Shibata Hiroko, Saitoh Satoshi, Kiyoshi Masato, Hayashi Yu, Inaba Kazue, Katsura Shinji, Sakurai Maho, Komine Yuka, Okabe Shinji, Ohbayashi Naomi, Kita Youko, Kito Hirokazu, Nakano Masako, Miyamoto Kana, Maruyama Akira, Miyahara Yuya, Noda Masanori, Nozawa Yasuyo, Shimbo Kazutaka, Kojima Shota, Honda Shinya, Torisu Tetsuo, Uchiyama Susumu, Ishii-Watabe Akiko
Division of Biological Chemistry and Biologicals, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa, 210-9501, Japan.
Pharmaceutical Technology Division, Analytical Development Department, Chugai Pharmaceutical Co. Ltd., 5-1 Ukima, 5-chome, Kita-ku, Tokyo, 115-8543, Japan.
AAPS J. 2025 Apr 3;27(3):75. doi: 10.1208/s12248-025-01056-3.
Protein aggregates and insoluble particles in biopharmaceutical products are impurities that can elicit immunogenicity. The protein aggregates and insoluble particles form during manufacturing and storage, and should be characterized to optimize the manufacturing process and establish a control strategy. Several issues regarding the evaluation and control of these particles have been concerned, and collaborative studies have been conducted in the Japan Biopharmaceutical Consortium to address them. However, there is still no consensus for utilizing analytical techniques in parallel to establish a control strategy for such protein aggregates and insoluble particles, which range in size from a few nanometers to several hundred micrometers. Therefore, in this study, we surveyed Japanese biopharmaceutical companies through a questionnaire including questions regarding analytical techniques used to establish control strategies for protein aggregates and insoluble particles at various development phases. To summary the survey results, we found that size exclusion chromatography, light obscuration, and visual inspection are consistently used from early development and formulation optimization stage to commercial manufacturing. Apart from the light obscuration method, flow imaging (FI) was the most commonly used technique for subvisible particle characterization; thus, the use of FI to establish a control strategy was documented. The recommendation for establishing a control strategy for protein aggregates and insoluble particles based on life-cycle of drug development are summarized.
生物制药产品中的蛋白质聚集体和不溶性颗粒是可能引发免疫原性的杂质。蛋白质聚集体和不溶性颗粒在生产和储存过程中形成，应对其进行表征以优化生产工艺并建立控制策略。关于这些颗粒的评估和控制存在若干问题，日本生物制药联盟已开展合作研究以解决这些问题。然而，对于并行使用分析技术来建立针对此类大小从几纳米到几百微米不等的蛋白质聚集体和不溶性颗粒的控制策略，仍未达成共识。因此，在本研究中，我们通过问卷调查对日本生物制药公司进行了调查，问卷包括有关在不同开发阶段用于建立蛋白质聚集体和不溶性颗粒控制策略的分析技术的问题。为总结调查结果，我们发现尺寸排阻色谱法、光阻法和目视检查从早期开发和制剂优化阶段到商业化生产都一直被使用。除光阻法外，流动成像（FI）是用于亚可见颗粒表征最常用的技术；因此，记录了使用FI建立控制策略的情况。总结了基于药物开发生命周期建立蛋白质聚集体和不溶性颗粒控制策略的建议。
