Inspection of Injectable Productsfor Visible Particulates

 

注射產品中可見顆粒的檢查  

 

Guidance for Industry

 

行業指南

 

TABLE OFCONTENTS

 

目錄

 

 I.   INTRODUCTION

介紹

II.  STATUTORY AND REGULATORY FRAMEWORK

法律法規框架

III.  CLINICAL RISK OF VISIBLE PARTICULATES

可見顆粒物的臨床風險

IV.  QUALITY RISK ASSESSMENT

質量風險評估

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

2. Facility and Equipment

設施和設備

3. Process

工藝

4. Special Injectable Product Considerations

特殊注射產品的考慮

B. Statistical Sampling

統計學抽樣

C. Training and Qualification

培訓和確認

D. Quality Assurance Through a Life Cycle Approach

通過生命周期方法實現質量保證

E. Actions To Address Nonconformance

解決不符合問題的措施

VI.  REFERENCES

參考文獻

 

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).

 

注射產品中的可見顆粒物會危及患者安全。本指南涉及開發和實施一種整體的基于風險的可見顆粒控制方法，該方法結合了產品開發、生產控制、目視檢查技術、顆粒識別、調查和糾正措施，旨在評估、糾正和預防可見顆粒物污染的風險。2本指南還澄清，僅滿足適用的美國藥典（USP）3標準通常不足以滿足注射產品的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.

 

內部顆粒是來自生產設備、產品配方或容器系統的顆粒。

 

Extrinsicparticulates are particulates that originate from the manufacturing environment andare foreign to the manufacturing process.

 

外來顆粒是源自生產環境的顆粒，是生產工藝的外來異物。 

 

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

 

注射產品通常是指根據《聯邦食品、藥品和化妝品法》（FD&C法案）第505條批準的可注射人用藥物，根據《聯邦食品、藥品和化妝品法》（FD&C法案）第512條批準或根據《聯邦食品、藥品和化妝品法》第571條批準的可注射動物藥物，以及根據《公共衛生服務法》第351條獲得許可的可注射生物制品。在某些情況下，可注射產品可以是藥物或生物制品組合產品的組成部分，例如預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定的現有要求。FDA指導文件，包括本指南，應僅被視為建議，除非引用了特定的監管或法定要求。在機構指南中使用"應該"一詞意味著建議或推薦了某些內容，但不是必需的。

 

II.  STATUTORYAND REGULATORY FRAMEWORK

 

法律法規框架

 

Undersection 501 of the FD&C Act, a drug product, including an injectableproduct, is deemed adulterated if:

 

根據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各不相同，可能取決于給藥途徑（例如，血管內、內臟、肌肉注射）、患者群體以及顆粒本身的性質或類別（例如，物理大小或形狀、數量、對某些細胞或組織的化學反應、免疫原性、感染性、致癌性）。血管內或內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。根據已發表的病例報告（Langille 2014;Doessegger等人，2012），涉及被可見顆粒污染的注射產品的嚴重不良事件包括：

 

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、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品后，可能有不同的不良事件風險。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、大手術史、癌癥、創傷、潛在感染、自身免疫性疾病、糖尿病相關性晚期血管炎、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

 

申請人在制定其質量目標產品概況以及為可見顆粒物建立適當的控制策略和接受標準時，應考慮這些臨床風險因素。

 

IV.  QUALITY RISK ASSESSMENT

 

風險評估

 

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品質量產生負面影響。為確保產品質量及減少臨床風險，制造商應在產品開發期間進行風險評估。14在此風險評估期間，制造商應確定可能污染注射產品的典型可見顆粒，并表征其尺寸范圍，數量和成分;確定每種類型的風險;并提供用于培訓目的的視覺描述（例如，典型缺陷的照片或圖紙）。15制造商還應考慮顆粒物的潛在來源、監測顆粒物的適當分析方法以及防止其存在于最終產品中的緩解策略。

 

Differentconsiderations are relevant depending on the category of particulates found duringthe risk assessment:

 

根據風險評估期間發現的顆粒物類別，不同的考慮因素是相關的：

 

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.

 

固有顆粒與特定產品或其配方（如蛋白質顆粒、脂質體或附聚物）相關，并被視為目標產品質量概況的一部分。如果它們是已批準產品的屬性并且滿足產品放行標準，則它們的存在不應導致拒絕單個單元或產品批次。對于含有固有顆粒（如混懸液或乳液）的難以檢測的產品，制造商應開發補充測試方法，以確保充分檢測可見顆粒（參見第五節，目視檢查程序考慮）。此外，制造商應在穩定性測試期間監控與時間相關的變化，這些變化可能導致固有顆粒的尺寸或數量增加，超出批準的接受標準。

 

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.

 

內部顆粒可能與制造過程有關。這些顆粒可能來自組件、容器和瓶蓋（例如，玻璃瓶、橡膠塞）和產品接觸加工設備（例如，管道、過濾器、墊圈）。制造商應在實際生產工藝之前通過對組件，容器和瓶蓋，包裝材料和制造設備的仔細選擇和質量控制來控制此類顆粒。此外，制造商應進行研究，以確定其制造過程是否產生顆粒。同樣，制造商應研究和了解加工、清洗和滅菌過程對制造設備的影響（即磨損），這些影響可能導致顆粒物隨時間推移而產生。這種工藝開發研究可以通過選擇適當的加工，清洗和滅菌程序以及確定設備壽命來最大限度地減少固有顆粒。制造商還應在指定的制造工廠評估廢品數據的趨勢，并使用生命周期管理方法來監測和控制其最終產品中與過程相關的固有顆粒。

 

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).

 

內部顆粒還可以與產品或其容器密閉系統的配方或穩定性有關（例如，由于活性藥物成分的沉淀，玻璃分層或蛋白質 - 硅油相互作用而形成的顆粒）。這些類型的顆粒物可以在產品放行后形成，并且其大小或數量在產品儲存期間會發生改變。制造商應在產品開發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險，以確定顆粒特性以及可能發生的任何時間依賴性顆粒的形成或發展。此外，應開發一種適用于表征和監測產品特異性顆粒的分析方法。通過開發過程中的配方優化和容器密閉系統篩選實現穩健的產品設計對于減少與產品相關的內在顆粒的形成至關重要。從這些研究中獲得的信息可用于支持特定于產品的檢測過程（例如，具有已知產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備的產品接觸面以外的來源。這些顆粒來自不打算與注射產品接觸的材料，可能會對產品質量產生負面影響，并可能表明可能存在微生物污染或其他CGMP問題。它們存在于最終產品中可能是由于制造設施中的惡劣條件（例如，環境控制不良;設備設計，老化和維護;設施位置，施工和維護;物料和人員流動）。制造設施必須符合CGMP標準，并具有適當的設計，以支持注射產品的制造（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.

 

制造商不應在制造過程中依靠下游調整來證明設計不佳的產品或工藝的合理性。相反，質量應該內置于制造過程中，從開發階段開始，在放大生產、工藝確認研究和商業制造期間繼續進行。16對可見顆粒物的成功管理還包括對受控狀態的警惕評估，早期發現不良工藝性能，以及在整個產品生命周期內有效改進工藝。

 

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.

 

主動應對風險是可見顆粒控制的生命周期方法的重要組成部分。在產品開發過程中進行的正式風險評估有助于過程理解，并為知識管理奠定基礎。其結果應用于建立適當的產品特定生產控制，并明確定義顆粒的工藝警戒限和行動限。應進行閾值研究，以確定可見顆粒的特征（例如，大小，形狀，顏色）可以由經培訓的人員可重復地檢測到。這些閾值研究也可以作為建立顆粒標準的基礎，這些標準將用于建立檢查程序，幫助避免檢查偏差，并允許制造商確認其制造過程是否處于受控狀態。

 

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，以確保注射產品基本上沒有可見顆粒。在可注射產品開發過程中，制造商應建立產品檢驗程序、統計抽樣計劃、驗收/拒收標準和檢驗結果評價程序。從另一個地點或另一種產品延續下來的檢驗程序可能并不總是適用于新產品。

 

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.

 

在工藝放大或轉移至合同制造商的過程中，應評估目視檢查方法，以確認它們在新的規模或制造現場仍然合適和有效。目視檢查程序應允許根據在整個產品生命周期中獲得的知識進行適當的調整。例如，如果批量大小、制造工藝或條件發生變化，則檢查程序和/或分析和統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包括操作人員的培訓和確認以及偏差調查，包括根本原因分析，糾正措施和預防措施。

 

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.

 

應使用經培訓和確認的人員，自動檢測技術或兩者的組合來檢測每個可注射產品的可見顆粒（以下簡稱100%檢測）。此外，質量部門應對每批產品進行抽樣，以進行驗收質量限值（AQL）測試。18目視檢查程序應確保放行時批次中出現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。本節包括100%檢查，統計抽樣，培訓和確認，通過生命周期方法進行質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.

 

制造商應在最終容器中最有可能檢測到可見顆粒的階段進行100%檢查（例如，在貼標之前，以最大限度地提高容器的透明度）。制造商應確保所使用的設備和將要進行目視檢查的物理環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

 

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。為確保可見顆粒物的控制，制造商必須有書面程序來接收、鑒定、儲存、處理、取樣、測試以及批準或拒絕組件和產品容器（包括接觸注射產品的設備和設備組件）（§ 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、容器和封蓋在適當情況下經過測試或檢查和批準（§ 211.84）。容器和封蓋不得改變產品的安全性、特性、強度、質量或純度（§§ 211.94（a）和 600.11（h）;另見第 4 部分）。

 

2.   Facilityand Equipment

 

設施和設備

 

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，必須設計，建造和配備設備，以防止注射產品被顆粒物污染。適用的CGMP法規包括：

 

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進行：

 

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品內容物的最大可見性。檢查工作站的光強度對于實現最大可見度也至關重要。制造商在確定理想強度時，應考慮容器的顏色、尺寸和形狀以及產品特性。

 

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，機器以恒定的速度旋轉產品，以通過經培訓的檢查員的視野。不合格品通過機械或手動剔除。

 

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.

 

自動檢測技術可用作注射產品檢測過程中調查的一部分，作為手動檢測的替代品，或作為額外的質量保證步驟。自動檢測技術可以使用不同的波長和傳感器來檢測無菌粉末、懸浮液或光保護注射產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（人工、半自動或自動），檢測環境都應不受干擾和無關光線的影響，并且檢測率應符合要求，并應允許進行徹底的目視檢查。制造商可以將獨立的檢測站作為單獨的單元或串聯連接的單元進行操作。某些檢測設備不需要受控的單獨設施進行可見顆粒物檢測。

 

Formanual and semi-automated inspections, the inspection environment should beergonomically designed for inspector comfort.

 

對于人工和半自動檢測，檢測環境應符合人體工程學設計，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，必須根據旨在確保適當性能的書面程序對設備進行日常校準或檢查，并且必須保留這些校準檢查的記錄（§  211.68）。設備也應經過適當的確認。有關詳細信息，請參閱第 V.C 節"培訓和確認"。

 

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，自動檢測技術可以提高可見顆粒物的可檢測性，因為機器的可變性通常比人員隨時間推移重復執行任務帶來的可變性更容易控制。在某些情況下，該技術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.

 

自動檢測技術可以讓制造商更好地控制產品質量。如果制造商從人工檢測更改為自動檢測，則可能需要調整過程中的行動限和警戒限。調整應基于在自動檢測設備評估和驗證過程中獲得的統計過程和批次數據分析。

 

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（例如，高速工業相機、可見二極管陣列、X射線、近場雷達、紫外和近紅外光譜）中，每種技術都有其優點和缺點，但如實施得當，所有這些都可以大大提高目視檢測的準確性。

 

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.

 

制造商應進行可見顆粒可檢測性、單位檢查持續時間、照明和疲勞時間框架的檢查可行性研究。這些研究應以科學為基礎，并使用適當的統計方法進行分析。根據研究結果，制造商可能需要調整顆粒標準或檢查過程，或者在某些情況下更換設備以提高準確性并降低患者風險。

 

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和過程控制程序（§ 211.100），其中應涵蓋目視檢查過程的各個方面。這些程序應包括對被檢查單元的處理（例如，旋轉、反轉、與光的距離）、無休息不間斷檢查的最長時長，以及根據目視檢查結果對被拒絕的產品進行處置和記錄。

 

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).

 

用于控制和監測顆粒物的完整程序19必須包括生產和工藝控制，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生，識別受影響的注射產品批次，并促進調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).

 

書面程序還應涵蓋如何進行100%檢查，以確保批次基本上沒有可見顆粒。所有記錄必須根據適用的法規要求（§211.188（b）（5）;另見§ 600.12）進行記錄。適當的書面程序有助于更全面地了解可見顆粒的潛在來源和數量，從而改進工藝設計。理解水平的提高還將促進更強大的顆粒物控制程序和更高質量的調查（見§  211.192）。

 

4. SpecialInjectable Product Considerations

 

特殊注射產品考慮

 

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.

 

大容量注射劑應接受與小容量注射產品相同水平的檢查。在許多情況下，由于施用的產品量以及患者連續多日給藥的可能性，大容量腸胃外的患者顆粒污染風險高于小容量注射產品。大容量注射劑的包裝和標簽（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。制造商應采取適當措施，確保對這些產品進行充分的100%檢查。如果包裝不允許在可接受的可見尺寸范圍內識別顆粒，則還可以進行補充破壞性測試，以確保這些產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.

 

不透明的產品和容器（例如凍干粉末、懸浮產品、有色小瓶）對目視檢查提出了明顯的挑戰。使用本指南中V.A.2節中描述的先進技術（例如X射線光譜）可以提供幫助，100%檢查后的補充破壞性測試也可以提供幫助，從而為產品質量提供額外的保證。但是，如果100%檢測中使用的技術經過驗證，可以達到或超過人工檢測能力，則可能不需要補充破壞性測試。制造商應進行可行性研究，以證明為特定產品選擇的技術的適用性。

 

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，制造商應采用統計上合理的抽樣計劃，經過驗證的檢查方法和適當的接受標準，以確保每個產品批次都符合預先建立的可見顆粒污染AQL。這與 USP 通則 <1> 和 <790> 一致;然而，對于高風險產品可能適用更嚴格的抽樣計劃和驗收標準。

 

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樣本數量和抽樣位置對批次中感興趣的屬性（例如，缺陷）20做出具體的統計質量陳述。制造商應根據特定類型產品缺陷的風險選擇其抽樣計劃。CGMP法規要求制造商確保注射產品的批次符合適當的標準和統計質量控制標準，作為其批準和放行的條件（§ 211.165）。

 

Manufacturersshould quantify the following parameters with respect to design and use of samplingplans21:

 

制造商應量化以下有關設計和使用抽樣計劃的參數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量屬性開發的操作特性曲線。

 

Accept/rejectcriteria, AQL, and unacceptable quality limit (also referred to as rejectable quality limit, limiting quality, or lot tolerance percent defective).

 

接受/拒絕標準、AQL 和不可接受的質量限度（也稱為可拒絕質量限、限制質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.

 

統計抽樣計劃的方法和接受標準應考慮患者風險、顆粒類型以及可能干擾顆粒物可見性的產品和容器特征。例如，可以遵循ASTM E2234制定一個適當的抽樣計劃，一個可接受的AQL進行無損/破壞性測試。希望為其特定產品提出替代性最低標準的公司應確保擬議標準有基于風險的理由。

 

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期間發現的外來顆粒物 - 這表明存在污染，無菌保證問題或其他CGMP違規行為 - 可能導致產品被視為摻假，即使符合統計抽樣接受標準。同樣，單個容器內的多個可見顆粒（外來或內部）可能表明生產問題，并應引發對批次的更多審查。

 

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品在分銷中的適用性（例如在產品投訴的情況下），制造商在評估給定產品批次的適用性時應考慮其他因素，例如設施和/或產品的歷史數據。

 

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§ 211.194（a）（2），"所有使用的測試方法的適用性應在實際使用條件下進行驗證。制造商還必須驗證和記錄用于確保每批產品符合最終放行和銷售標準的測試（§ 211.165（e））。

 

C.   Trainingand Qualification

 

培訓和確認

 

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)).

 

只有經認證的檢查人員和已確認的設備才能用于檢查注射產品的可見顆粒。進行檢查（100%檢查和AQL檢查）的人員必須經過充分的培訓（包括酌情定期再培訓或再確認）（§§ 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).

 

正式的培訓和確認程序促進了檢查人員或自動檢查機的一致性能，并有助于最大限度地減少不同檢查人員或機器之間的可變性（Melchore 2011）。該程序可以包括培訓材料，標準操作程序（SOP），崗位培訓和測試的組合。準檢查人員應接受相關CGMP要求的培訓，并且應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:

 

關于檢查設備：

 

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應進行確認。

 

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.

 

半自動檢測設備應在特定的瓶子旋轉速度和傳送帶速度下進行適當校準和確認。照明應進行確認以對有缺陷的產品進行準確的人工檢測。

 

Automatedinspection machines should be validated to meet or surpass human inspectioncapabilities and can be qualified using training standards or artificialintelligence technology.

 

自動檢測機應經過驗證，以達到或超過人工檢測能力，并可以使用培訓標準或人工智能技術進行確認。 

 

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.

 

對于人員確認和自動檢測系統驗證，應使用好的注射產品單元和含有可見顆粒的缺陷單元的混合（Melchore 2011）。該測試集應由質量保證人員準備和批準。制造商應從整個產品生命周期中收集的樣品、為模擬生產缺陷而創建的樣品或為代表藥品及其制造過程中可能發生的顆粒類型而購買的樣品中開發缺陷庫。質量保證人員應檢查有缺陷的樣品庫，并將樣品與已建立的標準進行比較，以便進行適當的分類。該庫應包含閾值研究中確定的視覺檢測下限的示例。如果發現新的顆粒物缺陷，應對其進行分析以確定其來源并將其添加到培訓庫中。

 

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超過 10–20%，并且測試集數量應足以在測試結果中提供足夠的置信度。經培訓的檢查人員應在缺陷單元納入測試集之前對其進行檢查，以確定在正常條件下是否可以檢測到其中的可見顆粒，并且應向測試對象掩蓋缺陷單元的身份。質量單位應控制測試集，以確保確認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.

 

質量部門還應建立和批準確認方案，以確定樣品測試集，測試持續時間，測試結果的分級方法，測試結果的文件，認證的接受標準以及測試失敗應采取的行動。方案還應規定再確認測試的方法和頻率。

 

D.  QualityAssurance Through a Life Cycle Approach

 

通過生命周期方法實現質量保證

 

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.

 

工藝性能和產品質量監控系統應提供信息，以確保在整個產品生命周期中進行工藝控制。工藝性能量度指標（例如，偏差、過程中缺陷結果、統計過程控制報告、設備和設施故障）提供有關制造過程中受控狀態的信息。產品質量指標（例如，穩定性測試結果、投訴、退回的產品）可以幫助確定產品中的顆粒物是否導致了事件。同樣，現場警報報告和不良事件報告可以揭示可能與顆粒物相關的質量問題。應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品或工藝設計中存在缺陷。例如，不一致的產品質量可能是由以下任何一個因素或多種因素共同導致的：

 

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.

 

不穩定的產品配方

 

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.

 

不適合其預期用途的設備和設施。

 

Personnel practices that generate particles.

 

產生顆粒的人員實踐

 

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.

 

如果調查發現產品或工藝設計中存在缺陷，則必須重新設計產品或工藝，以確保可重復的產品質量并減少顆粒物。

 

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.

 

制造商必須調查通過檢查過程、質量控制測試、投訴或批次故障導致的質量差異，并將其調查范圍擴大到可能受影響的其他批次（§§ 211.192 和 211.198）。此類調查應設法識別顆粒物并對其進行分類（內部或外來），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).

 

調查可以包括收嚴抽樣計劃，檢查顆粒以了解其來源，以及評估批放行的影響。調查應確定變異的來源，并確定適當的糾正措施和預防措施。該調查還可能揭示增強顆粒檢測穩健性的機會（例如，改進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，應進行生產檢查結果的調查：

 

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.

 

還應調查非典型趨勢。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準范圍內，但超出生產過程的統計（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.

 

產品批次的重新檢查可能是允許的，應進行適當的科學論證和根據批準的SOP進行，并收嚴接受標準。FDA不建議在嘗試放行具有非典型缺陷水平的批次時進行多次重新檢查。在計算中，未通過 AQL 重新檢查的樣品應與產品的任何其他檢查（例如，100%檢查和原始 AQL 目視檢查）的不合格品一起計數，以計算和核對批次中最終產品的所有單位。

 

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，應根據風險證明其合理性，并有質量部門監督，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.

 

客戶投訴必須根據適用的CGMP法規（§  211.198）進行處理，并應盡可能識別顆粒物，調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。

 

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.

 

確保注射產品的有效性、安全性和質量至關重要。因此，FDA建議使用基于風險的整體方法來控制可見顆粒物。這種方法包括使用強大的目視檢查程序以及實施其他相關的CGMP措施，以幫助確保注射產品不摻假，并且基本上沒有可見顆粒。