1.1 本指南为应用自动膜显微镜（AMM）测量肠胃外药物生产工艺和药品中存在的外来固体不溶性颗粒物的测试方法的开发提供了指导。有关AMM测试方法的确认要求，请参见实践 E3411 . 1.2 在AMM测试方法中，通过膜过滤器过滤含有悬浮颗粒的测试液体，颗粒保留在膜过滤器的表面上，用光学显微镜和数码相机对膜过滤器表面成像，并应用图像分析软件确定颗粒计数和颗粒尺寸。 1.3 AMM测试方法可应用于亚可见（<100µm）或可见（ ≥ 100µm）或在肠胃外药物生产的任何阶段存在的颗粒物。 1.4 由AMM测试方法表征的测试液体可以是工艺流体、药物物质或药物产品，或来自加工设备、药物容器、递送装置及其部件表面的液体提取物。 1.5 本指南不适用于肠胃外混悬液固有颗粒(例如细胞、蛋白质聚集体或疫苗佐剂)的表征或液滴(例如硅油)的表征。 1.6 单位- 以SI单位表示的值将被视为标准值。本标准不包括其他计量单位。 1.7 本标准并不旨在解决与其使用相关的所有安全性问题（如果有）。本标准的使用者有责任在使用前建立适当的安全、健康和环境实践并确定法规限制的适用性。 1.8 本国际标准是根据世界贸易组织技术性贸易壁垒委员会发布的《关于制定国际标准、指南和建议的原则的决定》中确立的国际公认的标准化原则制定的。 ======意义和用途====== 4.1 最终胃肠外制剂中存在外来固体和不溶性微粒是一种潜在危害，除了可能降低制剂质量、疗效和可用性外，还可能对接受制剂的患者造成伤害。4.2 本指南为AMM检测方法的开发提供了指导，该方法旨在对肠胃外药物生产中存在的微粒进行计数和测定。AMM测试方法由四个步骤组成:测试液体制备过程、过滤过程、图像采集过程和图像分析过程。 4.3 可以通过膜过滤器直接过滤从药物制造过程中取样的测试液体(诸如工艺流体、药物物质或药物产品)以产生分析膜。感兴趣的测试液体还可以包括通过提取(冲洗、洗涤和冲洗)工艺设备、药物容器、递送装置及其部件的表面而获得的液体提取物。分散在有时大表面积上的颗粒被收集在液体提取物中，并且在通过膜过滤器过滤后，浓缩到分析膜的相对小的表面积上。4.4 在图像采集过程中，通过光学显微镜和数码相机扫描分析膜，产生分析膜表面的多个图像。图像分析过程将多个图像拼接在一起，并确定哪些像素与单个颗粒相关联，哪些像素与膜过滤器背景相关联。对所得分割图像的分析确定存在于分析膜表面上的颗粒的颗粒计数和颗粒尺寸。 4.5 开发将AMM应用于肠胃外药物生产中可能存在的各种颗粒物质的计数和尺寸测定的测试方法提出了重大挑战。在肠胃外药物制造的各个阶段中，可以发现由不同材料组成、大小和形态不同的颗粒。尽管定义不同，但“固有”通常描述源自制剂成分和加工设备、最终容器和药物递送装置的构造材料的一类颗粒。“外在”通常描述源自人类操作者和制造过程周围环境的一类颗粒。固体和不溶性颗粒物质可包括但不限于纺织纤维、毛发纤维、纸纤维、塑料和弹性体颗粒、金属和陶瓷颗粒、皮肤薄片、灰尘、昆虫部分和其他有机物。半固体颗粒(例如蛋白质聚集体)或液滴(例如硅油)可能部分或完全穿透膜过滤器，因此通常不能通过AMM测试方法测量。AMM测试方法可用于测量细胞和基因疗法中药物产品、疫苗佐剂和细胞固有的颗粒物质。然而，固有颗粒的AMM测试方法的开发超出了本指南的范围。 4.6 本指南适用于AMM测试方法的开发，用于测量亚可见（<100µm）和可见（ ≥ 100µm)颗粒，如药典所述。本指南建议使用最大费雷特直径作为特征粒度参数。其他颗粒形态参数的测定超出了本指南的范围。

1.1 This guide provides guidance on the development of test methods that apply automated membrane microscopy (AMM) to the measurement of extraneous solid insoluble particulate matter present in parenteral pharmaceutical manufacturing processes and drug products. For the validation requirements for AMM test methods, see Practice E3411 . 1.2 In an AMM test method, a test liquid containing suspended particles is filtered through a membrane filter, the particles are retained on the surface of the membrane filter, the membrane filter surface is imaged with an optical microscope and digital camera, and application of image analysis software determines particle count and particle sizes. 1.3 AMM test methods may be applied to the measurement of the commonly defined size categories of subvisible (<100 µm) or visible ( ≥ 100 µm) or both particulate matter present during any stage of the manufacturing of parenteral pharmaceuticals. 1.4 The test liquid characterized by an AMM test method may be a process fluid, drug substance or drug product, or liquid extracts from the surfaces of processing equipment, drug containers, delivery devices, and components thereof. 1.5 This guide does not apply to the characterization of particles inherent to parenteral suspensions (for example, cells, protein aggregates, or vaccine adjuvants) or the characterization of liquid droplets (for example, silicone oil). 1.6 Units— The values stated in SI units are to be regarded as standard. No other units of measurement are included in this standard. 1.7 This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility of the user of this standard to establish appropriate safety, health, and environmental practices and determine the applicability of regulatory limitations prior to use. 1.8 This international standard was developed in accordance with internationally recognized principles on standardization established in the Decision on Principles for the Development of International Standards, Guides and Recommendations issued by the World Trade Organization Technical Barriers to Trade (TBT) Committee. ====== Significance And Use ====== 4.1 The presence of extraneous solid and insoluble particulate matter in a final parenteral drug product is a potential hazard that may cause harm to the patient receiving the drug product in addition to potentially reducing drug product quality, efficacy, and availability. 4.2 This guide provides guidance on the development of AMM test methods designed to count and size particulate matter present in the manufacturing of parenteral pharmaceuticals. An AMM test method consists of four steps: a test liquid preparation procedure, a filtration procedure, an image acquisition process, and an image analysis process. 4.3 Test liquids such as process fluids, drug substances, or drug products sampled from pharmaceutical manufacturing processes may be directly filtered through a membrane filter to create an analysis membrane. Test liquids of interest may also include liquid extracts obtained by extraction (rinsing, washing, and flushing) of the surfaces of process equipment, drug containers, delivery devices, and components thereof. Particles dispersed over sometimes large surface areas are collected in the liquid extract and, upon filtering through a membrane filter, become concentrated onto the relatively small surface area of an analysis membrane. 4.4 In the image acquisition process, the analysis membrane is scanned by an optical microscope and digital camera creating multiple images of the analysis membrane surface. The image analysis process stitches together the multiple images and determines which pixels are associated with individual particles and which pixels are associated with the membrane filter background. Analysis of the resulting segmented image determines the particle count and particle sizes of the particles present on the surface of the analysis membrane. 4.5 Development of test methods applying AMM to the counting and sizing of the wide variety of particulate matter potentially present in parenteral pharmaceutical manufacturing presents significant challenges. Particles composed of different materials, varying in size and morphology, may be found in the various stages of parenteral pharmaceutical manufacturing. Although definitions vary, “intrinsic” typically describes a class of particles originating from formulation ingredients and the materials of construction of processing equipment, final containers, and drug delivery devices. “Extrinsic” typically describes a class of particles originating from human operators and the environment surrounding the manufacturing process. Solid and insoluble particulate matter may include, but is not limited to, textile fibers, hair fibers, paper fibers, plastic and elastomeric particles, metal and ceramic particles, skin flakes, dust, insect parts, and other organic matter. Semi-solid particles (for example, protein aggregates) or liquid droplets (for example, silicone oils) may partially or completely penetrate membrane filters and, thus, are not usually measurable by an AMM test method. An AMM test method may be useful for the measurement of particulate matter inherent to drug products, vaccine adjuvants, and cells in cell and gene therapies. However, the development of AMM test methods for inherent particles is out of the scope of this guide. 4.6 This guide is applicable to the development of AMM test methods for measurement of particles in both the commonly defined size categories of subvisible (<100 µm) and visible ( ≥ 100 µm) particles as described in the pharmacopoeias. This guide recommends use of the maximum Feret diameter as a characteristic particle size parameter. Determination of other particle morphology parameters is out of the scope of this guide.