Residual Solvents: Alternate Validated Methods
by Nathan T. Whitford, Senior Chemist and Group Leader in Method Development and Validation
Since the USP General Chapter on Residual Solvents became effective on July 1, 2008, Lancaster Laboratories has seen a multitude of requests for many different solvent and sample matrix combinations. The new General Chapter applies to both monographed and non-monographed items, including all drug substances, excipients, and products “subject to relevant controls.” So a number of manufacturers have turned to Lancaster Laboratories for assistance. The methodology provided in the General Chapter can be utilized for many of these requests (Class 1 and Class 2, Mix A and B compounds). However, the Class 2, Mix C compounds, all of the Class 3 compounds, and any other unlisted solvents used in manufacturing, cannot be tested by the General Chapter’s GC method. In these cases, an alternate method may need to be developed and validated.
One approach Lancaster Laboratories analysts have been utilizing is a technique referred to as a self-validating method. This particular approach is a possible alternative to the traditional method development and validation project. The self-validating method parallels the USP General Chapter methodology but takes it a step further by using a minimum of a three point calibration curve rather than the single point method of additions indicated by the General Chapter.
Prior to performing the self-validating method, feasibility would be performed to determine an appropriate solvent that provides acceptable sample solubility. Chromatographic conditions would also be evaluated and optimized for the compounds being analyzed. Once this evaluation has been performed, a Lancaster Laboratories analyst would test the sample matrix (unfortified) along with direct fortification of the sample matrix at a minimum of three levels. These three levels will bracket the limit concentration and would typically be made at a tenth of the limit, the limit and two times the limit concentration. In addition, system suitability injections are made to ensure the system is precise and accurate by performing multiple injections of a standard prepared at the limit concentration along with evaluating the recovery of a second working standard preparation. Linear regression analysis of the curve that is generated from the fortified sample preparations yields the compounds concentration and may be considered a quantitative result provided the determined coefficient of determination is acceptable (r2 = 0.99) and the value falls within the range evaluated. Due to the method of additions approach utilized with the self-validating method, many of the tests performed in a traditional method validation are evaluated with each analysis. Linearity is directly determined at the actual time of analysis by evaluating the linear regression data available from the different fortification levels. Specificity can be determined by evaluation of a blank injection and the unfortified sample injections made during the analysis. If significant interference is observed, an alternate approach would be attempted. Accuracy, range, and precision are determined by evaluating the agreement of data from the different fortification levels in the presence of sample matrix. Quantitation will not be performed if the result is below the lowest fortification level, and the results will be reported as less than lowest level. The result is only reported as an estimate if the result exceeds the highest fortification level. Finally, the self-validating method evaluates a practical working limit of quantitation based on the concentration of the lowest fortification level. Although the actual LOQ may be significantly lower, this is beyond the scope of interest for quantitative evaluation of residual solvents around a much higher limit concentration.
The benefits to this self-validating method approach include a faster timeline when compared to the traditional method development and validation project. This approach is more cost effective than the traditional approach for clients having a short term or infrequent need for testing. Additionally, the approach parallels the USP General Chapter , while taking it a step further by utilizing multiple fortification levels. For samples that contain multiple solvents (five or more) or for samples in which testing will be performed frequently, the traditional method development and validation approach may prove to be a more cost effective analysis. Clients are encouraged to consult their internal SOPs regarding validation requirements since the self-validating method does not perform validation in the traditional sense.
For more information on residual solvent testing and the self-validating method approach, contact Pharmaceutical Business Development at 717-656-2300.