Analytical Method Validation for Testing of Limit of High Molecular Weight Proteins in Filgrastim Biopharmaceutical Products
Keywords:
filgrastim, high molecular weight proteins, aggregation, method validation, size exclusion chromatographyAbstract
Filgrastim is a biopharmaceutical drug used for treatment chemotherapy-induced neutropenia in cancer patients. High molecular weight proteins (HMWP) of filgrastim can lead to loss of efficacy and immunogenicity. Limit of HMWP is one of the test items showing quality of filgrastim products. However, a compendial method used for determination of these impurities in pharmaceutical products has not yet been available. In this study, a size-exclusion chromatographic (SE-HPLC) method was validated for determination of HMWP of filgrastim. Method validation conducted parameters including specificity, limit of quantitation (LOQ) and precision. The results showed that the analysis of HMWP of filgrastim was not interfered by the excipients and other reagents in the analytical system. The method was sensitive with the lowest limit of quantitation of 0.0002 mg/mL. In addition, the percent relative standard deviation of repeatability and intermediate precision was in a range of 1.9-3.5% and 1.9-7.3%, respectively. These values were within the limits calculated from Horwitz’s equation. Thus, the size-exclusion chromatography (SEC) method was specific, sensitive, precise and valid for determination of HMWP of filgrastim in pharmaceutical products. This validated method has been utilized as a standard method to quantify the HMWP of filgrastim in biopharmaceutical products collected from all over nation by the Thai FDA.
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[10] Bennett CL, Chen B, Hermanson T, Wyatt MD, Schulz RM, Georgantopoulos P, et al. Regulatory and clinical considerations for biosimilar oncology drugs. Lancet Oncol 2014;15: p. e594–605. doi:10.1016/S1470-2045(14)70365-1.
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[13] Hong P, Koza S, Bouvier ESP. Size-Exclusion Chromatography for the Analysis of Protein Biotherapeutics and their Aggregates. J Liq Chromatogr Relat Technol 2012;35: p. 2923–50. doi:10.1080/10826076.2012.743724.
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[15] Yu C-M, Mun S, Wang N-HL. Phenomena of insulin peak fronting in size exclusion chromatography and strategies to reduce fronting. J Chromatogr A 2008;1192: p. 121–9. doi:10.1016/j.chroma.2008.03.055.
[16] Brange J, Langkjaer L, Havelund S, Vølund A. Chemical stability of insulin. 1. Hydrolytic degradation during storage of pharmaceutical preparations. Pharm Res 1992;9: p. 715–26.
[17] Oliva A, Fariña J, Llabrés M. Development of two high-performance liquid chromatographic methods for the analysis and characterization of insulin and its degradation products in pharmaceutical preparations. J Chromatogr B Biomed Sci App 2000;749: p. 25–34. doi:10.1016/S0378-4347(00)00374-1.
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[19] Souza LM, Boone TC, Gabrilove J, Lai PH, Zsebo KM, Murdock DC, et al. Recombinant human granulocyte colony-stimulating factor: effects on normal and leukemic myeloid cells. Science 1986;232: p. 61–5. doi:10.1126/science.232.4746.61.
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[26] Thai Food and Drug Administration, Bureau of Drug Control. Searching and Statistic Information; Filgrastim. https://www.fda.moph.go.th/sites/Drug/ (accessed July 22, 2018).
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[34] International Conference on Harmonization (ICH). International Conference on Harmonization (ICH) of Technical Requirements for the Registration of Pharmaceuticals for Human Use, Validation of analytical procedures: Text and Methodology. ICH-Q2B 1996.
[35] Yin H. Method and Validation basics-HPLC case study 2011.
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