ABSTRACT
As the essential components in formulations, pharmaceutical excipients directly affect the safety, efficacy, and stability of drugs. Recently, safety incidents of pharmaceutical excipients posing seriously threats to the patients highlight the necessity of controlling the potential risks. Hence, it is indispensable for the industry to establish an effective risk assessment system of supply chain. In this study, an AHP-fuzzy comprehensive evaluation model was developed based on the analytic hierarchy process and fuzzy mathematical theory, which quantitatively assessed the risks of supply chain. Taking polysorbate 80 as the example for model analysis, it was concluded that polysorbate 80 for injection use is a high-risk ingredient in the supply chain compared to that for oral use to achieve safety application in clinic, thus measures should be taken to control and minimize those risks.
Subject(s)
Drug Industry/standards , Excipients/chemistry , Excipients/standards , Fuzzy Logic , Polysorbates/chemistry , Polysorbates/standards , Drug Evaluation, Preclinical/methods , Excipients/adverse effects , Polysorbates/adverse effects , Risk AssessmentABSTRACT
The fatty acid (FA) composition of polysorbate 80 (PS80), a sorbitan oleic acid ester copolymerized with about 20mole of ethylene oxide, is typically characterized by gas chromatography. Here, an alternative method was developed. After saponification with potassium hydroxide the FA fraction was collected with liquid-liquid extraction using methyl-tert-butyl ether. HPLC in combination with a Corona® charged aerosol detector (CAD) was applied for the separation and detection. The method was fully validated in terms of specificity, repeatability, limits of quantification, linearity, range, accuracy and robustness. The characterization of 16 different PS80 batches demonstrated variability regarding their FA composition, with e.g. the amount of oleic acid ranging from 67.8±0.7% to 96.6±1.4%. Furthermore, we identified petroselinic acid, a double-bond positional isomer to oleic acid in all batches, an FA not known to pharmacopoeias at present. In addition, 11-hydroxy-9-octadecenoic acid, an oxidation product of oleic acid was identified. Structure elucidation was performed by means of HPLC-MS/MS. In addition, the method was expanded to the evaluation of the free FAs. Having determined the entire FA composition, the acid value according to EP and USP can be calculated.
Subject(s)
Chromatography, High Pressure Liquid/methods , Fatty Acids/analysis , Polysorbates/chemistry , Surface-Active Agents/chemistry , Technology, Pharmaceutical/methods , Aerosols , Fatty Acids/chemistry , Limit of Detection , Liquid-Liquid Extraction , Polysorbates/standards , Reproducibility of Results , Surface-Active Agents/standards , Tandem Mass Spectrometry , Technology, Pharmaceutical/instrumentationABSTRACT
This manuscript addresses the capability of compendial methods in controlling polysorbate 80 (PS80) functionality. Based on the analysis of sixteen batches, functionality related characteristics (FRC) including critical micelle concentration (CMC), cloud point, hydrophilic-lipophilic balance (HLB) value and micelle molecular weight were correlated to chemical composition including fatty acids before and after hydrolysis, content of non-esterified polyethylene glycols and sorbitan polyethoxylates, sorbitan- and isosorbide polyethoxylate fatty acid mono- and diesters, polyoxyethylene diesters, and peroxide values. Batches from some suppliers had a high variability in functionality related characteristic (FRC), questioning the ability of the current monograph in controlling these. Interestingly, the combined use of the input parameters oleic acid content and peroxide value - both of which being monographed methods - resulted in a model adequately predicting CMC. Confining the batches to those complying with specifications for peroxide value proved oleic acid content alone as being predictive for CMC. Similarly, a four parameter model based on chemical analyses alone was instrumental in predicting the molecular weight of PS80 micelles. Improved models based on analytical outcome from fingerprint analyses are also presented. A road map controlling PS80 batches with respect to FRC and based on chemical analyses alone is provided for the formulator.
Subject(s)
Excipients/chemistry , Models, Chemical , Polysorbates/chemistry , Technology, Pharmaceutical/methods , Chemistry, Pharmaceutical , Chromatography, High Pressure Liquid , Excipients/analysis , Excipients/standards , Fatty Acids/analysis , Hydrophobic and Hydrophilic Interactions , Light , Micelles , Molecular Weight , Polyethylene Glycols/analysis , Polysorbates/analysis , Polysorbates/standards , Scattering, RadiationABSTRACT
Polysorbate 80 is one of the key components of protein formulations. It primarily inhibits interfacial damage of the protein molecule due to mechanical stress during shipping and handling. However, polysorbate 80 also affects the formulation photostability. Exposure to light of polysorbate 80 aqueous solution results in peroxide generation, which in turn may result in oxidation of the susceptible amino acid residues in the protein molecule. The purpose of this study was to determine if the photostability of our proprietary IgG(1) monoclonal antibody formulation containing polysorbate 80 is affected by the quality (grade/vendor) of polysorbate 80. Following four types of polysorbate 80 were tested: (1) Polysorbate 80 Super-Refined, Mallinckrodt Baker, (2) Polysorbate 80 NF, Mallinckrodt Baker, (3) Polysorbate 80 NF, EMD Chemicals, and (4) Ultra-pure Polysorbate 80 (HX), NOF Corporation. The samples were exposed to light as per ICH guidelines Q1B. The results of the study show that photostability of the antibody formulation is indeed affected by the quality of polysorbate 80. This study underscores the importance of carefully choosing the quality of polysorbate 80 to ensure the robustness of formulation.
