Total combined global risk assessment applied to pharmaceutical equivalence – A case study of ofloxacin medicines

Abstract

Pharmaceutical equivalence studies are critical for determining the interchangeability between test and reference medicines by ensuring that their chemical, physical, microbiological, and biological properties are identical. Typically, this equivalence is evaluated by comparing a single batch of generic medicine to a single batch of the reference medicine. However, regulatory authorities may mandate continuous monitoring of the medicine's quality to maintain compliance with standards. The objective of this study was to assess the total combined global risk of making false decisions regarding the pharmaceutical equivalence of test and reference medicines. To achieve this, ofloxacin ophthalmic solutions and ofloxacin tablets were subjected to pharmacopeial tests and assays. Particular and total global risks were estimated using the Monte Carlo method (MCM) implemented in a MS-Excel spreadsheet. Consumers' risk values were calculated based on the historical mean and standard deviation for quantitative tests or the probability of a compliant batch for qualitative tests. The risk values differed depending on whether the tests had interval specification limits or only minimum or maximum specification limits. Lower risk values were observed when historical means were far from the specification limits, the probability of a compliant batch was high, or when the standard deviation values were low. Similarly, for qualitative analysis, higher probabilities of a compliant batch led to lower consumers' risk values. Reduced risk values were also associated with historical means being distant from the specification limits and with a high probability of a compliant batch, or when standard deviation values were low. The total combined global risk of a false pharmaceutical equivalence decision was found to be significantly high (above 5%) under certain simulated conditions. These conditions include historical mean values close to the specification limits and/or an increased standard deviation of the manufacturing process. As a result, there is an increased risk of failing to establish pharmaceutical equivalence between test and reference medicines manufactured under such conditions.