Late Stage Pharmaceutical Development, Process Research and Development, Genentech Inc., 1 DNA Way, MS 56-1A, South San Francisco, California 94080, USA.
AAPS J. 2012 Jun;14(2):236-43. doi: 10.1208/s12248-012-9335-8. Epub 2012 Mar 6.
The analysis of particulates has been a longstanding challenge in biopharmaceutical drug product development and quality control because the active constituents themselves may form particulate matter as a degradation product that may be difficult to quantify. These analytical challenges were met with success as long as the definition of particulate matter remained well within the capabilities of the instruments and methods used to measure it. The current testing as per USP <788> for parenterals at ≤100 mL stipulates that the sample "passes" the test if the average number of particles present does not exceed 6,000 per container at ≥10 μm and does not exceed 600 per container at ≥25 μm. The new challenge, posed by regulatory direction and academic research, is to count and to characterize subvisible particulates that are ≤10 μm with the goal of providing higher resolution information about the particulate levels and potential consequences of this product quality attribute in vivo. The present discussion focuses on two parallel efforts: (a) to develop a model system for protein subvisible particulates in samples with high protein concentrations and (b) to evaluate the capabilities and limitations of different technologies available (at the time these studies were conducted) for subvisible and submicron particle (<1 μm in diameter) sizing and counting. Our findings illustrate the importance of using appropriate instrumentation that is adapted to the characteristics of the samples to be analyzed. Any sample manipulation to meet the capabilities and to accommodate the limitations of the analytical technique should be carefully evaluated.
微粒分析一直是生物制药产品开发和质量控制中的一个长期挑战，因为活性成分本身可能会形成作为降解产物的微粒物质，这可能难以定量。只要微粒物质的定义仍然在用于测量它的仪器和方法的能力范围内，这些分析挑战就取得了成功。目前，USP <788> 针对 ≤100 mL 的注射液规定，如果容器中每 ≥10 µm 的平均粒子数不超过 6000 个，且每 ≥25 µm 的平均粒子数不超过 600 个，则该样品“通过”测试。新的挑战来自监管方向和学术研究，是要对 ≤10 µm 的亚可见微粒进行计数和表征，目的是提供有关微粒水平和该产品质量属性在体内潜在后果的更高分辨率信息。目前的讨论集中在两个平行的努力上：(a) 开发一种用于高蛋白质浓度样品中蛋白质亚可见微粒的模型系统；(b) 评估不同现有技术（在进行这些研究时）用于亚可见和亚微米颗粒（<1 µm 直径）尺寸和计数的能力和局限性。我们的研究结果说明了使用适合要分析的样品特性的适当仪器的重要性。任何为满足分析技术的能力和适应其局限性而进行的样品处理都应仔细评估。
