1.1 本规程描述了从生物制药制造过程中使用的一次性组件和组件表面有效液体提取颗粒物的程序的开发、鉴定和常规应用要求。萃取产生液体中颗粒物的悬浮液，使颗粒物易于用于分析表征。 1.2 以国际单位制表示的数值应视为标准值。本标准不包括其他计量单位。 1.3 本标准并非旨在解决与其使用相关的所有安全问题（如有）。 本标准的用户有责任在使用前制定适当的安全、健康和环境实践，并确定监管限制的适用性。 1.4 本国际标准是根据世界贸易组织技术性贸易壁垒（TBT）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》中确立的国际公认标准化原则制定的。 ====意义和用途====== 4.1 用于生物制药制造的传统不锈钢工艺设备在实施前需要清洁和灭菌。 一次性使用系统（SUS）是一种独立设备，通常由塑料组件和组件组成，通常在洁净室中组装，并且在实施之前通常不会进行清洁或冲洗（过滤器除外，过滤器通常在使用之前进行冲洗）。颗粒物的SUS清洁度取决于SUS制造过程的质量，也取决于最终用户实施SUS时的护理和处理。 4.2 在制造一次性部件或组件的过程中，颗粒物可能粘附在SUS（BPSA）的内部（与流体接触）或外部表面。 SUS部件和组件的颗粒物目视检查通常受到半透明或不透明材料的限制，这些材料阻碍了可视化，尤其是内部流体接触表面的可视化。此外，在某些情况下，一次性组件的大尺寸显著降低了目视检查的有效性。更完整的颗粒物负荷评估需要一种使用测试液体从一次性使用部件或组件表面提取颗粒物的方法，该方法使颗粒易于使用计数、尺寸和化学/物理识别方法进行分析表征。 4.3 制药厂使用多种配置和尺寸的一次性组件和组件，如生物反应器、生物工艺容器、管道、连接器、夹具、阀门、传感器和过滤器。从具有易接近表面的小部件中提取颗粒物可能相对容易，但是，从具有不易接近内表面的大型复杂组件中提取颗粒物可能需要更大的努力。 4.4 由于一次性使用的部件和组件种类繁多，因此无法在普遍规定的试验液体体积和能量输入（冲洗/搅拌）条件下规范狭义的提取程序。 本实践中描述的方法具有灵活性和创新性，可以最大限度地实现粒子提取，这是专门针对感兴趣的组件或组件量身定制的。 4.5 在大多数情况下，相对少量的颗粒物在较大的表面积上不均匀分散，并且颗粒物的化学成分和形态也往往不均匀。具有受控数量的已知标准化颗粒物（模拟真实系统）的标准化一次性使用部件和组件的制备具有挑战性。因此，在制定颗粒提取程序时，需要一种实用且方便的方法来评估所选提取程序是否有效，并尽可能多地提取颗粒 4.6 证明从汽车部件表面有效提取颗粒的成熟标准化方法提供了指导（ISO 16232:2018，VDA 19第1部分）。此处描述的从一次性使用部件和组件表面提取颗粒物的标准实践紧密基于ISO 16232:2018汽车部件标准中描述的原则。这种“多次萃取”的萃取程序鉴定方法显著增加了吸附在表面的颗粒物在萃取时被去除的可能性，并且如此鉴定的萃取程序是有效的。 本规程中描述的资格标准基本上与ISO 16232:2018中描述的“下降标准”相同。本质上，该标准要求在鉴定过程中，所选提取程序必须在相对基础上达到大于90%的颗粒去除率。 4.7 请注意，本规程未规定颗粒计数和尺寸测量所需的颗粒测量方法。本规程中描述的提取程序的鉴定将与通常用于两种所谓“可见光”的颗粒测量方法兼容( ≥ 100微米）或“亚微米- 可见“（10至100微米）粒径范围（USP<788>、USP<1788>、USP<790>），包括光遮蔽、膜显微镜或动态流动成像等方法（指南 E3060 ). 为了使本规程有效，所选的颗粒测量方法应具备可靠测定颗粒数（相关粒径范围内的颗粒数）的资格。 4.8 为一次性使用部件和组件表面上的颗粒物选择提取程序的总体目标是最大限度地提高以有效、实用、一致和受控的方式提取颗粒的概率。

1.1 This practice describes the requirements for development, qualification, and routine application of a procedure for the effective liquid extraction of particulate matter from the surfaces of single-use components and assemblies designed for use in biopharmaceutical manufacturing processes. The extraction generates a suspension of particulate matter in liquid which makes the particulate matter readily available for analytical characterization. 1.2 The values stated in SI units are to be regarded as standard. No other units of measurement are included in this standard. 1.3 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. 1.4 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 Conventional stainless-steel process equipment for biopharmaceutical manufacturing require cleaning and sterilization prior to implementation. Single-use systems (SUS), stand-alone equipment typically composed of plastic components and assemblies, are usually assembled in cleanrooms and are usually not cleaned or rinsed prior to implementation (with the exception of filters, which are often rinsed prior to use). SUS cleanliness with respect to particulate matter depends upon the quality of the SUS manufacturing process, and also upon the care and handling of the SUS upon implementation by the end-user. 4.2 In the process of manufacturing single-use components or assemblies, particulate matter may adhere to the interior (fluid contacting) or exterior surfaces of SUS (BPSA). Visual inspection of SUS components and assemblies for particulate matter is often limited by translucent or opaque materials which inhibit visualization, especially of interior fluid-contacting surfaces. Also in some cases, the large size of single-use assemblies significantly reduces the effectiveness of visual inspections. A more complete assessment of particulate matter load requires a method to extract particulate matter from the surfaces of single-use components or assemblies using a test liquid, which makes the particles readily available for analytical characterization using counting, sizing and chemical/physical identification methods. 4.3 Pharmaceutical manufacturers use a wide variety of configurations and sizes of single-use components and assemblies, such as bioreactors, bioprocess containers, tubing, connectors, clamps, valves, sensors and filters. Extraction of particulate matter may be relatively easy from small components with readily accessible surfaces, however, extraction of particulate matter from large and complex assemblies with less readily accessible interior surfaces may require significantly more effort. 4.4 The wide variety of single-use components and assemblies inhibits specification of a narrowly defined extraction procedure with a universally prescribed volume of test liquid and energy input (rinsing/agitation) conditions. The approach described in this practice allows for flexibility and innovative approaches to maximize particle extraction which are specifically tailored to the component or assembly of interest. 4.5 In most cases, relatively small amounts of particulate matter are non-uniformly dispersed over large surface areas, and the particulate matter also is often inhomogeneous in chemical composition and morphology. Standardized single-use components and assemblies with controlled amounts of known standardized particulate matter which simulate real systems are challenging to prepare. Thus in the development of a particle extraction procedure, a practical and expedient methodology is required to assess whether the chosen extraction procedure is effective and extracts as many particles as practically possible 4.6 A well-established standardized methodology for demonstrating effective extraction of particles from the surfaces of automotive components provides guidance (ISO 16232:2018, VDA 19 Part 1). The standard practice described here for the extraction of particulate matter from the surfaces of single-use components and assemblies is closely based upon the principles described in the ISO 16232:2018 standard for automotive components. This “multiple extractions” approach to qualification of an extraction procedure significantly increases the probability that particulate matter adhering to surfaces is removed upon extraction, and that the extraction procedure so qualified is effective. The qualification criterion described in this practice is essentially the same as the “declining criterion” described in ISO 16232:2018. In essence, this criterion requires that during qualification the chosen extraction procedure must achieve an effectiveness of greater than 90% particle removal on a relative basis. 4.7 Note that this practice does not specify the particle measurement method required to count and size the particles. The qualification of the extraction procedure described in this practice will be compatible with particle measurement methods typically used for both so-called “visible” ( ≥ 100 micron) or “sub-visible” (10 to 100 micron) particle size ranges (USP <788>, USP <1788>, USP <790>), which includes methods such as light obscuration, membrane microscopy or dynamic flow imaging (Guide E3060 ). In order for this practice to be effective, the chosen particle measurement method shall have been qualified for reliable determination of the particle count (number of particles in the particle size range of interest). 4.8 The overall goal of a chosen extraction procedure for particulate matter on the surfaces of single-use components and assemblies is to maximize the probability that particles are extracted in an effective, practical, consistent and controlled way.