Metal Ion Leachates and the Physico-Chemical Stability of Biotherapeutic Drug Products
Sandeep Kumar, Shuxia Zhou and Satish K. Singh
Affiliation: Pfizer Inc., AA4, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA.
Keywords: Metal ion, aggregation, oxidation, protein, biotherapeutics.
Metal ions that leach into biotherapeutic drug product solution during manufacturing and storage, result in contamination that
can cause physico-chemical degradation of the active molecule. In this review, we describe various mechanisms by which metal ion
leachates can interact with therapeutic proteins and antibodies. Site-specific modifications due to metal catalyzed oxidation (MCO) of the
therapeutic proteins cause them to become destabilized and potentially increasingly aggregation prone. We have examined the molecular
sequences and structures for three case studies, human relaxin (hRlx), human growth hormone (hGH) and an IgG2 mAb to rationalize the
experimental findings related to their MCO. The analysis indicates that metal-binding sites lie in close spatial proximities to predicted
aggregation prone regions in these molecules. From the perspective of pharmaceutical development of biotherapeutic drugs, this link between
molecular origins of MCO and subsequent aggregation is undesirable. This article further suggests molecular design strategies involving
disruption of APRs that may also help mitigate the impact of metal ion leachates on biotherapeutic drug products as well as improving
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