特定產(chǎn)品具有非破壞性。
Part4將質(zhì)量源于設(shè)計(jì)納入包裝密封完整性測(cè)試計(jì)劃
Building a Quality by Design Approach intothe Container Closure Integrity Testing Program
Pharmaceutical QbD is a systematic approach to development that begins with predefined objectives and empha-sizes product and process understanding and control based on sound science and risk management.
制藥QbD是一種系統(tǒng)化的開發(fā)方法，從預(yù)定義的目標(biāo)開始，強(qiáng)調(diào)基于健全科學(xué)和風(fēng)險(xiǎn)管理的產(chǎn)品和過(guò)程理解和控制。
A QbD concept can be built into a CCIT program, including such elements as:
QbD概念可以構(gòu)建到CCIT計(jì)劃中，包括以下要素：
• Quality target product profile that identifies the critical quality attributes (CQAs) of the product-package system
確定產(chǎn)品-包裝系統(tǒng)關(guān)鍵質(zhì)量屬性（CQA）的質(zhì)量目標(biāo)產(chǎn)品配置文件
• Package design and understanding, including identification of critical material attributes that can affect package integrity
•包裝設(shè)計(jì)和理解，包括識(shí)別可能影響包裝完整性的關(guān)鍵材料屬性
• Process design and understanding, including identification of CPPs, linking the material attributes and process parameters to the CQAs
工藝設(shè)計(jì)和理解，包括識(shí)別CPP（關(guān)鍵工藝參數(shù)），將材料屬性和工藝參數(shù)與CQA聯(lián)系起來(lái)
• Control strategy that includes speci-fications for the productpackage confi-guration with respect to CCI as well as controls during each step of the manufacturing process that will help meet those specifications
控制策略，包括與包裝密封完整性有關(guān)的產(chǎn)品-包裝構(gòu)造規(guī)范，以及生產(chǎn)工藝中每個(gè)步驟的控制，以幫助滿足這些規(guī)范
• Regular quality checks on process capability and continual improvement initiatives
對(duì)工藝能力和持續(xù)改進(jìn)計(jì)劃進(jìn)行定期質(zhì)量檢查
One of the ways users can build QbD into a CCIT program is to employ a risk-based approach. A risk-based CCIT program is built on science-based decisions; it offers an ongoing database of product lifecycle CCIT results (also called a package integrity profile) and a risk management tool for package integrity assurance throughout the lifecycle of the product. The program should demonstrate CCI as a function of ongoing, operative variations that takes into consideration:
用戶將QbD構(gòu)建到CCIT程序中的方法之一是采用基于風(fēng)險(xiǎn)的方法。基于風(fēng)險(xiǎn)的CCIT計(jì)劃建立在基于科學(xué)的決策之上；它提供了一個(gè)產(chǎn)品生命周期CCIT結(jié)果的持續(xù)數(shù)據(jù)庫(kù)（也稱為包完整性概要文件）和一個(gè)風(fēng)險(xiǎn)管理工具，用于在產(chǎn)品的整個(gè)生命周期中保證包的完整性。該計(jì)劃應(yīng)證明包裝密封完整性是持續(xù)的、可操作的變化的函數(shù)，應(yīng)考慮到：
• Design and material of the package
•包裝的設(shè)計(jì)和材料
• Package assembly
•包裝組裝
• Processing conditions
•工藝條件
• Storage, distribution, and stability conditions
•儲(chǔ)存、分配和穩(wěn)定性條件
Following are some key aspects that can be used to build a risk-based CCIT program by considering QbD principles:
以下是通過(guò)考慮QbD原則，可用于構(gòu)建基于風(fēng)險(xiǎn)的CCIT計(jì)劃的一些關(guān)鍵方面：
• CCI over the entire lifecycle of product: The CCIT tool kit needs to demonstrate CCI over the entire lifecycle of the product. More than one test may be employed during a given product’s lifecycle based on the critical parameters to be controlled at that stage in the lifecycle of the product-package system. Section 6.4 discusses the lifecycle approach related to bulk flexible containers.
•產(chǎn)品整個(gè)生命周期內(nèi)的包裝密封完整性：CCIT工具包需要展示產(chǎn)品整個(gè)生命周期內(nèi)的包裝密封完整性。在給定產(chǎn)品的生命周期內(nèi)，根據(jù)產(chǎn)品包裝系統(tǒng)生命周期中該階段要控制的關(guān)鍵參數(shù)，可以采用一個(gè)以上的測(cè)試。第6.4節(jié)討論了與大體積柔性容器相關(guān)的生命周期方法。
Choice of deterministic versus probab-ilistic methods: Deterministic methods are those where the leakage event is based on phenomena that follow a predictable chain of events. Such methods require less preparation, are performed with instruments, and offer quantitative outcomes. Probabilistic methods offer qualitative outcomes that are subject to the probability of a series of events to occur but may still provide valuable information when properly applied. For example, some probabilistic methods may provide information on the location of a defect in a flexible pharmaceutical container. Some probab-ilistic methods may prove more advan-tageous than deterministic methods with respect to enhanced sensitivity. For example, internal-pressure testing has in some cases demonstrated sensitivity down to a smaller micron size when compared to the sensitivity established with a deterministic method.
確定性方法與概率方法的選擇：確定性方法是泄漏事件基于可預(yù)測(cè)事件鏈的現(xiàn)象的方法。這些方法需要較少的準(zhǔn)備，使用儀器進(jìn)行，并提供定量結(jié)果。概率方法提供的定性結(jié)果取決于一系列事件發(fā)生的概率，但在正確應(yīng)用時(shí)仍可能提供有價(jià)值的信息。例如，一些概率方法可以提供柔性藥物容器中缺陷位置的信息。在增強(qiáng)靈敏度方面，某些概率方法可能比確定性方法更為有利。例如，在某些情況下，與確定性方法確定的靈敏度相比，內(nèi)部壓力測(cè)試已證明靈敏度可降至更小的微米尺寸。
Choice of off-line versus in-line, on-line or at-line test methods: Implementation of a chosen CCIT method may vary in its nature depending on the stage in the product lifecycle and the CQAs pertaining to package integrity required at that specific time point.
離線與在線、隨線或近線測(cè)試方法的選擇：所選CCIT方法的實(shí)施在性質(zhì)上可能有所不同，這取決于產(chǎn)品生命周期中的階段以及與特定時(shí)間點(diǎn)所需的包裝完整性相關(guān)的CQA。
— Off-line methods: Measurement does not involve samples removed directly from the manufacturing line. Test methods are typically not high speed, are not integrated into the manufacturing line, and are usually implemented in a laboratory setting.
—離線方法：測(cè)量不涉及直接從生產(chǎn)線取出的樣品。測(cè)試方法通常不是高速的，沒(méi)有集成到生產(chǎn)線中，并且通常在實(shí)驗(yàn)室環(huán)境中實(shí)施。
— In-line methods: Measurement where the sample is not removed from the process stream and methods are not destructive to the sample (see Section 6.2).
— 在線方法：樣品未從工藝流中移除且方法不會(huì)破壞樣品的測(cè)量（見第6.2節(jié)）。
— On-line methods: Measurement where the sample is diverted from the manufacturing process and may be returned to the process stream; these test methods are not destructive to the sample (see Section 6.2).
— 隨線方法：樣品從制造過(guò)程轉(zhuǎn)移并可能返回工藝流的測(cè)量；這些試驗(yàn)方法不會(huì)破壞樣品（見第6.2節(jié)）。
— At-line methods: Measurement where the sample is removed, isolated from the process stream, and analyzed.
— 近線方法：從工藝流中分離樣品并進(jìn)行分析的測(cè)量。
In-line and on-line test methods are typically needed when 100% testing is required during manufacturing. At-line and off-line tests are better suited for testing based on a scientifically valid sampling plan, stability study, and development environments. The selected method(s) must be suitable for the intended use and scope of the specific CCIT. In-line and on-line methods can potentially provide greater assurance that all packages have integrity and can yield instant feedback in the event of package misassembly.
當(dāng)生產(chǎn)過(guò)程中需要100%的測(cè)試時(shí)，通常需要在線和隨線測(cè)試方法。近線和離線測(cè)試更適合基于科學(xué)有效的抽樣計(jì)劃、穩(wěn)定性研究和開發(fā)的測(cè)試。所選方法必須適合特定CCIT的預(yù)期用途和范圍。在線和隨線方法可以潛在地提供更大的保證，即所有包裝都具有完整性，并且在包裝錯(cuò)誤組裝的情況下可以產(chǎn)生即時(shí)反饋。
Sampling: Scientifically valid sampling plans should be based on risk assess-ment in association with appropriate statistical criteria. This could lead to various scenarios, including one where the occurrence of leaks is sufficient to require 100% testing due to a complex or highly variable manufacturing process. In cases where the process is under statistical control, sampling plans may be based on standards adhered to within the local quality management system.
抽樣：科學(xué)有效的抽樣計(jì)劃應(yīng)基于風(fēng)險(xiǎn)評(píng)估和適當(dāng)?shù)慕y(tǒng)計(jì)標(biāo)準(zhǔn)。這可能導(dǎo)致各種情況，包括由于復(fù)雜或高度可變的制造工藝，泄漏的發(fā)生足以要求100%的測(cè)試。當(dāng)工藝在統(tǒng)計(jì)數(shù)據(jù)的控制下，抽樣計(jì)劃可基于當(dāng)?shù)刭|(zhì)量管理體系內(nèi)遵守的標(biāo)準(zhǔn)制定。
Factors to consider for sampling plans include the complexity of the product-package design and related manufact-uring process, available test methods required to ensure product quality, and prior experience with similar configura-tions.
抽樣計(jì)劃考慮的因素包括產(chǎn)品包裝設(shè)計(jì)的復(fù)雜性和相關(guān)的生產(chǎn)工藝、確保產(chǎn)品質(zhì)量所需的可用測(cè)試方法和具有類似配置的先前經(jīng)驗(yàn)。
• Regardless of the nature of the test method (deterministic or probabilistic), the number of samples can provide sufficient confidence through risk assessment.
• 無(wú)論測(cè)試方法的性質(zhì)如何（確定性或概率性），樣本數(shù)量都可以通過(guò)風(fēng)險(xiǎn)評(píng)估提供足夠的置信度。
• Defining the MALL: CCI is established when a package meets its maximum allowable leak limit. Since product quality requirements define the MALL, the choice of test method may be based on the stage of the product lifecycle (initial development, routine manufac-turing, shelf life, and stability assess-ments) and should depend on the critical parameters to be controlled at the specific stage.
• 定義MALL：當(dāng)包裝滿足其最大允許泄漏限值時(shí)，包裝密封完整性便建立了。由于產(chǎn)品質(zhì)量要求定義了MALL，因此，測(cè)試方法的選擇可能基于產(chǎn)品生命周期的階段（初始開發(fā)、常規(guī)生產(chǎn)、貨架期和穩(wěn)定性評(píng)估），并應(yīng)取決于特定階段要控制的關(guān)鍵參數(shù)。
• Designing a CCIT tool kit: The CCIT tool kit should encompass different test methods that can be employed to detect defect types critical to product quality and sterility. Ideally, the tool kit would provide the user with not only details about the test method, its application, and leak detection capability, but also with testing efficiency, including testing speed (time taken to detect leaks of critical value) and throughput (rest times for sample equilibration and measure-ment of control groups). This information will help the user determine which CCIT can be implemented at each stage of the product lifecycle based on the desired CQAs to be achieved.
• 設(shè)計(jì)CCIT工具包：CCIT工具包應(yīng)包含可用于檢測(cè)對(duì)產(chǎn)品質(zhì)量和無(wú)菌性至關(guān)重要的缺陷類型的不同測(cè)試方法。理想情況下，工具包不僅向用戶提供有關(guān)測(cè)試方法、應(yīng)用和泄漏檢測(cè)能力的詳細(xì)信息，還提供測(cè)試效率，包括測(cè)試速度（檢測(cè)臨界值泄漏所需的時(shí)間）和通量（樣本平衡和對(duì)照組測(cè)量的休息時(shí)間）。該信息將幫助用戶根據(jù)要實(shí)現(xiàn)的預(yù)期CQA，確定在產(chǎn)品生命周期的每個(gè)階段可以實(shí)施哪些CCIT。
• Ensuring continuous improvement: In the event of a change to the package design, material, or manufacturing processing conditions (including steril-ization conditions), the risk-based strategy should be designed to trigger a review of the CCIT tool kit to ensure it includes test methods that can detect defects critical to product sterility and quality.
確保持續(xù)改進(jìn)：如果包裝設(shè)計(jì)、材料或生產(chǎn)工藝條件（包括滅菌條件）發(fā)生變化，基于風(fēng)險(xiǎn)的策略應(yīng)設(shè)計(jì)為觸發(fā)對(duì)CCIT工具包的審查，以確保其包括能夠檢測(cè)對(duì)產(chǎn)品無(wú)菌性和質(zhì)量至關(guān)重要的缺陷的測(cè)試方法。
風(fēng)險(xiǎn)評(píng)估
Risk Assessment
A risk-based approach using the quality tools mentioned in ICH Q9 can be a very effective way to assess sterile package integrity and testing applications. Following the lifecycle phases, relevant package integrity parameters are considered to determine product-package quality intent and how to evaluate the critical parameters that effectively impact the integrity of the CCS.
使用ICH Q9中提到的質(zhì)量工具的基于風(fēng)險(xiǎn)的方法是評(píng)估無(wú)菌包裝完整性和測(cè)試應(yīng)用的非常有效的方法。跟隨生命周期的階段，考慮相關(guān)包裝完整性參數(shù)，以確定產(chǎn)品包裝質(zhì)量意圖以及如何評(píng)估有效影響包裝密封系統(tǒng)完整性的關(guān)鍵參數(shù)。
A lifecycle assessment process provides ample time and opportunity to develop improved learning, better understanding, and ongoing generation of compelling data to support the risk of package integrity failure. This QbD approach consists of learning, evaluation, and control strategy determination. The impact or risk of an integrity failure is relevant to both patient and product. The complexity of a package integrity risk assessment is derived from the numerous inputs to the manufacturing and packaging processes and the multiple ways of evaluating the outcomes of these processes. A first step in risk assessment (e.g., using the Hazard Analysis Critical Control Points (HACCP) quality tool) is to identify each incremental process step and the appropriate materials relevant to that step. Next, a verification of the potential risk of failure (i.e., a leak) at the process step is made and a list drawn up of causal factors that might lead to each failure type. Another list is developed that indicates what controls may exist that could mitigate the risks. Subsequently, the risk tool can be used to determine what types of testing (monitoring) are valuable, how frequently testing should be performed, and where or what types of samples should be taken for evaluation.
生命周期評(píng)估過(guò)程提供了充足的時(shí)間和機(jī)會(huì)來(lái)改進(jìn)學(xué)習(xí)、更好的理解和持續(xù)生成引人注目的數(shù)據(jù)，以支持包完整性失敗的風(fēng)險(xiǎn)。這種QbD方法包括學(xué)習(xí)、評(píng)估和控制策略確定。完整性失效的影響或風(fēng)險(xiǎn)與患者和產(chǎn)品相關(guān)。包裝完整性風(fēng)險(xiǎn)評(píng)估的復(fù)雜性來(lái)源于生產(chǎn)和包裝工藝的大量輸入以及評(píng)估這些過(guò)程結(jié)果的多種方法。風(fēng)險(xiǎn)評(píng)估的第一步（例如，使用危害分析關(guān)鍵控制點(diǎn)（HACCP）質(zhì)量工具）是確定每個(gè)增量工藝步驟以及與該步驟相關(guān)的適當(dāng)材料。接下來(lái)，對(duì)工藝步驟中的潛在失敗風(fēng)險(xiǎn)（即泄漏）進(jìn)行驗(yàn)證，并列出可能導(dǎo)致每種失敗類型的原因。另一份清單也需要制定，用以說(shuō)明可能存在哪些控制措施可以減輕風(fēng)險(xiǎn)。隨后，可以使用風(fēng)險(xiǎn)工具來(lái)確定哪些類型的測(cè)試（監(jiān)測(cè)）是有價(jià)值的，應(yīng)多久進(jìn)行一次測(cè)試，以及應(yīng)在何處或采取何種類型的樣本進(jìn)行評(píng)估。
Similar to Six Sigma thinking (define-measure-analyze-improve-control), the risk assessment process is an ongoing methodology for quality improvement.
與6 Sigma思想（定義-測(cè)量-分析-改進(jìn)-控制）類似，風(fēng)險(xiǎn)評(píng)估過(guò)程是一種持續(xù)的質(zhì)量改進(jìn)方法。
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