(T1330-11-70) Are Globally Marketed Generic 1% Clotrimazole Creams Pharmaceutically Equivalent?

Purpose: The draft FDA guidance¹ published in October 2022 presents an option of in vitro release test (IVRT) studies as a biowaiver for topical drug products submitted in Abbreviated New Drug Applications (ANDAs). However, the product specific guidance for 1% clotrimazole (CLZ) topical cream does not provide an in vitro option for biowaiver and requires a clinical endpoint study to demonstrate bioequivalence. The main objective was to use IVRT to investigate pharmaceutical equivalence of several 1% CLZ topical creams from two countries - South Africa (SA) and Canada (CA). The resulting data based on the assessment of qualitative (Q1), quantitative (Q2) properties and arrangement of matter (Q3) between the various products indicate the utility of IVRT to accurately assess “sameness” and inequivalence, thereby implicating the potential to justify a biowaiver.

Methods: An IVRT method to characterize the release of CLZ from topical creams was developed by selecting appropriate membrane, receptor medium, dose, sampling duration and intervals, etc. (see Table 1 for optimized parameters). The IVRT method was validated and IVRT runs conducted in accordance with the latest FDA guidances¹. A relatively new concept of supplemental selectivity introduced in the new draft guidance was included as a validation parameter, where formulations with the same concentration of CLZ as the reference were used – Test cream A containing different excipients and manufactured using a different method and Test cream B containing the exact same ingredients as the reference. Furthermore, in order to demonstrate the high discriminatory ability of the method, 1% CLZ cream was tested against itself as a positive control and creams containing 0.7% and 1.4% CLZ served as negative controls. The IVRT method was then applied to conduct comparative IVRT runs on five generic products marketed in SA which were compared with the SA reference product (R1) and a Canadian generic (T1) compared against its reference listed drug (RLD) in Canada. In addition, a comparison between the reference products from SA (R1) and Canada (R2) was undertaken. Confirmation of “sameness” was based on the FDA’s acceptance criteria^1,2 of 75-133.33% using a 90% confidence interval.

Results: An IVRT system was qualified and accordingly validated for the various criteria enlisted in the draft FDA guidance. Importantly, the runs conducted to validate the supplemental selectivity revealed that Test cream B which comprised of the same type and quantity of excipients as the RLD, passed the “sameness” acceptance criterion, whereas Test cream A, consisting of different inactive ingredients than the RLD indicated inequivalence. The discriminatory power of the method was confirmed when it showed “sameness” with the positive control and inequivalence with the negative controls. All five SA-marketed generic creams showed pharmaceutical inequivalence to the SA reference product (Figure 2a) indicating Q1/Q2/Q3 differences between the products. Interestingly, despite containing the same excipients as both reference products, the Canadian generic (T1) showed substantially lower release rate compared to creams R1 and R2 (Figure 2b) which could be attributed to Q2/Q3 differences. As expected, the RLDs from both the countries demonstrated pharmaceutical equivalence.

Conclusion: The data clearly indicate that the investigated marketed generic 1% clotrimazole creams were not pharmaceutically equivalent. The validated IVRT method showed the potential to accurately measure the release from 1% CLZ creams and demonstrated supplemental selectivity and appropriate discriminatory power to identify "sameness" and/ or differences, if any. Furthermore, it displayed the requisite ability to discriminate between the various marketed 1% CLZ creams, including some products with relatively insignificant formulation differences and others with substantially dissimilar attributes relating to Q1/Q2/Q3. The results indicate the utility of this method to support biowaiver for CLZ creams, thereby obviating the need for cost-, labour-, and time-intensive clinical studies and facilitating faster entry of affordable generic products into the market.

References: 1. U.S. Food and Drug Administration. Guidance for Industry: In Vitro Release Test Studies for Topical Drug Products Submitted in ANDAs; Centre for Drug Evaluation and Research: Rockville, MD, USA, 2022.
2. US Food and Drug Administration. Guidance for Industry: Nonsterile Semisolid Dosage Forms, Scale-up and Post Approval Changes, Chemistry, Manufacturing, and Control; In vitro Release Testing and In vivo Bioequivalence Documentation (SUPAC-SS); Center for Drug Evaluation and Research: Rockville, MD, USA, 1997.

Acknowledgements: This work was supported by a National Research Foundation Scholarship, South Africa, and the Biopharmaceutics Research Institute (BRI), Rhodes University, Grahamstown, South Africa.

Table 1. Optimized IVRT parameters

Figure 1. Release rates of CLZ from the creams used for assessing (a) supplemental activity; (b) discriminatory ability

Figure 2. Comparative IVRT of generic creams marketed in (a) South Africa; (b) Canada