Mechanisms of color formation in drug substance and mitigation strategies for the manufacture and storage of therapeutic proteins produced using mammalian cell culture. (November 2019)

• Record Type: Journal Article
• Authors: Du, Cheng; Xu, Jianlin; Song, Hangtian; Tao, Li; Lewandowski, Angela; Ghose, Sanchayita; Borys, Michael C.; Li, Zheng Jian
• Is Part Of: Process biochemistry. Volume 86(2019)
• Page Start: 127
• Page End: 135
• Publication Date: 2019-11
• Subjects: AGEs advanced glycation end products -- CHO chinese hamster ovary -- DO dissolved oxygen -- DS drug substance -- HMW high molecular weight -- ICH international conference on harmonization -- CIE international commission on illumination -- Kyn kynurenine -- mAbs monoclonal antibodies -- NFK N-formylkynurenine -- NIFTY normalized intrinsic fluorescence intensiTY -- ROS reactive oxygen species -- Trp tryptophan; Protein drug substance color -- Cell culture manufacturing -- Chemically defined media -- High concentration formulation -- Drug substance storage -- Light; Biochemical engineering -- Periodicals; Biotechnology -- Periodicals; Biochemistry -- periodicals; Biotechnology -- periodicals; Chemical Engineering -- periodicals; Génie biochimique -- Périodiques; Biotechnologie -- Périodiques; Biochemical engineering; Biotechnology; Periodicals; 660.63
• DOI: 10.1016/j.procbio.2019.08.013
• Languages: English
• ISSNs: 1359-5113

Abstract

Graphical abstract: Highlights: Protein color test is important for product release, comparability and stability. Atypical color can be introduced during most manufacturing steps and storage. Color assay methods, mechanisms and mitigation strategies are summarized. Color formation is mainly associated with Trp oxidation products and/or B12 . Major factors include iron, B12, light, temperature, aeration, and ROS. Abstract: Drug substance (DS) appearance is an important quality attribute that is tested before product release. Color variation in DS batches or color change during storage can be indicative of the presence of contaminants, impurities or degradation products and may be linked to the manufacturing process, DS formulation or the stability of the therapeutic proteins. Atypical DS color other than colorless or pale yellow has been recently observed and may result in rejected manufacturing batches and financial loss due to concerns on product quality and visually matching placebo in clinical trials. This review focuses on the origins of atypical color and changes in DS during manufacturing processes using mammalian cell culture and storage. The purposes here are to understand the link between changes in the DS color and various process parameters and to provide necessary information to our readers regarding product quality control strategies with respect to DS color.