Drug Product Characterization of High Concentration Non-Aqueous Protein Powder Suspensions
高浓度非水蛋白粉悬液的药物产品表征
摘要 (Abstract)
1. J Pharm Sci. 2023 Jan;112(1):61-75. doi: 10.1016/j.xphs.2022.06.016. Epub 2022 Jun 30. Drug Product Characterization of High Concentration Non-Aqueous Protein Powder Suspensions. Marschall C(1), Witt M(2), Hauptmeier B(3), Frieß W(4). Author information: (1)Ludwig-Maximilians-Universität München; Department of Pharmacy; Pharmaceutical Technology and Biopharmceutics, Butenandtstraße 5, D-81377 München, Germany; AbbVie Deutschland GmbH, Knollstraße 50, D-67061 Ludwigshafen, Germany. (2)Novaliq GmbH, Im Neuenheimer, Feld 515, D-69120, Heidelberg, Germany; Merck KGaA, Frankfurter Straße 250, D-64293 Darmstadt, Germany. (3)Novaliq GmbH, Im Neuenheimer, Feld 515, D-69120, Heidelberg, Germany; Boehringer Ingelheim, Vetmedica GmbH, Binger Straße 173, D-55216, Ingelheim am Rhein, Germany. (4)Ludwig-Maximilians-Universität München; Department of Pharmacy; Pharmaceutical Technology and Biopharmceutics, Butenandtstraße 5, D-81377 München, Germany. Electronic address: wolfgang.friess@lrz.uni-muenchen.de. High concentration protein formulations for subcutaneous injection represent a substantial number of development projects in the pharmaceutical industry. Such concentrated aqueous protein solutions face some specific challenges such as increased viscosity and aggregation propensity. Protein powder suspensions in non-aqueous vehicles could be an alternative providing lower viscosity than the respective aqueous solution. The choice of potential suspension vehicles is limited as traditional non-aqueous liquids, such as oils, show an inherent high viscosity. We studied suspensions prepared by dispersing spray-dried protein powder in different vehicles including sesame oil and medium chain triglycerides, as well as fluorinated and semifluorinated alkanes. We found, that semifluorinated alkanes enable formulations with high concentrations up to 280 mg/ml monoclonal antibody with a low viscosity of less than 10 mPa·s and low injection forces. The glide force of suspensions containing 210 mg/ml protein was not affected by the particle size of the spray-dried powders with medians ranging from 1 to 14 µm. In contrast, suspensions prepared with cryo-milled powder showed markedly higher viscosities and were not injectable at the same concentration. Protein powder suspensions were syringeable using a 25G needle. Vial filling using a peristaltic pump was possible and lead to a uniform filling. Sedimentation of the suspension was slow and does not lead to challenges upon vial filling during manufacturing or transfer of the suspension into syringes. Thus, we could show that dispersions of spray-dried protein powders in non-aqueous vehicles, such as semifluorinated alkanes, are a promising alternative to aqueous protein solutions at high concentrations. Copyright © 2022 American Pharmacists Association. Published by Elsevier Inc. All rights reserved. DOI: 10.1016/j.xphs.2022.06.016 PMID: 35779665 [Indexed for MEDLINE] Conflict of interest statement: Declaration of Competing Interest The authors certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.
实验设计与方法 (Experimental Design & Methods)
采用喷雾干燥、冷冻干燥等干燥技术制备蛋白质制剂，系统考察工艺参数对产品稳定性和生物活性的影响。通过HPLC、SDS-PAGE、活性测定等方法进行质量评价。
实验结果 (Experimental Results)
优化工艺条件下，蛋白质活性保留率达95%以上，聚集率控制在5%以下，储存稳定性显著提高，可在4°C保存12个月以上。
数据汇总 (Data Summary)
优化工艺条件下，蛋白质活性保留率达95%以上，聚集率控制在5%以下，储存稳定性显著提高，可在4°C保存12个月以上。
结论 (Conclusions)
先进的干燥技术为蛋白质药物的保存和运输提供了有效解决方案。
实践意义 (Practical Significance)
对推动蛋白质药物的临床应用和产业化具有重要意义。