Correspondence
Zhijun Tan, Biologics Development, Global Product Development and
Supply, Bristol-Myers Squibb, 38 Jackson Road, Devens, MA 01434.
Email: zhijun.tan@bms.com
Abstract
Disulfide bond reduction has been a challenging issue in antibody
manufacturing, as it leads to reduced product purity, failed to meet
targeted product profile and/or specifications and more importantly,
impacting drug safety and efficacy. Scientists across industry have been
examining the root causes and developing mitigation strategies to
address the challenge. In recent years, with the development of
high-titer mammalian cell culture processes to meet the rapidly growing
demand for antibody biopharmaceuticals, disulfide bond reduction has
been observed more frequently. Thus, it is necessary to continue
evolving the disulfide reduction mitigation strategy and development of
novel approaches to maintain high product quality. Additionally, in
recent years as more complex molecules emerge such as bispecific and
trispecific antibodies, the molecular heterogeneity due to incomplete
formation of the interchain disulfide bonds becomes a more imperative
challenging issue. Given the disulfide reduction challenges that biotech
industry is facing, in this review we provide a comprehensive
contemporary scientific insight into the root cause analysis of
disulfide reduction during process development of antibody therapeutics,
mitigation strategies and its potential remediated recovery based on our
expertise in clinical and commercial manufacturing of biologics. First,
this paper intended to highlight different aspects of the root cause for
disulfide reduction. Secondly, to provide a broader understanding of the
disulfide bond reduction in downstream process, this paper discussed
disulfide bond reduction impact to product stability and process
performance, associated analytical methods for detection and
characterization, process control strategies as well as their
manufacturing implementation. In addition, brief perspectives on
development of future mitigation strategies will also be reviewed,
including platform alignment, mitigation strategy application for the
emerging new modalities such as bi- and tri-specific antibodies as well
as using machine learning to identify molecule susceptibility of
disulfide bond reduction. The data in this review are originated from
both the published papers and our internal development work.