1.1 生物治疗药物和疫苗易受内在蛋白质聚集体形成的影响，这可能会在产品保质期内发生变化。也可能存在固有颗粒，包括赋形剂、硅油和来自工艺、容器/封盖、设备或输送装置的其他颗粒，以及来自所含工艺外部来源的外来颗粒。在整个产品生命周期（从初始表征和配方到成品到期）中监测和识别亚可见颗粒的来源可以优化产品开发、工艺设计、改进工艺控制、改进制造工艺，并确保批量生产- 保持一致性。 1.2 了解颗粒的性质及其来源是采取行动调整制造过程以确保最终产品质量的关键。动态成像显微镜是一种有用的技术，用于在产品开发、过程中和商业释放期间进行颗粒分析和表征（蛋白质类和其他类型），在以下情况下对亚可见颗粒进行敏感检测和表征: ≥ 2和 ≤ 100微米（如果有数据，也可以报告更小和更大的颗粒）。 在该技术中，亮场照明用于直接在过程流中捕获图像，或在连续样本流通过位于成像系统视野中的流动池时捕获图像。算法执行粒子检测例程。这一过程是动态成像过程中的关键步骤。样本中的数字颗粒图像由图像形态学分析软件处理，该软件对颗粒的大小、数量和其他形态参数进行量化。动态成像粒子分析仪可以通过将粒子数除以成像流体的体积，直接确定每单位体积的粒子数（即粒子浓度），作为粒子大小的函数（参见 附录X1 ). 1.3 本指南将描述在生物制造过程中应用动态成像识别颗粒的潜在来源和原因的最佳实践和注意事项。这些结果可用于监测这些颗粒，并在可能的情况下调整制造过程以避免其形成。本指南还将介绍动态成像分析的基本原理，包括图像分析方法、样品制备、仪器校准和验证以及数据报告。 1.4 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。 1.5 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和健康实践，并确定监管限制的适用性。 ====意义和用途====== 4.1 本指南将包括制造商对生物制造操作中亚可见颗粒的来源和潜在原因的考虑，以及使用动态成像颗粒分析仪作为建议的常用监测方法。 本指南将介绍使用动态成像显微镜进行颗粒分析的以下组成部分:基本原理、操作、图像分析方法、样品处理、仪器校准和数据报告。

1.1 Biotherapeutic drugs and vaccines are susceptible to inherent protein aggregate formation which may change over the product shelf life. Intrinsic particles, including excipients, silicone oil, and other particles from the process, container/closures, equipment or delivery devices, and extrinsic particles which originate from sources outside of the contained process, may also be present. Monitoring and identifying the source of the subvisible particles throughout the product life cycle (from initial characterization and formulation through finished product expiry) can optimize product development, process design, improve process control, improve the manufacturing process, and ensure lot-to-lot consistency. 1.2 Understanding the nature of particles and their source is a key to the ability to take actions to adjust the manufacturing process to ensure final product quality. Dynamic imaging microscopy is a useful technique for particle analysis and characterization (proteinaceous and other types) during product development, in-process and commercial release with a sensitive detection and characterization of subvisible particles at ≥ 2 and ≤ 100 micrometers (although smaller and larger particles may also be reported if data are available). In this technique brightfield illumination is used to capture images either directly in a process stream, or as a continuous sample stream passes through a flow cell positioned in the field of view of an imaging system. An algorithm performs a particle detection routine. This process is a key step during dynamic imaging. The digital particle images in the sample are processed by image morphology analysis software that quantifies the particles in size, count, and other morphological parameters. Dynamic imaging particle analyzers can produce direct determinations of the particle count per unit volume (that is, particle concentration), as a function of particle size by dividing the particle count by the volume of imaged fluid (see Appendix X1 ). 1.3 This guide will describe best practices and considerations in applying dynamic imaging to identification of potential sources and causes of particles during biomanufacturing. These results can be used to monitor these particles and where possible, to adjust the manufacturing process to avoid their formation. This guide will also address the fundamental principles of dynamic imaging analysis including image analysis methods, sample preparation, instrument calibration and verification and data reporting. 1.4 The values stated in SI units are to be regarded as standard. No other units of measurement are included in this standard. 1.5 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 and health practices and determine the applicability of regulatory limitations prior to use. ====== Significance And Use ====== 4.1 This guide will encompass considerations for manufacturers regarding sources and potential causes of subvisible particles in biomanufacturing operations and the use of dynamic imaging particle analyzers as a suggested common method to monitor them. The guide will address the following components of particle analysis using dynamic imaging microscopy: fundamental principles, operation, image analysis methods, sample handling, instrument calibration, and data reporting.