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Inspection of Injectable Productsfor Visible Particulates
注射產(chǎn)品中可見顆粒的檢查
Guidance for Industry
行業(yè)指南
TABLE OFCONTENTS
目錄
I. INTRODUCTION
介紹
II. STATUTORY AND REGULATORY FRAMEWORK
法律法規(guī)框架
III. CLINICAL RISK OF VISIBLE PARTICULATES
可見顆粒物的臨床風(fēng)險
IV. QUALITY RISK ASSESSMENT
質(zhì)量風(fēng)險評估
V. VISUAL INSPECTION PROGRAM CONSIDERATIONS
目視檢查的程序考慮
A. 100% Inspection
100%檢查
1. Components and Container Closure Systems
部件和容器密封系統(tǒng)
2. Facility and Equipment
設(shè)施和設(shè)備
3. Process
工藝
4. Special Injectable Product Considerations
特殊注射產(chǎn)品的考慮
B. Statistical Sampling
統(tǒng)計學(xué)抽樣
C. Training and Qualification
培訓(xùn)和確認(rèn)
D. Quality Assurance Through a Life Cycle Approach
通過生命周期方法實現(xiàn)質(zhì)量保證
E. Actions To Address Nonconformance
解決不符合問題的措施
VI. REFERENCES
參考文獻(xiàn)
I. INTRODUCTION
介紹
Visibleparticulates in injectable products can jeopardize patient safety. Thisguidance addresses the development and implementation of a holistic, risk-basedapproach to visible particulate control that incorporates product development,manufacturing controls, visual inspection techniques, particulate identification,investigation, and corrective actions designed to assess, correct, and preventthe risk of visible particulate contamination.2The guidance also clarifies that meeting an applicable United StatesPharmacopeia (USP)3compendialstandard alone is not generally sufficient for meeting the current goodmanufacturing practice (CGMP) requirements for the manufacture of injectableproducts. The guidance does not cover subvisible particulates4 or physical defects that products are typicallyinspected for along with inspection for visible particulates (e.g., containerintegrity flaws, fill volume, appearance of lyophilized cake/suspensionsolids).
注射產(chǎn)品中的可見顆粒物會危及患者安全。本指南涉及開發(fā)和實施一種整體的基于風(fēng)險的可見顆?？刂品椒ǎ摲椒ńY(jié)合了產(chǎn)品開發(fā)、生產(chǎn)控制、目視檢查技術(shù)、顆粒識別、調(diào)查和糾正措施，旨在評估、糾正和預(yù)防可見顆粒物污染的風(fēng)險。2本指南還澄清，僅滿足適用的美國藥典（USP）3標(biāo)準(zhǔn)通常不足以滿足注射產(chǎn)品的CGMP要求。本指南不包括亞可見顆粒4或物理缺陷（例如，容器完整性缺陷，灌裝量，凍干粉/懸浮固體的外觀）。
For thepurpose of this guidance:
本指南的目的：
Particulates refer to mobile, undissolvedparticles other than gas bubbles that are unintentionally present in aninjectable product.5They varyin nature (e.g., metal, glass, dust, fiber, rubber, polymer, mold, degradantprecipitate) and can be divided into three categories6:
顆粒是指注射產(chǎn)品中意外存在的氣泡以外的可移動的、不溶的粒子。5它們的性質(zhì)不同（例如，金屬，玻璃，灰塵，纖維，橡膠，聚合物，霉菌，降解物沉淀），可分為三類：
Inherentparticulates are particulates that are an innate product characteristic.
固有顆粒是指產(chǎn)品特性所固有的顆粒。
Intrinsicparticulates are particulates that are derived from the manufacturing equipment,product formulation, or container system.
內(nèi)部顆粒是來自生產(chǎn)設(shè)備、產(chǎn)品配方或容器系統(tǒng)的顆粒。
Extrinsicparticulates are particulates that originate from the manufacturing environment andare foreign to the manufacturing process.
外來顆粒是源自生產(chǎn)環(huán)境的顆粒，是生產(chǎn)工藝的外來異物。
Injectable products generally refer to injectablehuman drugs approved under section 505 of the Federal Food, Drug, and CosmeticAct (FD&C Act), injectable animal drugs approved under section 512 orconditionally approved under section 571 of the FD&C Act, and injectablebiological products licensed under section 351 of the Public Health ServiceAct. In some cases, the injectable product may be a drug or biological productconstituent part of a combination product, such as a drug or biological productprefilled into a syringe (see 21 CFR part 3).7
注射產(chǎn)品通常是指根據(jù)《聯(lián)邦食品、藥品和化妝品法》（FD&C法案）第505條批準(zhǔn)的可注射人用藥物，根據(jù)《聯(lián)邦食品、藥品和化妝品法》（FD&C法案）第512條批準(zhǔn)或根據(jù)《聯(lián)邦食品、藥品和化妝品法》第571條批準(zhǔn)的可注射動物藥物，以及根據(jù)《公共衛(wèi)生服務(wù)法》第351條獲得許可的可注射生物制品。在某些情況下，可注射產(chǎn)品可以是藥物或生物制品組合產(chǎn)品的組成部分，例如預(yù)先填充到注射器中的藥物或生物制品（見21 CFR第3部分）。
Thecontents of this document do not have the force and effect of law and are notmeant to bind the public in any way, unless specifically incorporated into acontract. This document is intended only to provide clarity to the publicregarding existing requirements under the law. FDA guidance documents,including this guidance, should be viewed only as recommendations, unlessspecific regulatory or statutory requirements are cited. The use of the word should in Agency guidance means thatsomething is suggested or recommended, but not required.
本文件的內(nèi)容不具有法律效力，除非特別納入合同，否則無意以任何方式約束公眾。本文件僅用于向公眾明確法律規(guī)定的現(xiàn)有要求。FDA指導(dǎo)文件，包括本指南，應(yīng)僅被視為建議，除非引用了特定的監(jiān)管或法定要求。在機(jī)構(gòu)指南中使用"應(yīng)該"一詞意味著建議或推薦了某些內(nèi)容，但不是必需的。
II. STATUTORYAND REGULATORY FRAMEWORK
法律法規(guī)框架
Undersection 501 of the FD&C Act, a drug product, including an injectableproduct, is deemed adulterated if:
根據(jù)FD&C法案第501條，藥品(包括注射用藥品)在以下情況下被視為摻假:
略
III. CLINICALRISK OF VISIBLE PARTICULATES
可見顆粒的臨床風(fēng)險
Theclinical manifestations of adverse events caused by particulate contaminationvary and may depend on the route of administration (e.g., intravascular,intravisceral, intramuscular), patient population, and nature or class of theparticulates themselves (e.g., physical size or shape, quantity, chemicalreactivity to certain cells or tissues, immunogenicity, infectivity,carcinogenicity). Particulates in intravascular or intravisceral injectionsgenerally can cause more adverse events than those in subcutaneous orintramuscular injections. According to published case reports (Langille 2014;Doessegger et al. 2012), serious adverse events involving injectable productscontaminated with visible particulates have included:
由顆粒物污染引起的不良事件的臨床表現(xiàn)各不相同，可能取決于給藥途徑（例如，血管內(nèi)、內(nèi)臟、肌肉注射）、患者群體以及顆粒本身的性質(zhì)或類別（例如，物理大小或形狀、數(shù)量、對某些細(xì)胞或組織的化學(xué)反應(yīng)、免疫原性、感染性、致癌性）。血管內(nèi)或內(nèi)臟注射中的顆粒物通常比皮下或肌肉注射中的顆粒物引起更多的不良事件。根據(jù)已發(fā)表的病例報告（Langille 2014;Doessegger等人，2012），涉及被可見顆粒污染的注射產(chǎn)品的嚴(yán)重不良事件包括：
At thesystemic level, infection and venous and arterial emboli (thrombotic ornonthrombotic).
全身感染以及靜脈和動脈栓塞（血栓性或非血栓性）。
Microscopic emboli, abscesses, and granulomas in visceralorgans.
內(nèi)臟器官的微栓塞、膿腫和肉芽腫。
Phlebitis, inflammatory reactions, granulomas, andinfections at injection sites.
靜脈炎、炎癥反應(yīng)、肉芽腫和注射部位感染。
Furthermore,different patient populations may have different risks for developing adverseevents after exposure to injectable products contaminated with particulates.Risk factors include age (e.g., pediatric and elderly patients), personal orfamily history of thrombophilia, major surgery, cancer, trauma, underlying infection,autoimmune disease, diabetes-associated late-stage vasculitis, obesity, andsmoking.12
此外，不同的患者群體在暴露于被顆粒物污染的注射產(chǎn)品后，可能有不同的不良事件風(fēng)險。危險因素包括年齡（例如，兒童和老年患者）、易栓癥的個人或家族史、大手術(shù)史、癌癥、創(chuàng)傷、潛在感染、自身免疫性疾病、糖尿病相關(guān)性晚期血管炎、肥胖和吸煙。
Applicantsshould consider these clinical risk factors when developing their qualitytarget product profile and in establishing an appropriate control strategy andacceptance criteria for visible particulates.13
申請人在制定其質(zhì)量目標(biāo)產(chǎn)品概況以及為可見顆粒物建立適當(dāng)?shù)目刂撇呗院徒邮軜?biāo)準(zhǔn)時，應(yīng)考慮這些臨床風(fēng)險因素。
IV. QUALITY RISK ASSESSMENT
風(fēng)險評估
Visibleparticulates can have a negative effect on overall product quality. To ensureproduct quality and to limit clinical risk, manufacturers should conduct a riskassessment during product development.14During this risk assessment, manufacturers shouldidentify the typical visible particulates that could contaminate the injectableproduct and characterize their size ranges, quantity, and composition;determine risks for each type; and provide a visual description (e.g., photographsor drawings of typical defects) to be used for training purposes.15Manufacturersshould also consider the potential sources of particulates, appropriateanalytical methods to monitor them, and mitigation strategies to prevent theirpresence in the final product.
可見顆粒會對整體產(chǎn)品質(zhì)量產(chǎn)生負(fù)面影響。為確保產(chǎn)品質(zhì)量及減少臨床風(fēng)險，制造商應(yīng)在產(chǎn)品開發(fā)期間進(jìn)行風(fēng)險評估。14在此風(fēng)險評估期間，制造商應(yīng)確定可能污染注射產(chǎn)品的典型可見顆粒，并表征其尺寸范圍，數(shù)量和成分;確定每種類型的風(fēng)險;并提供用于培訓(xùn)目的的視覺描述（例如，典型缺陷的照片或圖紙）。15制造商還應(yīng)考慮顆粒物的潛在來源、監(jiān)測顆粒物的適當(dāng)分析方法以及防止其存在于最終產(chǎn)品中的緩解策略。
Differentconsiderations are relevant depending on the category of particulates found duringthe risk assessment:
根據(jù)風(fēng)險評估期間發(fā)現(xiàn)的顆粒物類別，不同的考慮因素是相關(guān)的：
Inherent particulates areassociated with specific products or their formulations—such as proteinaceousparticulates, liposomes, or agglomerates—and are considered part of the qualitytarget product profile. Their presence should not be cause for rejection ofindividual units or product batches if they are a property of the approved productand product release specifications are met. For hard-to-inspect productscontaining inherent particulates, such as suspensions or emulsions, manufacturersshould develop supplemental testing methods to ensure adequate detection ofvisible particulates (see section V, Visual Inspection Program Considerations).In addition, manufacturers should monitor time-dependent changes duringstability testing that may lead to increases in size or number beyond theapproved acceptance criteria.
固有顆粒與特定產(chǎn)品或其配方（如蛋白質(zhì)顆粒、脂質(zhì)體或附聚物）相關(guān)，并被視為目標(biāo)產(chǎn)品質(zhì)量概況的一部分。如果它們是已批準(zhǔn)產(chǎn)品的屬性并且滿足產(chǎn)品放行標(biāo)準(zhǔn)，則它們的存在不應(yīng)導(dǎo)致拒絕單個單元或產(chǎn)品批次。對于含有固有顆粒（如混懸液或乳液）的難以檢測的產(chǎn)品，制造商應(yīng)開發(fā)補(bǔ)充測試方法，以確保充分檢測可見顆粒（參見第五節(jié)，目視檢查程序考慮）。此外，制造商應(yīng)在穩(wěn)定性測試期間監(jiān)控與時間相關(guān)的變化，這些變化可能導(dǎo)致固有顆粒的尺寸或數(shù)量增加，超出批準(zhǔn)的接受標(biāo)準(zhǔn)。
Intrinsic particulates can be related to the manufacturingprocess. Such particulates could come from components, containers and closures(e.g., glass vials, rubber stoppers), and product contact processing equipment(e.g., tubing, filters, gaskets). Manufacturers should control suchparticulates before the actual manufacturing process through careful selectionand quality control of components, containers and closures, packagingmaterials, and manufacturing equipment. Additionally, manufacturers shouldconduct studies to determine whether their manufacturing processes generateparticulates. Similarly, manufacturers should study and understand the impactof handling, washing, and sterilization processes on manufacturing equipment (i.e.,wear and tear) that could lead to particulate generation over time. Suchprocess development studies can minimize intrinsic particulates by informingselection of the appropriate handling, washing, and sterilization proceduresand establishing equipment life spans. Manufacturers should also evaluatetrends in reject data at designated manufacturing facilities and use a lifecycle management approach to monitor and control process-related intrinsicparticulates in their final products.
內(nèi)部顆粒可能與制造過程有關(guān)。這些顆?？赡軄碜越M件、容器和瓶蓋（例如，玻璃瓶、橡膠塞）和產(chǎn)品接觸加工設(shè)備（例如，管道、過濾器、墊圈）。制造商應(yīng)在實際生產(chǎn)工藝之前通過對組件，容器和瓶蓋，包裝材料和制造設(shè)備的仔細(xì)選擇和質(zhì)量控制來控制此類顆粒。此外，制造商應(yīng)進(jìn)行研究，以確定其制造過程是否產(chǎn)生顆粒。同樣，制造商應(yīng)研究和了解加工、清洗和滅菌過程對制造設(shè)備的影響（即磨損），這些影響可能導(dǎo)致顆粒物隨時間推移而產(chǎn)生。這種工藝開發(fā)研究可以通過選擇適當(dāng)?shù)募庸?，清洗和滅菌程序以及確定設(shè)備壽命來最大限度地減少固有顆粒。制造商還應(yīng)在指定的制造工廠評估廢品數(shù)據(jù)的趨勢，并使用生命周期管理方法來監(jiān)測和控制其最終產(chǎn)品中與過程相關(guān)的固有顆粒。
Intrinsic particulates can also be related to the formulation or stabilityof the product or its container closure (e.g., particulates formed because ofprecipitation of active pharmaceutical ingredients, glass delamination, orprotein-silicone oil interaction). These types of particulates can form afterproduct release and can change in size or number when the product is stored.Manufacturers should study the risk of this type of intrinsic particulateforming under accelerated or stressed conditions in the product developmentphase to determine particulate characteristics and any time-dependentparticulate formation or growth that can occur. In addition, an analyticalmethod suitable for characterizing and monitoring product-specific particulatesshould be developed. A robust product design achieved through formulationoptimization and container closure screening during development is critical toreduce the formation of product-related intrinsic particulates. Informationobtained from these studies can be used to support product-specific inspectionprocesses (e.g., particulate seeding for test kits with known product-specificintrinsic particulates, particulate identification, and rejectionclassification).
內(nèi)部顆粒還可以與產(chǎn)品或其容器密閉系統(tǒng)的配方或穩(wěn)定性有關(guān)（例如，由于活性藥物成分的沉淀，玻璃分層或蛋白質(zhì) - 硅油相互作用而形成的顆粒）。這些類型的顆粒物可以在產(chǎn)品放行后形成，并且其大小或數(shù)量在產(chǎn)品儲存期間會發(fā)生改變。制造商應(yīng)在產(chǎn)品開發(fā)階段研究在加速或破壞條件下形成這種類型的固有顆粒的風(fēng)險，以確定顆粒特性以及可能發(fā)生的任何時間依賴性顆粒的形成或發(fā)展。此外，應(yīng)開發(fā)一種適用于表征和監(jiān)測產(chǎn)品特異性顆粒的分析方法。通過開發(fā)過程中的配方優(yōu)化和容器密閉系統(tǒng)篩選實現(xiàn)穩(wěn)健的產(chǎn)品設(shè)計對于減少與產(chǎn)品相關(guān)的內(nèi)在顆粒的形成至關(guān)重要。從這些研究中獲得的信息可用于支持特定于產(chǎn)品的檢測過程（例如，具有已知產(chǎn)品特異性固有顆粒的檢測試劑盒的顆粒篩選，顆粒鑒定和剔除分類）。
Extrinsic particulates arisefrom sources other than the formulation’s components, the containers andclosures, or the manufacturing equipment’s product contact surfaces. Theseparticulates, derived from materials not intended to be in contact with theinjectable product, can negatively affect product quality and could indicatepossible microbial contamination or another CGMP issue. Their presence in thefinal product can occur because of poor conditions in the manufacturingfacility (e.g., poor environmental control; equipment design, age, andmaintenance; facility location, construction, and maintenance; material andpersonnel flows). Manufacturing facilities must be CGMP compliant and ofappropriate design to support the manufacture of injectable products (see 21CFR part 211, subpart C; § 211.63; and part 4).
外來顆粒來自配方組分、容器和瓶蓋或制造設(shè)備的產(chǎn)品接觸面以外的來源。這些顆粒來自不打算與注射產(chǎn)品接觸的材料，可能會對產(chǎn)品質(zhì)量產(chǎn)生負(fù)面影響，并可能表明可能存在微生物污染或其他CGMP問題。它們存在于最終產(chǎn)品中可能是由于制造設(shè)施中的惡劣條件（例如，環(huán)境控制不良;設(shè)備設(shè)計，老化和維護(hù);設(shè)施位置，施工和維護(hù);物料和人員流動）。制造設(shè)施必須符合CGMP標(biāo)準(zhǔn)，并具有適當(dāng)?shù)脑O(shè)計，以支持注射產(chǎn)品的制造（參見21 CFR第211部分，子部分C;§ 211.63;和第4部分）。
Manufacturersshould not rely on downstream adjustments during manufacturing to justify apoorly designed product or process. Instead, quality should be built into themanufacturing process, starting with the development phase and continuingduring scale-up, process qualification studies, and commercial manufacturing.16Successfulmanagement of visible particulates also includes vigilant assessment of thestate of control, early detection of poor process performance, and effectiveprocess improvement throughout the product’s life cycle.
制造商不應(yīng)在制造過程中依靠下游調(diào)整來證明設(shè)計不佳的產(chǎn)品或工藝的合理性。相反，質(zhì)量應(yīng)該內(nèi)置于制造過程中，從開發(fā)階段開始，在放大生產(chǎn)、工藝確認(rèn)研究和商業(yè)制造期間繼續(xù)進(jìn)行。16對可見顆粒物的成功管理還包括對受控狀態(tài)的警惕評估，早期發(fā)現(xiàn)不良工藝性能，以及在整個產(chǎn)品生命周期內(nèi)有效改進(jìn)工藝。
Proactively addressing risk is animportant part of a life cycle approach to visible particulate control. Formalrisk assessments conducted during product development contribute to processunderstanding and form a foundation for knowledge management. Their resultsshould be used to establish adequate product-specific production controls andclearly defined in-process alert and action limits for particulates. Thresholdstudies should be conducted to determine the characteristics (e.g., size,shape, color) of visible particulates that can be reproducibly detected bytrained personnel. These threshold studies can also be the basis forestablishing particulate standards that will be used to establish inspectionprocedures, help avoid inspection bias, and allow manufacturers to verify theirmanufacturing processes are in a state of control.
主動應(yīng)對風(fēng)險是可見顆?？刂频纳芷诜椒ǖ闹匾M成部分。在產(chǎn)品開發(fā)過程中進(jìn)行的正式風(fēng)險評估有助于過程理解，并為知識管理奠定基礎(chǔ)。其結(jié)果應(yīng)用于建立適當(dāng)?shù)漠a(chǎn)品特定生產(chǎn)控制，并明確定義顆粒的工藝警戒限和行動限。應(yīng)進(jìn)行閾值研究，以確定可見顆粒的特征（例如，大小，形狀，顏色）可以由經(jīng)培訓(xùn)的人員可重復(fù)地檢測到。這些閾值研究也可以作為建立顆粒標(biāo)準(zhǔn)的基礎(chǔ)，這些標(biāo)準(zhǔn)將用于建立檢查程序，幫助避免檢查偏差，并允許制造商確認(rèn)其制造過程是否處于受控狀態(tài)。
V. VISUALINSPECTION PROGRAM CONSIDERATIONS
目視檢查程序的考慮點
Visualinspection can be viewed as part of a larger program to ensure that injectableproducts are essentially free of visible particulates.17Duringinjectable product development, manufacturers should establish procedures forinspecting the product, statistical sampling plan(s), acceptance/rejection criteria,and procedures for evaluating inspection results. Inspection procedures carriedover from another site or another product may not always be suitable for a newproduct.
目視檢查可以看作是一個更大的計劃的一部分，以確保注射產(chǎn)品基本上沒有可見顆粒。在可注射產(chǎn)品開發(fā)過程中，制造商應(yīng)建立產(chǎn)品檢驗程序、統(tǒng)計抽樣計劃、驗收/拒收標(biāo)準(zhǔn)和檢驗結(jié)果評價程序。從另一個地點或另一種產(chǎn)品延續(xù)下來的檢驗程序可能并不總是適用于新產(chǎn)品。
Duringprocess scale- up or transfer to contract manufacturers, the visual inspectionmethods should be assessed to confirm they are still appropriate and valid atthe new scale or manufacturing site. The visual inspection program should allowfor appropriate adaptations based on knowledge gained throughout the product’slife cycle. For example, the inspection procedures and/or analytical andstatistical methods may need revision if the batch size, manufacturing process,or conditions change.
在工藝放大或轉(zhuǎn)移至合同制造商的過程中，應(yīng)評估目視檢查方法，以確認(rèn)它們在新的規(guī)?；蛑圃飕F(xiàn)場仍然合適和有效。目視檢查程序應(yīng)允許根據(jù)在整個產(chǎn)品生命周期中獲得的知識進(jìn)行適當(dāng)?shù)恼{(diào)整。例如，如果批量大小、制造工藝或條件發(fā)生變化，則檢查程序和/或分析和統(tǒng)計方法可能需要修訂。
Inaddition to inspection, a visible particulate control program should includethe training and qualification of operators and investigation of discrepancies,including root cause analysis, corrective actions, and preventive actions.
除檢查外，可見顆粒物控制計劃還應(yīng)包括操作人員的培訓(xùn)和確認(rèn)以及偏差調(diào)查，包括根本原因分析，糾正措施和預(yù)防措施。
Trainedand qualified personnel, automated inspection technology, or a combination of bothshould be used to inspect each unit of injectable product for visibleparticulates (hereinafter 100% inspection).In addition, the quality unit should sample each batch for acceptance quality limit (AQL) testing. 18A visualinspection program should ensure that any visible particulates present in thebatch at the time of release are only those that have a low probability ofdetection because they are of a size approaching the visible detection limit.This section covers 100% inspection, statistical sampling, training andqualification, quality assurance through a life cycle approach, and actions toaddress nonconformance.
應(yīng)使用經(jīng)培訓(xùn)和確認(rèn)的人員，自動檢測技術(shù)或兩者的組合來檢測每個可注射產(chǎn)品的可見顆粒（以下簡稱100%檢測）。此外，質(zhì)量部門應(yīng)對每批產(chǎn)品進(jìn)行抽樣，以進(jìn)行驗收質(zhì)量限值（AQL）測試。18目視檢查程序應(yīng)確保放行時批次中出現(xiàn)的任何可見顆粒僅是那些由于其大小接近可見檢測極限而被檢測到的概率較低的顆粒。本節(jié)包括100%檢查，統(tǒng)計抽樣，培訓(xùn)和確認(rèn)，通過生命周期方法進(jìn)行質(zhì)量保證以及解決不符合情況的措施。
A. 100%Inspection
100%檢查
Manufacturersshould conduct 100% inspection during the stage at which there is the greatestlikelihood that visible particulates will be detected in the final container(e.g., before labeling to maximize container clarity). Manufacturers shouldensure that the equipment used and the physical environment where visualinspection will be performed are designed to minimize variability and maximizedetectability in the inspection process.
制造商應(yīng)在最終容器中最有可能檢測到可見顆粒的階段進(jìn)行100%檢查（例如，在貼標(biāo)之前，以最大限度地提高容器的透明度）。制造商應(yīng)確保所使用的設(shè)備和將要進(jìn)行目視檢查的物理環(huán)境以最大限度地減少檢查過程中的可變性和提高可檢測性。
Important factors to considerfollow.
需要考慮的重要因素如下。
1. Componentsand Container Closure Systems
組件和容器密閉系統(tǒng)
Visibleparticulate contamination could be traced to components or container closuresystems. To ensure visible particulate control, manufacturers must have writtenprocedures for the receipt, identification, storage, handling, sampling,testing, and approval or rejection of components and product containers(including devices and device components that contact injectable products) (§211.80; see also part 4). Such procedures must ensure that components andcontainers and closures are tested or examined and approved, as appropriate,before use in manufacturing(§211.84). Containers and closures must not alter the product’s safety, identity,strength, quality, or purity (§§ 211.94(a) and 600.11(h); see also part 4).
可見顆粒污染可能追溯到組件或容器封閉系統(tǒng)。為確?？梢婎w粒物的控制，制造商必須有書面程序來接收、鑒定、儲存、處理、取樣、測試以及批準(zhǔn)或拒絕組件和產(chǎn)品容器（包括接觸注射產(chǎn)品的設(shè)備和設(shè)備組件）（§ 211.80;另見第4部分）。此類程序必須確保在用于制造之前，組件、容器和封蓋在適當(dāng)情況下經(jīng)過測試或檢查和批準(zhǔn)（§ 211.84）。容器和封蓋不得改變產(chǎn)品的安全性、特性、強(qiáng)度、質(zhì)量或純度（§§ 211.94（a）和 600.11（h）;另見第 4 部分）。
2. Facilityand Equipment
設(shè)施和設(shè)備
To complywith CGMP requirements, manufacturing facilities must be designed, constructed,and outfitted with equipment to prevent injectable products from beingcontaminated with particulates. Applicable CGMP regulations include:
為了符合CGMP要求，必須設(shè)計，建造和配備設(shè)備，以防止注射產(chǎn)品被顆粒物污染。適用的CGMP法規(guī)包括：
Buildings and facilities (§§ 211.42 through 211.58and 600.11).
Equipment design, size, and location (§ 211.63).
Equipment construction (§§ 211.65 and 600.11).
Equipment cleaning and maintenance (§§ 211.67 and600.11).
Inspections can be conductedmanually and/or using a range of automated inspection techniques:
檢測可以人工和/或使用一系列自動檢測技術(shù)進(jìn)行：
For manual inspections, the inspectionstation should have a backdrop of one or more solid colors (e.g., black andwhite) to provide adequate contrast and to allow maximum visibility of productcontents. The light intensity of the inspection station is also critical toachieving maximum visibility. Manufacturers should consider container color,size, and shape as well as product characteristics when determining the idealintensity.
對于人工檢查，檢查工作站應(yīng)具有一種或多種純色（例如，黑白）的背景，以提供足夠的對比度并允許產(chǎn)品內(nèi)容物的最大可見性。檢查工作站的光強(qiáng)度對于實現(xiàn)最大可見度也至關(guān)重要。制造商在確定理想強(qiáng)度時，應(yīng)考慮容器的顏色、尺寸和形狀以及產(chǎn)品特性。
During semi-automated inspections, a machinerotates the product at a constant rate past a trained inspector’s field ofvision. Rejected products are removed mechanically or by hand.
在半自動檢測過程中，機(jī)器以恒定的速度旋轉(zhuǎn)產(chǎn)品，以通過經(jīng)培訓(xùn)的檢查員的視野。不合格品通過機(jī)械或手動剔除。
Automated inspection technology can beused as part of an investigation in the inspection process for injectableproducts, as a replacement for manual inspection, or as an additional qualityassurance step. Automated inspection technology can use different wavelengthsand sensors to detect hard-to-see particulates in sterile powder, suspensions,or light-protected injection products for which visual inspection is notcompletely effective.
自動檢測技術(shù)可用作注射產(chǎn)品檢測過程中調(diào)查的一部分，作為手動檢測的替代品，或作為額外的質(zhì)量保證步驟。自動檢測技術(shù)可以使用不同的波長和傳感器來檢測無菌粉末、懸浮液或光保護(hù)注射產(chǎn)品中難以看到的顆粒，這些顆粒的目視檢測并不完全有效。
Regardlessof the technique—manual, semi-automated, or automated—the inspectionenvironment should be free from distractions and extraneous light, and theinspection rate should be qualified and should allow for thorough visualinspection. Manufacturers can operate independent inspection stations asseparate units or units that are connected in a series. Some inspection equipmentdoes not require controlled separate facilities for visible particulateinspection.
無論采用何種技術(shù)（人工、半自動或自動），檢測環(huán)境都應(yīng)不受干擾和無關(guān)光線的影響，并且檢測率應(yīng)符合要求，并應(yīng)允許進(jìn)行徹底的目視檢查。制造商可以將獨立的檢測站作為單獨的單元或串聯(lián)連接的單元進(jìn)行操作。某些檢測設(shè)備不需要受控的單獨設(shè)施進(jìn)行可見顆粒物檢測。
Formanual and semi-automated inspections, the inspection environment should beergonomically designed for inspector comfort.
對于人工和半自動檢測，檢測環(huán)境應(yīng)符合人體工程學(xué)設(shè)計，以確保檢測人員的舒適性。
Forsemi-automated and automated inspections, equipment must be routinelycalibrated, inspected, or checked in accordance with a written program designedto ensure proper performance, and records of those calibration checks andinspections must be maintained (§ 211.68). Equipment should also be properlyqualified. See section V.C, Training and Qualification, for more information.
對于半自動和自動檢查，必須根據(jù)旨在確保適當(dāng)性能的書面程序?qū)υO(shè)備進(jìn)行日常校準(zhǔn)或檢查，并且必須保留這些校準(zhǔn)檢查的記錄（§ 211.68）。設(shè)備也應(yīng)經(jīng)過適當(dāng)?shù)拇_認(rèn)。有關(guān)詳細(xì)信息，請參閱第 V.C 節(jié)"培訓(xùn)和確認(rèn)"。
Whencompared with manual inspection, automated inspection technology may improvedetectability of visible particulates because machine variability is generallyeasier to control than the variability individual personnel can bring to tasksperformed repetitively over time. In some cases, the technology can detecthigher levels of specific visible particulates. In others, it can detectparticulates at the lower end of the visual inspection range with greaterstatistical reliability when compared with manual and semi-automated inspectionof the same product (Melchore 2010).
與人工檢查相比，自動檢測技術(shù)可以提高可見顆粒物的可檢測性，因為機(jī)器的可變性通常比人員隨時間推移重復(fù)執(zhí)行任務(wù)帶來的可變性更容易控制。在某些情況下，該技術(shù)可以檢測更高水平的特定可見顆粒。在其他情況下，與同一產(chǎn)品的人工和半自動檢測相比，它可以檢測視覺檢測范圍下端的顆粒物，具有更高的統(tǒng)計可靠性（Melchore 2010）。
Automatedinspection technology may allow manufacturers to better control productquality. Manufacturers may need to adjust in-process action and alert limits ifthey change from manual to automated inspection. Adjustments should be based onstatistical process and batch data analysis obtained during evaluation andvalidation of automated inspection equipment.
自動檢測技術(shù)可以讓制造商更好地控制產(chǎn)品質(zhì)量。如果制造商從人工檢測更改為自動檢測，則可能需要調(diào)整過程中的行動限和警戒限。調(diào)整應(yīng)基于在自動檢測設(shè)備評估和驗證過程中獲得的統(tǒng)計過程和批次數(shù)據(jù)分析。
Among theautomated inspection technologies currently in use (e.g., high-speed industrialcamera, visible diode array, X-ray, near-field radar, ultraviolet and nearinfrared spectroscopy), each has its advantages and disadvantages but, ifproperly implemented, all can substantially improve the accuracy of visualinspection.
在目前使用的自動檢測技術(shù)（例如，高速工業(yè)相機(jī)、可見二極管陣列、X射線、近場雷達(dá)、紫外和近紅外光譜）中，每種技術(shù)都有其優(yōu)點和缺點，但如實施得當(dāng)，所有這些都可以大大提高目視檢測的準(zhǔn)確性。
3. Process
工藝
Manufacturersshould conduct inspection feasibility studies for visible particulatedetectability, unit inspection duration, illumination, and fatigue time frame.These studies should be scientifically based and analyzed using appropriate statisticalmethodology. Depending on thestudy results, manufacturers mayneed to adjust particulate standards or inspection processes or, in some cases,change equipment to improve accuracy and reduce patient risk.
制造商應(yīng)進(jìn)行可見顆?？蓹z測性、單位檢查持續(xù)時間、照明和疲勞時間框架的檢查可行性研究。這些研究應(yīng)以科學(xué)為基礎(chǔ)，并使用適當(dāng)?shù)慕y(tǒng)計方法進(jìn)行分析。根據(jù)研究結(jié)果，制造商可能需要調(diào)整顆粒標(biāo)準(zhǔn)或檢查過程，或者在某些情況下更換設(shè)備以提高準(zhǔn)確性并降低患者風(fēng)險。
Manufacturersmust implement written procedures for production and process controls (§211.100), which should cover each aspect of the visual inspection process. Suchprocedures should cover handling of the units (e.g., swirling, inversion,distance from light), maximum length of the inspection period without a restbreak, and disposition and documentation of products that were rejected basedon the results of the visual inspection.
制造商必須實施書面的生產(chǎn)和過程控制程序（§ 211.100），其中應(yīng)涵蓋目視檢查過程的各個方面。這些程序應(yīng)包括對被檢查單元的處理（例如，旋轉(zhuǎn)、反轉(zhuǎn)、與光的距離）、無休息不間斷檢查的最長時長，以及根據(jù)目視檢查結(jié)果對被拒絕的產(chǎn)品進(jìn)行處置和記錄。
Acomplete program19for the control and monitoring of particulatematter must include written procedures for production and process control,sampling and testing of in-process materials, and control of microbiologicalcontamination that are designed to minimize the occurrence of visibleparticulates, identify affected batches of injectable product, and facilitateinvestigation to determine the sources of visible particulates (§§ 211.100,211.110, and 211.113).
用于控制和監(jiān)測顆粒物的完整程序19必須包括生產(chǎn)和工藝控制，工藝物料的取樣和測試以及微生物污染控制的書面程序，旨在最大限度地減少可見顆粒的發(fā)生，識別受影響的注射產(chǎn)品批次，并促進(jìn)調(diào)查以確定可見顆粒的來源（§§ 211.100， 211.110 和211.113）。
Writtenprocedures should also cover how to conduct 100% inspections to ensure batchesare essentially free of visible particulates. All records must be documented inaccordance with applicable regulatory requirements (§ 211.188(b)(5); see also §600.12). Adequate written procedures can contribute to a more thorough understandingof the potential sources and quantity of visible particulates, leading toimprovements in process design. The increased level of understanding would alsopromote a more robust particulate control program and higher qualityinvestigations (see § 211.192).
書面程序還應(yīng)涵蓋如何進(jìn)行100%檢查，以確保批次基本上沒有可見顆粒。所有記錄必須根據(jù)適用的法規(guī)要求（§211.188（b）（5）;另見§ 600.12）進(jìn)行記錄。適當(dāng)?shù)臅娉绦蛴兄诟娴亓私饪梢婎w粒的潛在來源和數(shù)量，從而改進(jìn)工藝設(shè)計。理解水平的提高還將促進(jìn)更強(qiáng)大的顆粒物控制程序和更高質(zhì)量的調(diào)查（見§ 211.192）。
4. SpecialInjectable Product Considerations
特殊注射產(chǎn)品考慮
Large volume parenterals should undergo the same level ofinspection as small volume injectable products. In many cases, patient riskfrom particulate contamination is higher for large volume parenterals than forsmall volume injectable products because of the volume of product administeredand the potential for a patient to receive a continuous administration overmany days. Packaging and labeling of large volume parenterals (e.g., overwrapsand printing on the flexible bags) can interfere with visual inspection. Largevolume intravenous bags that have an outer bag can be particularly challengingto inspect. Manufacturers should take appropriate measures to ensure adequate100% inspection of these products. Supplemental destructive testing may also bewarranted to ensure these products are essentially free of visible particulatesif the packaging does not allow for the identification of particulates withinthe accepted visible size range.
大容量注射劑應(yīng)接受與小容量注射產(chǎn)品相同水平的檢查。在許多情況下，由于施用的產(chǎn)品量以及患者連續(xù)多日給藥的可能性，大容量腸胃外的患者顆粒污染風(fēng)險高于小容量注射產(chǎn)品。大容量注射劑的包裝和標(biāo)簽（例如，在軟袋上外包裝和印刷）可能會干擾目視檢查。具有外袋的大容量靜脈注射袋可能特別難以檢查。制造商應(yīng)采取適當(dāng)措施，確保對這些產(chǎn)品進(jìn)行充分的100%檢查。如果包裝不允許在可接受的可見尺寸范圍內(nèi)識別顆粒，則還可以進(jìn)行補(bǔ)充破壞性測試，以確保這些產(chǎn)品基本不含可見顆粒。
Opaque products and containers (e.g.,lyophilized powders, suspension products, tinted vials) present obviouschallenges to visual inspection. Using advanced technologies such as those describedin section V.A.2 in this guidance (e.g., X-ray spectroscopy) can help, as cansupplemental destructive testing after the 100% inspection, which providesadditional assurance of product quality. Supplemental destructive testing maynot be warranted, however, if the technology used in the 100% inspection isvalidated to meet or surpass human inspection capabilities. Manufacturersshould conduct a feasibility study to demonstrate the suitability of thetechnology selected for the specific product.
不透明的產(chǎn)品和容器（例如凍干粉末、懸浮產(chǎn)品、有色小瓶）對目視檢查提出了明顯的挑戰(zhàn)。使用本指南中V.A.2節(jié)中描述的先進(jìn)技術(shù)（例如X射線光譜）可以提供幫助，100%檢查后的補(bǔ)充破壞性測試也可以提供幫助，從而為產(chǎn)品質(zhì)量提供額外的保證。但是，如果100%檢測中使用的技術(shù)經(jīng)過驗證，可以達(dá)到或超過人工檢測能力，則可能不需要補(bǔ)充破壞性測試。制造商應(yīng)進(jìn)行可行性研究，以證明為特定產(chǎn)品選擇的技術(shù)的適用性。
B. StatisticalSampling
抽樣程序
Following100% inspection, manufacturers should employ statistically sound samplingplans, validated inspection methods, and appropriate acceptance criteria toensure that each product batch meets a pre-established AQL for visibleparticulate contamination. This is consistent with USP General Chapters<1> and <790>; however, a more stringent sampling plan and acceptancecriteria may be appropriate for higher risk products.
在100%檢查之后，制造商應(yīng)采用統(tǒng)計上合理的抽樣計劃，經(jīng)過驗證的檢查方法和適當(dāng)?shù)慕邮軜?biāo)準(zhǔn)，以確保每個產(chǎn)品批次都符合預(yù)先建立的可見顆粒污染AQL。這與 USP 通則 <1> 和 <790> 一致;然而，對于高風(fēng)險產(chǎn)品可能適用更嚴(yán)格的抽樣計劃和驗收標(biāo)準(zhǔn)。
Asampling plan allows the user to make a specific statistical quality statement20about theattribute of interest (e.g., a defect) in a batch based on the sample size andsampling locations. Manufacturers should select their sampling plans inaccordance with the risk for a particular type of product defect. CGMPregulations require manufacturers to ensure that batches of injectable productsmeet appropriate specifications and statistical quality control criteria as acondition for their approval and release (§ 211.165).
抽樣計劃允許用戶根據(jù)樣本數(shù)量和抽樣位置對批次中感興趣的屬性（例如，缺陷）20做出具體的統(tǒng)計質(zhì)量陳述。制造商應(yīng)根據(jù)特定類型產(chǎn)品缺陷的風(fēng)險選擇其抽樣計劃。CGMP法規(guī)要求制造商確保注射產(chǎn)品的批次符合適當(dāng)?shù)臉?biāo)準(zhǔn)和統(tǒng)計質(zhì)量控制標(biāo)準(zhǔn)，作為其批準(zhǔn)和放行的條件（§ 211.165）。
Manufacturersshould quantify the following parameters with respect to design and use of samplingplans21:
制造商應(yīng)量化以下有關(guān)設(shè)計和使用抽樣計劃的參數(shù)21：
Operatingcharacteristic curves developed for each defect classification or qualityattribute that is being tested.
為正在測試的每個缺陷分類或質(zhì)量屬性開發(fā)的操作特性曲線。
Accept/rejectcriteria, AQL, and unacceptable quality limit (also referred to as rejectable quality limit, limiting quality, or lot tolerance percent defective).
接受/拒絕標(biāo)準(zhǔn)、AQL 和不可接受的質(zhì)量限度（也稱為可拒絕質(zhì)量限、限制質(zhì)量或批次公差百分比缺陷）。
Themethodology and acceptance criteria for the statistical sampling plan should considerpatient risk, particulate type, and product and container characteristics thatmay interfere with particulate visibility. For example, an adequate samplingplan with an acceptable AQL for nondestructive/destructive testing could followASTM E2234.22Firms that wish to propose an alternative minimumstandard for their specific product should ensure that there is a risk-basedjustification for the proposed standard.
統(tǒng)計抽樣計劃的方法和接受標(biāo)準(zhǔn)應(yīng)考慮患者風(fēng)險、顆粒類型以及可能干擾顆粒物可見性的產(chǎn)品和容器特征。例如，可以遵循ASTM E2234制定一個適當(dāng)?shù)某闃佑媱潱粋€可接受的AQL進(jìn)行無損/破壞性測試。希望為其特定產(chǎn)品提出替代性最低標(biāo)準(zhǔn)的公司應(yīng)確保擬議標(biāo)準(zhǔn)有基于風(fēng)險的理由。
Extrinsicparticulates identified during 100% inspection or AQL of the batch—whichsuggests the presence of filth, sterility assurance issues, or other CGMPviolations—may result in product that could be considered adulterated, even ifthe statistical sampling acceptance criteria are met. Likewise, multiplevisible particulates (extrinsic or intrinsic) within a single container may beindicative of manufacturing problems and should trigger increased scrutiny ofthe batch.
在100%檢查或該批次的AQL期間發(fā)現(xiàn)的外來顆粒物 - 這表明存在污染，無菌保證問題或其他CGMP違規(guī)行為 - 可能導(dǎo)致產(chǎn)品被視為摻假，即使符合統(tǒng)計抽樣接受標(biāo)準(zhǔn)。同樣，單個容器內(nèi)的多個可見顆粒（外來或內(nèi)部）可能表明生產(chǎn)問題，并應(yīng)引發(fā)對批次的更多審查。
Ifretained samples are used to evaluate the suitability of product indistribution (such as in the case of product complaints), manufacturers should consideradditional factors such as historical data for the facility and/or product whenevaluating the suitability of a given product batch.
如果使用留樣樣品來評估產(chǎn)品在分銷中的適用性（例如在產(chǎn)品投訴的情況下），制造商在評估給定產(chǎn)品批次的適用性時應(yīng)考慮其他因素，例如設(shè)施和/或產(chǎn)品的歷史數(shù)據(jù)。
According to § 211.194(a)(2), “the suitability ofall testing methods used shall be verified under actual conditions of use.”Manufacturers also must validate and document tests used to ensure that eachbatch of the product conforms to final specifications for release anddistribution (§ 211.165(e)).
根據(jù)§ 211.194（a）（2），"所有使用的測試方法的適用性應(yīng)在實際使用條件下進(jìn)行驗證。制造商還必須驗證和記錄用于確保每批產(chǎn)品符合最終放行和銷售標(biāo)準(zhǔn)的測試（§ 211.165（e））。
C. Trainingand Qualification
培訓(xùn)和確認(rèn)
Onlycertified inspectors and qualified equipment should be used to inspectinjectable products for visible particulates. Personnel conducting inspections(100% inspection and AQL inspection) must be adequately trained (including, asappropriate, periodic retraining or requalification) (§§ 211.25 and 600.10(b)).
只有經(jīng)認(rèn)證的檢查人員和已確認(rèn)的設(shè)備才能用于檢查注射產(chǎn)品的可見顆粒。進(jìn)行檢查（100%檢查和AQL檢查）的人員必須經(jīng)過充分的培訓(xùn)（包括酌情定期再培訓(xùn)或再確認(rèn)）（§§ 211.25和600.10（b））。
Formalizedtraining and qualification programs promote consistent performance byindividual inspectors or automated inspection machines and help minimizevariability among different inspectors or machines (Melchore 2011). The programcan include a combination of training materials, standard operating procedures(SOPs), on-the-job training, and testing. Inspector candidates should betrained in the relevant CGMP requirements and should have normal near visualacuity (with or without the use of corrective lenses) and no impairment ofcolor vision (Ricci et al. 1998).
正式的培訓(xùn)和確認(rèn)程序促進(jìn)了檢查人員或自動檢查機(jī)的一致性能，并有助于最大限度地減少不同檢查人員或機(jī)器之間的可變性（Melchore 2011）。該程序可以包括培訓(xùn)材料，標(biāo)準(zhǔn)操作程序（SOP），崗位培訓(xùn)和測試的組合。準(zhǔn)檢查人員應(yīng)接受相關(guān)CGMP要求的培訓(xùn)，并且應(yīng)具有正常的近距視敏度（無論是否使用矯正鏡片）并且沒有色覺障礙（Ricci等人，1998年）。
Regarding inspection equipment:
關(guān)于檢查設(shè)備：
Thespecific backdrop and light intensity selected for manual inspection stationsshould be qualified.
為人工檢查站選擇的特定的背景和光強(qiáng)應(yīng)進(jìn)行確認(rèn)。
Semi-automatedinspection equipment should be properly calibrated and qualified at a specificvial-spin and belt speed. Lighting should also be qualified to allow foraccurate human detection of defective products.
半自動檢測設(shè)備應(yīng)在特定的瓶子旋轉(zhuǎn)速度和傳送帶速度下進(jìn)行適當(dāng)校準(zhǔn)和確認(rèn)。照明應(yīng)進(jìn)行確認(rèn)以對有缺陷的產(chǎn)品進(jìn)行準(zhǔn)確的人工檢測。
Automatedinspection machines should be validated to meet or surpass human inspectioncapabilities and can be qualified using training standards or artificialintelligence technology.
自動檢測機(jī)應(yīng)經(jīng)過驗證，以達(dá)到或超過人工檢測能力，并可以使用培訓(xùn)標(biāo)準(zhǔn)或人工智能技術(shù)進(jìn)行確認(rèn)。
Forpersonnel qualification and automated inspection systems validation, a mixtureof good injectable product units and defective units containing visibleparticulates should be used (Melchore 2011). This test set should be preparedand approved by quality assurance staff. Manufacturers should develop librariesof defective units from samples collected throughout the product life cycle,samples created to simulate production defects, or samples purchased to berepresentative of the types of particulates likely to occur for the drugproduct and its manufacturing process. Quality assurance staff should reviewthe library of defective samples and compare the samples to establishedstandards for proper classification. The library should contain examples fromthe lower limits of visual detection determined in the threshold studies. If anew particulate matter defect is identified, it should be analyzed to determineits source and added to the training library.
對于人員確認(rèn)和自動檢測系統(tǒng)驗證，應(yīng)使用好的注射產(chǎn)品單元和含有可見顆粒的缺陷單元的混合（Melchore 2011）。該測試集應(yīng)由質(zhì)量保證人員準(zhǔn)備和批準(zhǔn)。制造商應(yīng)從整個產(chǎn)品生命周期中收集的樣品、為模擬生產(chǎn)缺陷而創(chuàng)建的樣品或為代表藥品及其制造過程中可能發(fā)生的顆粒類型而購買的樣品中開發(fā)缺陷庫。質(zhì)量保證人員應(yīng)檢查有缺陷的樣品庫，并將樣品與已建立的標(biāo)準(zhǔn)進(jìn)行比較，以便進(jìn)行適當(dāng)?shù)姆诸悺Ｔ搸鞈?yīng)包含閾值研究中確定的視覺檢測下限的示例。如果發(fā)現(xiàn)新的顆粒物缺陷，應(yīng)對其進(jìn)行分析以確定其來源并將其添加到培訓(xùn)庫中。
Typically, the percentage ofdefective units in a test set should not exceed 10–20 percent, and the test setquantities should be sufficient to provide an adequate degree of confidence inthe test results. Trained inspectors should review defective units before theyare included in the test set to determine if the visible particulates in themcan be detected under normal conditions, and the identity of defective unitsshould be masked to test subjects. The quality unit should control the testsets to ensure that qualification tests are not manipulated or biased.
通常，測試集中缺陷單元的百分比不應(yīng)超過 10–20%，并且測試集數(shù)量應(yīng)足以在測試結(jié)果中提供足夠的置信度。經(jīng)培訓(xùn)的檢查人員應(yīng)在缺陷單元納入測試集之前對其進(jìn)行檢查，以確定在正常條件下是否可以檢測到其中的可見顆粒，并且應(yīng)向測試對象掩蓋缺陷單元的身份。質(zhì)量單位應(yīng)控制測試集，以確保確認(rèn)測試不受操縱或偏頗。
Thequality unit should also establish and approve qualification protocols thatidentify the sample test sets, test duration, grading method for test results,documentation of test results, acceptance criteria for certification, andactions to be taken for test failures. The protocols should also specify requalificationtesting methods and frequency.
質(zhì)量部門還應(yīng)建立和批準(zhǔn)確認(rèn)方案，以確定樣品測試集，測試持續(xù)時間，測試結(jié)果的分級方法，測試結(jié)果的文件，認(rèn)證的接受標(biāo)準(zhǔn)以及測試失敗應(yīng)采取的行動。方案還應(yīng)規(guī)定再確認(rèn)測試的方法和頻率。
D. QualityAssurance Through a Life Cycle Approach
通過生命周期方法實現(xiàn)質(zhì)量保證
Processperformance and product quality monitoring systems should provide informationto ensure process control throughout a product’s life cycle. Process performancemeasurements (e.g., deviations, in-process defect results, statistical processcontrol reports, equipment and facility breakdowns) provide information on thestate of control during manufacturing. Product quality indicators (e.g.,stability test results, complaints, returned product) can help determinewhether particulate matter in the product caused an event. Similarly, fieldalert reports and adverse event reports could reveal possibleparticulates-related quality issues. This information should be used to evaluatethe effectiveness of visible particulate control strategies.
工藝性能和產(chǎn)品質(zhì)量監(jiān)控系統(tǒng)應(yīng)提供信息，以確保在整個產(chǎn)品生命周期中進(jìn)行工藝控制。工藝性能量度指標(biāo)（例如，偏差、過程中缺陷結(jié)果、統(tǒng)計過程控制報告、設(shè)備和設(shè)施故障）提供有關(guān)制造過程中受控狀態(tài)的信息。產(chǎn)品質(zhì)量指標(biāo)（例如，穩(wěn)定性測試結(jié)果、投訴、退回的產(chǎn)品）可以幫助確定產(chǎn)品中的顆粒物是否導(dǎo)致了事件。同樣，現(xiàn)場警報報告和不良事件報告可以揭示可能與顆粒物相關(guān)的質(zhì)量問題。應(yīng)使用這些信息來評估可見顆粒物控制策略的有效性。
Trends ofincreased particulate contamination, identification of new types ofparticulates, or particulates that exceed alert or action limits may indicate aflaw in product or process design. For example, inconsistent product qualitycould be caused by any one or a combination of these factors:
顆粒物污染增加的趨勢、新型顆粒物的識別或超過警戒限或行動限的顆粒物的識別可能表明產(chǎn)品或工藝設(shè)計中存在缺陷。例如，不一致的產(chǎn)品質(zhì)量可能是由以下任何一個因素或多種因素共同導(dǎo)致的：
Inadequate controls of components, containers, orclosures.
對組件、容器或瓶蓋的控制不足
A product formulation that is not stable.
不穩(wěn)定的產(chǎn)品配方
Uncontrolled changes to the manufacturing process.
制造過程的不受控制的變化。
Equipment and facilities that are not suitable fortheir intended use.
不適合其預(yù)期用途的設(shè)備和設(shè)施。
Personnel practices that generate particles.
產(chǎn)生顆粒的人員實踐
If aninvestigation reveals a flaw in product or process design, it is important toredesign the product or process to ensure reproducible product quality andreduction of particulate matter.
如果調(diào)查發(fā)現(xiàn)產(chǎn)品或工藝設(shè)計中存在缺陷，則必須重新設(shè)計產(chǎn)品或工藝，以確?？芍貜?fù)的產(chǎn)品質(zhì)量并減少顆粒物。
E. ActionsTo Address Nonconformance
解決不符合問題的措施
Manufacturersmust investigate quality discrepancies identified through the inspectionprocess, quality control testing, complaints, or as a result of a batch failureand extend their investigation to other batches that may be affected (§§ 211.192and 211.198). Such investigations should seek to identify the particulates and categorize them (intrinsic orextrinsic) because the presence of certain categories of particulates couldindicate CGMP issues or sterility failures.
制造商必須調(diào)查通過檢查過程、質(zhì)量控制測試、投訴或批次故障導(dǎo)致的質(zhì)量差異，并將其調(diào)查范圍擴(kuò)大到可能受影響的其他批次（§§ 211.192 和 211.198）。此類調(diào)查應(yīng)設(shè)法識別顆粒物并對其進(jìn)行分類（內(nèi)部或外來），因為某些類別的顆粒物的存在可能表明CGMP問題或無菌失敗。
Investigationscan include tightened sampling plans, examination of particles to understandtheir origin, and evaluation of batch release impact. The investigation shoulddetermine the sources of the variation and identify appropriate correctiveactions and preventive actions. The investigations may also revealopportunities to enhance the robustness of particle detection (e.g.,improvements to the 100% inspection or AQL inspection program).
調(diào)查可以包括收嚴(yán)抽樣計劃，檢查顆粒以了解其來源，以及評估批放行的影響。調(diào)查應(yīng)確定變異的來源，并確定適當(dāng)?shù)募m正措施和預(yù)防措施。該調(diào)查還可能揭示增強(qiáng)顆粒檢測穩(wěn)健性的機(jī)會（例如，改進(jìn)100%檢測或AQL檢測程序）。
Investigationsof manufacturing inspection outcomes should be conducted in situations such asthe following:
在以下情況下，應(yīng)進(jìn)行生產(chǎn)檢查結(jié)果的調(diào)查：
Individual or total defect limits are exceeded.
單個缺陷或缺陷總量超出限度。
A batch fails to meet AQL limits.
批次無法滿足 AQL 限度
Atypicaltrends should also be investigated. This includes examining defective unitsremoved from a batch that are within in-process specifications but outside ofstatistical (historical) trend limits for the manufacturing process ordefective units with visible particulates that have not been commonly observed.
還應(yīng)調(diào)查非典型趨勢。這包括檢查從批次中剔除的缺陷單元，這些批次在中控的標(biāo)準(zhǔn)范圍內(nèi)，但超出生產(chǎn)過程的統(tǒng)計（歷史）趨勢限度，或者缺陷單元具有通常未觀察到的可見顆粒。
Reinspectionof product batches may be permissible with appropriate scientific justificationand should be conducted according to approved SOPs with tightened acceptancecriteria. FDA does not recommend more than one reinspection in an attempt torelease a batch with atypical defect levels. Samples failing the AQLreinspection should be counted along with rejects from any other inspection ofthe product (e.g., such as 100% inspection and the original AQL visualinspection) in calculations to account for and reconcile all units of finalproduct in the batch.
產(chǎn)品批次的重新檢查可能是允許的，應(yīng)進(jìn)行適當(dāng)?shù)目茖W(xué)論證和根據(jù)批準(zhǔn)的SOP進(jìn)行，并收嚴(yán)接受標(biāo)準(zhǔn)。FDA不建議在嘗試放行具有非典型缺陷水平的批次時進(jìn)行多次重新檢查。在計算中，未通過 AQL 重新檢查的樣品應(yīng)與產(chǎn)品的任何其他檢查（例如，100%檢查和原始 AQL 目視檢查）的不合格品一起計數(shù)，以計算和核對批次中最終產(chǎn)品的所有單位。
Correctiveactions, such as reinspection, should be justified based on risk and havequality unit oversight and must be documented consistent with applicablewritten procedures (§ 211.100(b)).
糾正措施，如重新檢查，應(yīng)根據(jù)風(fēng)險證明其合理性，并有質(zhì)量部門監(jiān)督，并且必須與適用的書面程序保持一致的記錄（§ 211.100（b））。
Customercomplaints must be handled according to applicable CGMP regulations (§ 211.198)and should result in particulate identification whenever possible, aninvestigation into the potential source of the particulate, corrective actions(if necessary), and analysis of the batch’s retain samples for evidence ofvisible particulate contamination.
客戶投訴必須根據(jù)適用的CGMP法規(guī)（§ 211.198）進(jìn)行處理，并應(yīng)盡可能識別顆粒物，調(diào)查顆粒物的潛在來源，采取糾正措施（如有必要），并分析批次的保留樣品，以獲得可見顆粒污染的證據(jù)。
Ensuringthe effectiveness, safety, and quality of injectable products is of utmost importance.Therefore, FDA recommends the use of a holistic, risk-based approach to visibleparticulate control. This approach includes the use of a robust visualinspection program along with the implementation of other relevant CGMP measuresto help ensure that injectable products are not adulterated and are essentiallyfree of visible particulates.
確保注射產(chǎn)品的有效性、安全性和質(zhì)量至關(guān)重要。因此，F(xiàn)DA建議使用基于風(fēng)險的整體方法來控制可見顆粒物。這種方法包括使用強(qiáng)大的目視檢查程序以及實施其他相關(guān)的CGMP措施，以幫助確保注射產(chǎn)品不摻假，并且基本上沒有可見顆粒。
來源：GMP辦公室
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