Patro Sugunakar Y, Freund Erwin, Chang Byeong S
Amgen Inc., Thousand Oaks, CA 91320, USA.
Biotechnol Annu Rev. 2002;8:55-84. doi: 10.1016/s1387-2656(02)08004-3.
One of the challenges for the successful commercialization of therapeutic proteins is to maintain the safety and efficacy of the protein during the manufacturing process, storage, and administration. To achieve this, the purified form of the protein drug is usually "formulated" with carefully selected excipients. The operations that occur subsequent to protein purification, such as freezing of the purified protein bulk, thawing of the bulk, formulation (excipient addition), sterile filtration, filling, freeze-drying, and inspection are commonly referred as "formulation and fill-finish operations". This review is focused on the protein formulation and fill-finish operations, critical process parameters at each operation, and the process considerations required for maintaining safety and efficacy of the drug during manufacturing and storage. Since proteins have complex molecular structures that can influence the protein stability, the reader is first introduced to salient concepts related to protein structure. This is followed by a review of the possible protein-degradation mechanisms and how a variety of external factors can contribute to protein degradation during the in vitro processing of the protein drug. The reader is then introduced to each of the formulation and fill-finish operations mentioned above, the possible degradations during each unit-operation, and process considerations necessary to avoid those degradations.
治疗性蛋白质成功商业化面临的挑战之一是在制造过程、储存和给药期间维持蛋白质的安全性和有效性。为实现这一点，蛋白质药物的纯化形式通常与精心挑选的辅料一起“配制”。蛋白质纯化后进行的操作，如纯化蛋白质原液的冷冻、原液的解冻、配制（添加辅料）、无菌过滤、灌装、冻干和检验，通常被称为“配制和灌装-最终操作”。本综述聚焦于蛋白质配制和灌装-最终操作、每个操作的关键工艺参数，以及在制造和储存期间维持药物安全性和有效性所需的工艺考量。由于蛋白质具有复杂的分子结构，会影响蛋白质稳定性，因此首先向读者介绍与蛋白质结构相关的重要概念。接下来综述可能的蛋白质降解机制，以及在蛋白质药物的体外加工过程中各种外部因素如何导致蛋白质降解。然后向读者介绍上述每个配制和灌装-最终操作、每个单元操作期间可能的降解，以及避免这些降解所需的工艺考量。
