Nidhi Doshi1, Kyle Ritchie2, Tamanna Shobha3, Jamie Giddings2, Kathrin Gregoritza4, Rosalynn Taing2, Stephen Rumbelow5, Jeff Chu6, Anthony Tomlinson2, Aadithya Kannan2, Miguel Saggu2, Si Kai Cai4, Victor Nicoulin4, Wenqiang Liu2, Steve Russell6, Lin Luis2, Sandeep Yadav3. 1. Pharmaceutical Development, Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA. doshin1@gene.com. 2. Pharmaceutical Development, Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA. 3. Pharmaceutical Technical Innovation, Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA. 4. Pharma Technical Development Biologics, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4054, Basel, Switzerland. 5. Croda Inc, 777 Scudders Mill Road, Bldg. 2, Plainsboro, NJ, 08536, USA. 6. Analytical Operations, Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA.
Abstract
PURPOSE: To evaluate a modified high purity polysorbate 20 (RO HP PS20)-with lower levels of stearate, palmitate and myristate esters than the non-modified HP PS20-as a surfactant in biopharmaceutical drug products (DP). RO HP PS20 was designed to provide functional equivalence as a surfactant while delaying the onset of free fatty acid (FFA) particle formation upon hydrolytic degradation relative to HP PS20. METHODS: Analytical characterization of RO HP PS20 raw material included fatty acid ester (FAE) distribution, higher order ester (HOE) fraction, FFA levels and trace metals. Functional assessments included 1) vial and intravenous bag agitation; 2) oxidation via a placebo and methionine surrogate study; and 3) hydrolytic PS20 degradation studies to evaluate FFA particle formation with and without metal nucleation. RESULTS: Interfacial protection and oxidation propensity were comparable between the two polysorbates. Upon hydrolytic degradation, FFA particle onset was delayed in RO HP PS20. The delay was more pronounced when HOEs of PS20 were preferentially degraded. Furthermore, the hydrolytic degradants of RO HP PS20 formed fewer particles in the presence of spiked aluminum. CONCLUSION: This work highlights the criticality of having tighter control on long chain FAE levels of PS20 to reduce the occurrence of FFA particle formation upon hydrolytic degradation and lower the variability in its onset. By simultaneously meeting compendial PS20 specifications while narrowing the allowable range for each FAE and shifting its composition towards the shorter carbon chain species, RO HP PS20 provides a promising alternative to HP PS20 for biopharmaceutical DPs.
PURPOSE: To evaluate a modified high purity polysorbate 20 (RO HP PS20)-with lower levels of stearate, palmitate and myristate esters than the non-modified HP PS20-as a surfactant in biopharmaceutical drug products (DP). RO HP PS20 was designed to provide functional equivalence as a surfactant while delaying the onset of free fatty acid (FFA) particle formation upon hydrolytic degradation relative to HP PS20. METHODS: Analytical characterization of RO HP PS20 raw material included fatty acid ester (FAE) distribution, higher order ester (HOE) fraction, FFA levels and trace metals. Functional assessments included 1) vial and intravenous bag agitation; 2) oxidation via a placebo and methionine surrogate study; and 3) hydrolytic PS20 degradation studies to evaluate FFA particle formation with and without metal nucleation. RESULTS: Interfacial protection and oxidation propensity were comparable between the two polysorbates. Upon hydrolytic degradation, FFA particle onset was delayed in RO HP PS20. The delay was more pronounced when HOEs of PS20 were preferentially degraded. Furthermore, the hydrolytic degradants of RO HP PS20 formed fewer particles in the presence of spiked aluminum. CONCLUSION: This work highlights the criticality of having tighter control on long chain FAE levels of PS20 to reduce the occurrence of FFA particle formation upon hydrolytic degradation and lower the variability in its onset. By simultaneously meeting compendial PS20 specifications while narrowing the allowable range for each FAE and shifting its composition towards the shorter carbon chain species, RO HP PS20 provides a promising alternative to HP PS20 for biopharmaceutical DPs.
Authors: Josephine Chiu; Kristin N Valente; Nicholas E Levy; Lie Min; Abraham M Lenhoff; Kelvin H Lee Journal: Biotechnol Bioeng Date: 2016-12-27 Impact factor: 4.530
Authors: Hanns-Christian Mahler; Franziska Huber; Ravuri S K Kishore; Jürgen Reindl; Peter Rückert; Robert Müller Journal: J Pharm Sci Date: 2010-06 Impact factor: 3.534