Gikanga Benson, Chen Yufei, Stauch Oliver B, Maa Yuh-Fun
Pharmaceutical Processing and Technology Development, Genentech, a member of the Roche Group, South San Francisco, CA 94080.
Pharmaceutical Processing and Technology Development, Genentech, a member of the Roche Group, South San Francisco, CA 94080
PDA J Pharm Sci Technol. 2015 Mar-Apr;69(2):284-96. doi: 10.5731/pdajpst.2015.01031.
Using bottom-mounted mixers, particularly those that are magnetically driven, is becoming increasingly common during the mixing process in pharmaceutical and biotechnology manufacturing because of their associated low risk of contamination, ease of use, and ability to accommodate low minimum mixing volumes. Despite these benefits, the impact of bottom-mounted mixers on biologic drug product is not yet fully understood and is scarcely reported. This study evaluated four bottom-mounted mixers to assess their impact on monoclonal antibody formulations. Changes in product quality (size variants, particles, and turbidity) and impact on process performance (sterile filtration) were evaluated after mixing. The results suggested that mixers that are designed to function with no contact between the impeller and the drive unit are the most favorable and gentle to monoclonal antibody molecules. Designs with contact or a narrow clearance tended to shear and grind the protein and resulted in high particle count in the liquid, which would subsequently foul a filter membrane during sterile filtration using a 0.22 μm pore size filter. Despite particle formation, increases in turbidity of the protein solution and protein aggregation/fragmentation were not detected. Further particle analysis indicated particles in the range of 0.2-2 μm are responsible for filter fouling. A small-scale screening model was developed using two types of magnetic stir bars mimicking the presence or absence of contact between the impeller and drive unit in the bottom-mounted mixers. The model is capable of differentiating the sensitivity of monoclonal antibody formulations to bottom-mounted mixers with a small sample size. This study fills an important gap in understanding a critical bioprocess unit operation.
Mixing is an important unit operation in drug product manufacturing for compounding (dilution, pooling, homogenization, etc.). The current trend in adopting disposable bottom-mounted mixers has raised concerns about their impact on drug product quality and process performance. However, investigations into the effects of their use for biopharmaceutical products, particularly monoclonal antibody formulations, are rarely published. The purpose of this study is three-fold: (1) to understand the impact of bottom-mounted disposable mixer design on drug product quality and process performance, (2) to identify the mixing mechanism that is most gentle to protein particle formation, (3) to apply the learning to practical mixing operations using bottom-mounted mixers. The outcomes of this study will benefit scientists and engineers who develop biologic product manufacturing process by providing a better understanding of mixing principles and challenges.
在制药和生物技术制造的混合过程中，使用底部安装的搅拌器，特别是那些磁力驱动的搅拌器，正变得越来越普遍，因为它们具有污染风险低、易于使用以及能够适应低至最小混合体积的特点。尽管有这些优点，但底部安装搅拌器对生物药品的影响尚未完全了解，且鲜有报道。本研究评估了四种底部安装的搅拌器，以评估它们对单克隆抗体制剂的影响。混合后评估了产品质量（大小变体、颗粒和浊度）的变化以及对工艺性能（无菌过滤）的影响。结果表明，设计为叶轮与驱动单元无接触运行的搅拌器对单克隆抗体分子最为有利且温和。有接触或间隙狭窄的设计往往会剪切和研磨蛋白质，并导致液体中颗粒计数较高，这随后会在使用孔径为0.22μm的过滤器进行无菌过滤时堵塞滤膜。尽管形成了颗粒，但未检测到蛋白质溶液的浊度增加以及蛋白质聚集/碎片化。进一步的颗粒分析表明，0.2 - 2μm范围内的颗粒是导致过滤器堵塞的原因。使用两种模拟底部安装搅拌器中叶轮与驱动单元接触或不接触情况的磁力搅拌棒开发了一个小规模筛选模型。该模型能够以小样本量区分单克隆抗体制剂对底部安装搅拌器的敏感性。本研究填补了理解关键生物工艺单元操作方面的一个重要空白。
混合是药品制造中用于配料（稀释、合并、均质化等）的重要单元操作。当前采用一次性底部安装搅拌器的趋势引发了对其对药品质量和工艺性能影响的担忧。然而，关于其在生物制药产品，特别是单克隆抗体制剂方面使用效果的研究很少发表。本研究的目的有三个方面：（1）了解底部安装的一次性搅拌器设计对药品质量和工艺性能的影响，（2）确定对蛋白质颗粒形成最温和的混合机制，（3）将所学应用于使用底部安装搅拌器的实际混合操作。本研究的结果将有助于开发生物产品制造工艺的科学家和工程师更好地理解混合原理和挑战。
