Organic solvents constitute a major fraction in the synthesis of pharmaceutical products. The manufacturing process for active pharmaceutical ingredients (APIs) may contribute to residual solvents remaining in the final product. Producers need to monitor and control the levels of residual solvents for several reasons—including safety, effect on crystalline form, solubility, bio-availability, and stability.
Therefore, all products must be tested to assess whether the solvents used during the manufacturing processes are within the accepted limits. Quality assurance laboratories routinely use the United States Pharmacopeia (USP) Method <467>.
Procedures for identification and quantification
The USP <467> monograph specifies the different classes of solvents per their toxicity, sets the concentration limits according to their health hazard, and describes the assay procedure for the solvents. A complete list of all the solvents that may be used in manufacturing processes is not mentioned under these classes. Therefore, the final products should be screened according to the solvents used during their specific manufacturing process.
The method is composed of three analytical procedures for identification and quantification.
- Procedure A: Identification and limit testing. Uses a G43 phase (624-type column).
- Procedure B: Confirms whether or not an identified solvent is above the regulated limits. Uses a G16 phase (WAX-type column).
- Procedure C: Quantitative test using a G43 phase or G16 phase, depending on which produced fewer coelutions.
USP <467> analytical flowchart for residual solvent analysis.
Columns for excellent performance
Agilent J&W DB-Select 624 UI columns have shown excellent performance for residual solvent analysis according to USP <467> Procedure A. Repeatability was generally better than 2.5% RSD for Class 1, Class 2A, and Class 2B solvents. Once a residual solvent was identified above the permitted daily exposure (PDE) limit, Procedure B is performed to confirm analyte identity. The Agilent J&W DB-WAX UI GC column has been successfully used as a confirmation column, because it yields an alternate selectivity compared to that of a G43 column.
Agilent J&W DB-Select 624 UI columns
Recommended instruments
For this method, Chemetrix can recommend state-of-the-art analytical instruments. With best-in-class technology and powerful software, the Agilent 7697A headspace sampler is packed with the latest productivity-boosting features. It’s unique sampling design allows you to use hydrogen as a carrier gas, delivering optimal chromatography and helping to future-proof your lab.
Agilent 7697A Headspace Sampler
Based on the Agilent Intuvo 9000 GC system, Agilent Residual Solvent Analyzers are factory pretested and preconfigured to deliver results, fast, while saving precious startup time. What’s more, their analytical precision exceeds USP method requirements for the three classes of residual solvents. It’s chemically tested to ensure optimal analysis of class 1 and class 2A/B solvents and labs can begin system calibration and validation immediately following installation.
A critical process
Residual Solvent Analysis is a must in any manufacturing environment where solvents form part of the production process. Because this process is so critical, using the correct instruments suited for the lab requirements can save time and boost accuracy.
Quality control at the heart of it all
At every stage of the quality control process, Chemetrix can assist labs with full end-to-end solutions for your residual solvent analysis. Our team of qualified professionals can share a comprehensive portfolio of solutions, including different instrument models, software and consumables, that work together to provide accurate and reproducible results.
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