FDA《⾏业指南：注射产品可见颗粒的检查》，中英⽂对照版来了！
⾏业指南：注射剂可见异物的检查》草案，该⽂件已完成翻译，现
12⽉14⽇，FDA发布了《⾏业指南：注射剂可见异物的检查
分享给⼤家，如下：
Inspection of Injectable Productsfor Visible Particulates
注射产品中可见颗粒的检查
Guidance for Industry
⾏业指南
TABLE OFCONTENTS
⽬录
I. INTRODUCTION
介绍
II. STATUTORY AND REGULATORY FRAMEWORK
法律法规框架
III. CLINICAL RISK OF VISIBLE PARTICULATES
可见颗粒物的临床风险
IV. QUALITY RISK ASSESSMENT
质量风险评估
V. VISUAL INSPECTION PROGRAM CONSIDERATIONS
⽬视检查的程序考虑
经典小吃A. 100% Inspection
100%检查
1. Components and Container Closure Systems
qq个性签名网好听的手机来电铃声部件和容器密封系统
2. Facility and Equipment
设施和设备
3. Process
⼯艺
4. Special Injectable Product Considerations
特殊注射产品的考虑
B. Statistical Sampling
统计学抽样
C. Training and Qualification
培训和确认
D. Quality Assurance Through a Life Cycle Approach
通过⽣命周期⽅法实现质量保证
E. Actions To Address Nonconformance
解决不符合问题的措施
VI. REFERENCES
参考⽂献
I. INTRODUCTION
介绍
Visibleparticulates in injectable products can jeopardize patient safety. Thisguidance
address the development and implementation of a holistic, risk-badapproach to visible
particulate control that incorporates product development,manufacturing controls, visual谁的本领大教案
inspection techniques, particulate identification,investigation, and corrective actions designed
to asss, 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).
注射产品中的可见颗粒物会危及患者安全。本指南涉及开发和实施⼀种整体的基于风险的可见颗粒控制⽅法，该⽅法结合了产品开发、⽣产控制、⽬视检查技术、颗粒识别、调查和纠正措施，旨在评估、纠正和预防可见颗粒物污染的风险。2本指南还澄清，仅满⾜适⽤的美国药典（USP）3标准通常
不⾜以满⾜注射产品的CGMP要求。本指南不包括亚可见颗粒4或物理缺陷（例如，容器完整性缺陷，灌装量，冻⼲粉/悬浮固体的外观）。
For thepurpo of this guidance:
本指南的⽬的：
Particulates refer to mobile, undissolvedparticles other than gas bubbles that are unintentionally prent in aninjectable product.5They varyin nature (e.g., metal, glass, dust, fiber, rubber, polymer, mold, degradantprecipitate) and can be divided into three categories6：颗粒是指注射产品中意外存在的⽓泡以外的可移动的、不溶的粒⼦。5它们的性质不同（例如，⾦属，玻璃，灰尘，纤维，橡胶，聚合物，霉菌，降解物沉淀），可分为三类：
Inherentparticulates are particulates that are an innate product characteristic.
智能电饭煲怎么用固有颗粒是指产品特性所固有的颗粒。
Intrinsicparticulates are particulates that are derived from the manufacturing equipment,product formulation, or container system.
内部颗粒是来⾃⽣产设备、产品配⽅或容器系统的颗粒。
Extrinsicparticulates are particulates that originate from the manufacturing environment andare foreign to the manufacturing process.
外来颗粒是源⾃⽣产环境的颗粒，是⽣产⼯艺的外来异物。
Injectable products generally refer to injectablehuman drugs approved under ction 505 of the Federal Food, Drug, and CosmeticAct (FD&C Act), injectable animal drugs approved under ction 512 orconditionally approved under ction 571 of the FD&C Act, and injectablebiological products licend under ction 351 of the Public Health ServiceAct. In some cas, 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 (e 21 CFR part 3).7
注射产品通常是指根据《联邦⾷品、药品和化妆品法》（FD&C法案）第505条批准的可注射⼈⽤药物，根据《联邦⾷品、药品和化妆品法》（FD&C法案）第512条批准或根据《联邦⾷品、药品和化妆品法》第571条批准的可注射动物药物，以及根据《公共卫⽣服务法》第351条获得许可的可注射⽣物制品。在某些情况下，可注射产品可以是药物或⽣物制品组合产品的组成部分，例如预先填充到注射器中的药物或⽣物制品（见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 p
ublic 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 u of the word should in Agency guidance means thatsomething is suggested or recommended, but not required.
本⽂件的内容不具有法律效⼒，除⾮特别纳⼊合同，否则⽆意以任何⽅式约束公众。本⽂件仅⽤于向公众明确法律规定的现有要求。FDA指导⽂件，包括本指南，应仅被视为建议，除⾮引⽤了特定的监管或法定要求。在机构指南中使⽤'应该'⼀词意味着建议或推荐了某些内容，但不是必需的。
II. STATUTORYAND REGULATORY FRAMEWORK
法律法规框架
Underction 501 of the FD&C Act, a drug product, including an injectableproduct, is deemed adulterated if:
根据FD&C法案第501条，药品(包括注射⽤药品)在以下情况下被视为掺假:
略
III. CLINICALRISK OF VISIBLE PARTICULATES
可见颗粒的临床风险
Theclinical manifestations of adver events caud by particulate contaminationvary and may depend on the route of administration (e.g., intravascular,intravisceral, intramuscular), patient population, and nature or class of theparticulates themlves (e.g., physical size or shape, quantity, chemicalreactivity to certain cells or tissues, immunogenicity,
infectivity,carcinogenicity). Particulates in intravascular or intravisceral injectionsgenerally can cau more adver events than tho in subcutaneous orintramuscular injections. According to published ca reports (Langille 2014;Doesgger et al. 2012), rious adver events involving injectable productscontaminated with visible particulates have included:
由颗粒物污染引起的不良事件的临床表现各不相同，可能取决于给药途径（例如，⾎管内、内脏、肌⾁注射）、患者群体以及颗粒本⾝的性质或类别（例如，物理⼤⼩或形状、数量、对某些细胞或组织的化学反应、免疫原性、感染性、致癌性）。⾎管内或内脏注射中的颗粒物通常⽐⽪下或肌⾁注射中的颗粒物引起更多的不良事件。根据已发表的病例报告（Langille 2014;Doesgger等⼈，2012），涉及被可见颗粒污染的注射产品的严重不良事件包括：
At thesystemic level, infection and venous and arterial emboli (thrombotic ornonthrombotic).
全⾝感染以及静脉和动脉栓塞（⾎栓性或⾮⾎栓性）。
Microscopic emboli, abscess, and granulomas in visceralorgans.
内脏器官的微栓塞、脓肿和⾁芽肿。
Phlebitis, inflammatory reactions, granulomas, andinfections at injection sites.
静脉炎、炎症反应、⾁芽肿和注射部位感染。
Furthermore,different patient populations may have different risks for developing adverevents 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 dia, diabetes-associated late-stage vasculitis, obesity, andsmoking.12
感恩卡片制作图片
此外，不同的患者群体在暴露于被颗粒物污染的注射产品后，可能有不同的不良事件风险。危险因素包括年龄（例如，⼉童和⽼年患者）、易栓症的个⼈或家族史、⼤⼿术史、癌症、创伤、潜在感染、⾃⾝免疫性疾病、糖尿病相关性晚期⾎管炎、肥胖和吸烟。
Applicantsshould consider the clinical risk factors when developing their qualitytarget product profile and in establishing an appropriate control strategy andacceptance criteria for visible particulates.13
申请⼈在制定其质量⽬标产品概况以及为可见颗粒物建⽴适当的控制策略和接受标准时，应考虑这些临床风险因素。
IV. QUALITY RISK ASSESSMENT
风险评估
Visibleparticulates can have a negative effect on overall product quality. To ensureproduct quality and to limit clinical risk, manufacturers should conduct a riskasssment during product development.14During this risk asssment, 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 ud for training
purpos.15Manufacturersshould also consider the potential sources of particulates,
appropriateanalytical methods to monitor them, and mitigation strategies to prevent theirprence in the final product.
可见颗粒会对整体产品质量产⽣负⾯影响。为确保产品质量及减少临床风险，制造商应在产品开发期间进⾏风险评估。14在此风险评估期间，制造商应确定可能污染注射产品的典型可见颗粒，并表征其尺⼨范围，数量和成分；确定每种类型的风险；并提供⽤于培训⽬的的视觉描述（例如，典型缺陷的照⽚或图纸）。15制造商还应考虑颗粒物的潜在来源、监测颗粒物的适当分析⽅法以及防⽌其存在于最终产品中的缓解策略。
Differentconsiderations are relevant depending on the category of particulates found duringthe risk asssment:
根据风险评估期间发现的颗粒物类别，不同的考虑因素是相关的：
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 prence should not be cau for rejection ofindividual units or product batches if they are a property of the approved productand product relea specifications are met. For hard-to-inspect productscontaining inherent particulates, such as suspensions or emulsions, manufacturer
sshould develop supplemental testing methods to ensure adequate detection ofvisible particulates (e ction V, Visual Inspection Program Considerations).In addition, manufacturers should monitor time-dependent changes duringstability testing that may lead to increas in size or number beyond theapproved acceptance criteria.
固有颗粒与特定产品或其配⽅（如蛋⽩质颗粒、脂质体或附聚物）相关，并被视为⽬标产品质固有颗粒mp3音乐
量概况的⼀部分。如果它们是已批准产品的属性并且满⾜产品放⾏标准，则它们的存在不应导致拒绝单个单元或产品批次。对于含有固有颗粒（如混悬液或乳液）的难以检测的产品，制造商应开发补充测试⽅法，以确保充分检测可见颗粒（参见第五节，⽬视检查程序考虑）。此外，制造商应在稳定性测试期间监控与时间相关的变化，这些变化可能导致固有颗粒的尺⼨或数量增加，超出批准的接受标准。
Intrinsic particulates can be related to the manufacturingprocess. Such particulates could come from components, containers and , glass vials, rubber stoppers), and product contact processing , tubing, filters, gaskets). Manufacturers should control suchparticulates before the actual manufacturing process through careful lectionand quality control of components,
containers and closures, packagingmaterials, and manufacturing equipment. Additionally, manufacturers shouldconduct studies to determine whether their manufacturing process generateparticulates. Similarly, manufacturers should study and understand the impactof handling, washing, and sterilization process on manufacturing equipment (i.e.,wear and tear) that could lead to particulate generation over time. Suchprocess development studies can minimize intrinsic particulates by informinglection of the appropriate handling, washing, and sterilization proceduresand establishing equipment life spans. Manufacturers should also evaluatetrends in reject data at designated manufacturing facilities and u a lifecycle management approach to monitor and control process-related intrinsicparticulates in their final products.
内部颗粒可能与制造过程有关。这些颗粒可能来⾃组件、容器和瓶盖（例如，玻璃瓶、橡胶
内部颗粒
塞）和产品接触加⼯设备（例如，管道、过滤器、垫圈）。制造商应在实际⽣产⼯艺之前通过对组件，容器和瓶盖，包装材料和制造设备的仔细选择和质量控制来控制此类颗粒。此外，制造商应进⾏研究，以确定其制造过程是否产⽣颗粒。同样，制造商应研究和了解加⼯、清洗和灭菌过程对制造设备的影响（即磨损），这些影响可能导致颗粒物随时间推移⽽产⽣。这种⼯艺开发研究可以通过选择
适当的加⼯，清洗和灭菌程序以及确定设备寿命来最⼤限度地减少固有颗粒。制造商还应在指定的制造⼯⼚评估废品数据的趋势，并使⽤⽣命周期管理⽅法来监测和控制其最终产品中与过程相关的固有颗粒。
Intrinsic particulates can also be related to the formulation or stabilityof the product or its container closure (e.g., particulates formed becau ofprecipitation of active pharmaceutical ingredients, glass delamination, orprotein-silicone oil interaction). The types of particulates can form afterproduct relea 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 stresd conditions in the product developmentpha 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 the studies can be ud to support product-specific inspectionprocess (e.g., particulate eding for test kits with known product-specificintrinsic particulates, particulate identification, and rejectionclassification).
大雁塔简介
内部颗粒
内部颗粒还可以与产品或其容器密闭系统的配⽅或稳定性有关（例如，由于活性药物成分的沉淀，玻璃分层或蛋⽩质 - 硅油相互作⽤⽽形成的颗粒）。这些类型的颗粒物可以在产品放⾏后形成，并且其⼤⼩或数量在产品储存期间会发⽣改变。制造商应在产品开发阶段研究在加速或破坏条件下形成这种类型的固有颗粒的风险，以确定颗粒特性以及可能发⽣的任何时间依赖性颗粒的形成或发展。此外，应开发⼀种适⽤于表征和监测产品特异性颗粒的分析⽅法。通过开发过程中的配⽅优化和容器密闭系统筛选实现稳健的产品设计对于减少与产品相关的内在颗粒的形成⾄关重要。从这些研究中获得的信息可⽤于⽀持特定于产品的检测过程（例如，具有已知产品特异性固有颗粒的检测试剂盒的颗粒筛选，颗粒鉴定和剔除分类）。
Extrinsic particulates arifrom sources other than the formulation’s components, the containers andclosures, or the manufacturing equipment’s product contact surfaces. Theparticulates, 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 prence in thefinal product can occur becau 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 of
appropriate design to support the manufacture of injectable products (e 21CFR part 211, subpart C; §211.63; and part 4).
外来颗粒来⾃配⽅组分、容器和瓶盖或制造设备的产品接触⾯以外的来源。这些颗粒来⾃不打外来颗粒
算与注射产品接触的材料，可能会对产品质量产⽣负⾯影响，并可能表明可能存在微⽣物污染或其他CGMP问题。它们存在于最终产品中可能是由于制造设施中的恶劣条件（例如，环境控制不良；设备设计，⽼化和维护；设施位置，施⼯和维护；物料和⼈员流动）。制造设施必须符合CGMP标准，并具有适当的设计，以⽀持注射产品的制造（参见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 pha and continuingduring scale-up, process qualification studies, and commercial manufacturing.16Successfulmanagement of visible particulates also includes vigilant asssment of thestate of control, early detection of poor process performance, and effectiveprocess improvement throughout the product’s life cycle.
制造商不应在制造过程中依靠下游调整来证明设计不佳的产品或⼯艺的合理性。相反，质量应该内置于制造过程中，从开发阶段开始，在放⼤⽣产、⼯艺确认研究和商业制造期间继续进⾏。16对可见颗粒物的成功管理还包括对受控状态的警惕评估，早期发现不良⼯艺性能，以及在整个产品⽣命周期内有效改进⼯艺。
Proactively addressing risk is animportant part of a life cycle approach to visible particulate control. Formalrisk asssments conducted during product development contribute to processunderstanding and form a foundation for knowledge management. Their resultsshould be ud 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. The threshold studies can also be the basis forestablishing particulate standards that will be ud to establish inspectionprocedures, help avoid inspection bias, and allow manufacturers to verify theirmanufacturing process are in a state of control.
