IgG Particle Formation during Filling Pump Operation: A Case Study of Heterogeneous Nucleation on Stainless Steel Nanoparticles
IgG Particle Formation during Filling Pump Operation: A Case Study of Heterogeneous Nucleation on Stainless Steel Nanoparticles
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DOI：
10.1002/jps.21419
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发表时间：
2009-01-01
影响因子：
3.8
通讯作者：
Carpenter, John F.
中科院分区：
文献类型：
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作者：
Tyagi, Anil K.;Randolph, Theodore W.;Carpenter, John F.
本研究调查了与使用容积式活塞泵灌装小瓶相关的因素，导致IgG制剂中形成蛋白质颗粒。我们假设纳米粒子从泵的溶液接触表面脱落，使蛋白质聚集和粒子形成成核。在临床生产地点灌装的IgG制剂小瓶含有少量可见颗粒，每mL约100，000个颗粒（1.5-3 μ m）。在使用相同型号（National Instruments FUS-10）泵的实验室研究中，泵送20 mg/mL IgG制剂导致每mL约300，000个颗粒（1.5-3 μ m）。泵送无蛋白制剂导致每毫升13，000个颗粒（1.5-15 μ m）。99%以上的颗粒尺寸为0.25-0.95 μ m。将不含蛋白质的泵送溶液与等体积的40 mg/mL IgG混合，得到300，000个颗粒（1.5-15 μ m）/mL。此外，将IgG制剂与30，000/mL不锈钢纳米颗粒混合导致每mL形成30，000个蛋白质微粒（1.5-15 μ m）。红外光谱表明，通过泵送或与钢纳米颗粒混合形成的微粒中的IgG的二级结构受到最小的扰动。我们的研究结果表明，由泵脱落的异物纳米颗粒可以作为形成蛋白质微粒的异质核。(C)2008 Wiley-Liss，Inc.和American Pharmacologist Association J Pharm Sci 98：94-104，2009
This study investigated factors associated with vial filling with a positive displacement piston pump leading to formation of protein particles in a formulation of an IgG. We hypothesized that nanoparticles shed from the pump's solution-contact surfaces nucleated protein aggregation and particle formation. Vials of IgG formulation filled at a clinical manufacturing site contained a few visible particles and about 100,000 particles (1.5-3 mu m) per mL. In laboratory studies with the same model (National Instruments FUS-10) of pump, pumping of 20 mg/mL IgG formulation resulted in about 300,000 particles (1.5-3 pm) per mL. Pumping of protein-free formulation resulted in 13,000 particles (1.5-15 mu m) per mL. More than 99% of the particles were 0.25-0.95 mu m in size. Mixing of protein-free pumped solution with an equal volume of 40 mg/mL IgG resulted in 300,000 particles (1.5-15 mu m) per mL. Also, mixing IgG formulation with 30,000/mL stainless steel nanoparticles resulted in formation of 30,000 protein microparticles (1.5-15 mu m) per mL. Infrared spectroscopy showed that secondary structure of IgG in microparticles formed by pumping or mixing with steel nanoparticles was minimally perturbed. Our results document that nanoparticles of foreign materials shed by pumps can serve as heterogeneous nuclei for formation of protein microparticles. (C) 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:94-104, 2009