Implications of trace levels of redox-active metals in drug-product formulation

• Published in: Biopharm International Vol. 27; no. 4; p. 30
• Main Authors: Sadineni, Vikram, Chandrasekharan, Sangita, Nassar, Munir N
• Format: Magazine Article Trade Publication Article
• Language: English
• Published: Monmouth Junction MJH Life Sciences Media 01-04-2014; MultiMedia Healthcare Inc
• Subjects: Amino acids; Biosynthesis; Chloride; Chromatography; Degassing of metals; Free radicals; Manufacturing; Metals; Molecular weight; Oxidation; Particle size; Pharmaceutical industry; Proteins
• ISSN: 1542-166X; 1939-1862

Results generated during the development of commercial formulation of the model monoclonal antibody (mAb), Biologic A, have indicated the formation of higher-molecular-weight species (aggregates) and fragmented species of the mAb. The role of residual redox-active metals on the degradation was inconclusive because quantification of trace levels of transition metals is not feasible with traditional techniques. To confirm the metal-catalyzed degradation of mAb, studies were conducted, in which protein formulations were spiked with 1 ppm (parts per million) of metals, and the stability evaluated in the presence and absence of metal chelators. The presence of minute amounts of chelators, such as ethylenediaminetetraacetic acid (EDTA) or diethylene triamine pentaacetic acid (DTPA), helped minimize the degradation of mAb. More importantly, the presence of chelators in the drug-product formulation helps to sequester the trace and undetectable/unquantifiable amounts of metals present as impurities in highly purified parenteral-grade excipients, such as buffer components, stabilizers, and tonicity modifiers. Incorporation of metal chelators also aids in preventing the browning of formulated drug-substance solutions upon long-term storage in bags or bottles by preventing oxidation of tryptophan residues in proteins. [PUBLICATION ABSTRACT]