Definition of multivariate acceptance limits (guard-bands) applied to pharmaceutical equivalence assessment

Abstract

The quality assessment of medicines involves multiple compliance parameters, such as identity, dosage, purity, potency, content uniformity, disintegration time, dissolution rate, among others. The measurement uncertainty associated with a measured value can affect the conformity assessment and, consequently, it impacts decision-making. Even if the particular risks are acceptable, the total risk may be significantly high. Thus, the aim of this work was to develop a procedure for the definition of acceptance (or rejection) limits applied to multiple compliance assessments, that ensure acceptable particular and total risks. The multiple compliance assessments were performed and applied in the pharmaceutical equivalence studies for cisplatin injectable solution, carboplatin injectable solution, ranitidine tablets, and acetaminophen oral solution from several manufacturers. Pharmaceutical equivalence studies were performed adopting pharmacopeial analytical procedures. All chromatographic system suitability results complied with the requirements regarding the resolution between peaks, the capacity factor, the tailing factor, the theoretical plates, and the relative standard deviation for replicate injections. Univariate and multivariate guard-bands (g and g', respectively) were calculated by multiplying the standard uncertainty (u) by an appropriate univariate and multivariate coverage factor (k and k', respectively).The values of multivariate guard band (g') were higher than the values of univariate guard bands (g), which leads to more restrictive acceptance intervals. Measured values between the conventional and the multivariate acceptance limits will ensure particular risk values below the maximum acceptable value, however, the total risk may be significantly high. On the other hand, measured values within the multivariate acceptance limits ensure that particular risk values and total risk value are below the maximum acceptable value The application of multivariate guard bands is a simple way to ensure reduced particular and total risks of false conformity decisions, which is of great interest to regulatory agencies and the manufactures of the medicines.

Keywords: Conformity assessment; Guard-band; Measurement Uncertainty; Multivariate analysis.