A newfangled study using risk silhouette and uncertainty approximation for quantification of acyclovir in diverse formulation

Abstract

Risk assessment and uncertainty approximation are two major and important parameters that need to be adopted for the development of pharmaceutical process to ensure reliable results. Additionally, there is a need to switch from the traditional method validation checklist to provide a high level of assurance of method reliability to measure quality attribute of a drug product. In the present work, evaluation of risk profile, combined standard uncertainty and expanded uncertainty in the analysis of acyclovir were studied. Uncertainty was calculated using cause-effect approach, and to make it more accurately applicable a method was validated in our laboratory as per the ICH guidelines. While assessing the results of validation, the calibration model was justified by the lack of fit and Levene׳s test. Risk profile represents the future applications of this method. In uncertainty the major contribution is due to sample concentration and mass. This work demonstrates the application of theoretical concepts of calibration model tests, relative bias, risk profile and uncertainty in routine methods used for analysis in pharmaceutical field.

Keywords: Acyclovir; Combined standard uncertainty; Expanded uncertainty; Relative bias; Risk profile.

Fig. 1

Cause-effect diagram constructed to identify the sources of uncertainty. The major identified sources are concentration of sample C₁₀, precision of method, recovery of method, volume of volumetric flask V₁₀ and sample mass.

Fig. 2

Standard residual plot of four different series representing absence of outliers in all different concentration levels.

Fig. 3

Accuracy profile of acyclovir determination in (A) tablets, (B) skin cream, (C) eye ointment, (D) injection obtained after application of linear regression using calibration standards prepared with the matrix. The plain line is the relative bias, the dashed lines are the 95% β-expectation tolerance limits and the dotted curves represent the acceptance limits (± 5%). The dots represent the relative back calculated concentrations of the validation standards.

Fig. 4

Standard residual plot confirming absence of outliers in determination of accuracy of (A) tablets, (B) skin cream, (C) eye ointment and (D) injection.

Fig. 5

Uncertainty profile for acyclovir determination in (A) tablets, (B) skin cream, (C) eye ointment, (D) injection representing different components contributing in overall uncertainty and showing the maximum effect due to concentration of sample.