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Computer-aided engineering. --- MATLAB. --- SPICE (Computer file) --- Engineering --- CAE --- Data processing --- Simulation program with integrated circuit emphasis --- MATLAB (Computer program) --- MATLAB (Computer file) --- Matrix laboratory

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Background: This study focuses on how to perform Quality Control (QC) testing of critical reagents in pharmaceutical industry. They are labeled as ‘critical’ because lot-to-lot variability can occur and may cause an impact on method performance. QC testing requires validated Test Methods (TMs) in which critical reagents can be used. For this reason, critical reagents must be qualified prior to their intended use. Critical reagents used during QC testing encompass two categories (large and small molecules), three types (Internal Controls (ICs), Reference Standards (RSs) and Critical Reagents/Consumables (CR/CCs)) of which qualitative or quantitative large molecule critical reagent subtypes, and major, minor, or authentic small molecule RS subtypes exist. Objectives: This study focuses on how to perform QC testing of critical reagents. The aim is to find out in more detail how to perform case-by-case qualifications and re-evaluations of large molecule critical reagents. In addition, an in-use shelf life is determined for major Multi-use (MU) small molecule RSs. Methods: During QC it is needed to show presence of certain substances in the final drug product. Therefore, qualitative large molecule critical reagents were (re-)qualified to identify excipients and Drug substance (DS) in vaccines. In addition, quantitative large molecule critical reagents were (re-)qualified to semi-quantitatively determine sample purity or quantify substances in Drug Product (DP). Methods used included Slot Blot, Enzyme Linked Immunosorbent Assay (ELISA) double sandwich model, Hydrophobic Interaction Chromatography (HIC), Anion Exchange Chromatography (AEC), and applying Six Sigma. Besides, an in-use shelf life is determined for major MU small molecule RS based on historical data. Results: An antibody was qualified to specifically detect Human Serum Albumin (HSA) in a vaccine, using the optimal working dilution determined as 1/500 (2,00 µg/mL). It was considered equivalent to the previous qualified antibody lot. In addition, the current qualified antibody CR/CC and HSA IC were re-evaluated and approved for their continued use in the Slot Blot based TM. Furthermore, three polyclonal antibodies were successfully re-evaluated to identify the vaccine DS by means of an ELISA double sandwich model. In the case of the anti-inflammatory DP a Root Cause Analysis (RCA) was carried out due to a shift in the historical data. As a result, a new temporary range was qualified for the quantitative large molecule IC etanercept to relatively quantify sample purity by means of HIC. The DP, sialic acid standard and filter were successfully re-evaluated in their unique combination to quantify free saccharides in a vaccine DP. Besides, an in-use shelf life of 134 and 100 days was assigned to the Lidocaine Hydrochloride Monohydrate and Timolol Maleate RSs respectively, in which their in-use stability is guaranteed. Conclusion: The applied methods are considered sufficient for their analytical purpose in industry. In addition, the qualification approach meets the World Health Organizations’ recommendations. There was dealt with RCA and deviations. All QC tests were carried out and critical reagents were (re-)qualified to assure high quality medicinal products will reach the patients.