Similarity Factor f2: A Global Overview

Introduction

Dissolution testing is a critical aspect of pharmaceutical development and quality control. It serves multiple purposes, such as guiding the development of new formulations, monitoring the quality of drug products, assessing the impact of post-approval changes, and in some cases, predicting the in vivo performance of a drug product. A key metric used in dissolution testing is the similarity factor, f2, which provides a quantitative measure to compare the dissolution profiles of two drug products.

The f2 metric is widely accepted due to its simplicity and ease of calculation. It is particularly useful for regulatory submissions, where demonstrating the similarity between dissolution profiles can potentially waive the need for in vivo bioequivalence studies. However, global regulatory expectations for applying the f2 test are not harmonized, leading to significant challenges for pharmaceutical companies operating in multiple markets. This article provides an in-depth overview of the f2 similarity factor, focusing on the divergent regulatory requirements across various regions and their implications for the pharmaceutical industry.

Global Regulatory Expectations

Regulatory harmonization in pharmaceutical testing is crucial for ensuring consistent quality and efficacy of drug products globally. Despite this, there are notable differences in how regulatory authorities in different regions apply the f2 similarity factor for dissolution profile comparisons. These differences can result in increased manufacturing costs, hinder science-based approaches, and delay patient access to medications.

Regulatory Landscape

United States (FDA) The FDA recommends the use of the f2 test for comparing dissolution profiles as part of its Scale-Up and Post-Approval Changes (SUPAC) guidance. According to the FDA, an f2 value of 50 or higher indicates similarity between the test and reference products. This criterion is applied under identical conditions for both products, before and after formulation changes. The FDA’s guidelines also consider the Biopharmaceutics Classification System (BCS) and the therapeutic index of the drug in their recommendations.

European Union (EMA) The EMA's guideline on the investigation of bioequivalence similarly endorses the f2 test, particularly when a product has been reformulated or its manufacturing method modified. The EMA requires in vivo bioequivalence studies for such changes unless justified otherwise. The guideline also provides specific recommendations for dissolution testing at various time points to adequately characterize the dissolution profile.

Asia (Japan and China) In Japan, the Pharmaceuticals and Medical Devices Agency (PMDA) requires the f2 test for bioequivalence studies and recommends comparing the mean results of test and reference formulations. Japanese guidelines also specify the use of screening experiments to determine appropriate dissolution media and reference lots. China’s regulatory framework mirrors these requirements, emphasizing the need for multiple dissolution media and well-defined time points in the f2 calculations.

Other Regions Regulatory requirements in other regions, such as Brazil, India, and South Korea, exhibit similar but distinct expectations for the f2 test. For instance, Brazil requires the coefficient of variation at the 15-minute time point to not exceed 10%, adding another layer of complexity to the testing process. India’s guidelines are less specific, often requiring adequate sampling to achieve near-complete dissolution.

Comparative Dissolution Methods Comparative dissolution testing can be conducted using model-independent or model-dependent methods. The f2 test falls into the model-independent category, providing a straightforward approach to comparing dissolution profiles. It requires dissolution data at multiple time points to accurately characterize the profile.

Statistical Considerations The f2 value is calculated using a logarithmic transformation of the sum of squared differences between the test and reference profiles. An f2 value between 50 and 100 indicates similarity, with 100 representing identical profiles. When the variability in dissolution results is high, alternative statistical methods, such as bootstrapping or the two one-sided t test (TOST), may be employed.

Criteria for Exemptions from f2 Comparisons Exemptions from f2 comparisons are generally allowed when both the test and reference products dissolve more than 85% within 15 minutes. This criterion is adopted by several regulatory authorities, including the FDA and EMA, although specific requirements can vary by country.

Minimum Number of Time Points Most regulatory guidelines stipulate a minimum of three time points for f2 calculations, excluding zero. However, some regions require more frequent sampling, particularly for rapidly dissolving products, to ensure an accurate characterization of the dissolution profile.

Last Time Point Considerations The determination of the last time point for f2 calculations varies globally. Some guidelines recommend considering data until both the test and reference products reach 85% dissolution, while others only require one product to meet this criterion. This variability can significantly impact the conclusion of similarity assessments.

Coefficient of Variation Criteria The coefficient of variation (CV) is another critical factor in f2 calculations. Generally, a CV of no more than 20% at early time points and no more than 10% at later time points is acceptable. However, the definition of "early" time points and specific CV criteria can differ across regions, complicating the harmonization of dissolution testing standards.

Harmonization of f2 criteria

Achieving global harmonization of f2 criteria would alleviate many challenges faced by the pharmaceutical industry. Current divergences in regulatory expectations lead to redundant testing and increased costs, without necessarily enhancing product safety or efficacy. A concerted effort by regulatory authorities and industry stakeholders is needed to establish unified guidelines for dissolution similarity assessments.

Conclusion

The similarity factor f2 plays a vital role in the comparative assessment of dissolution profiles. Despite its widespread acceptance, global regulatory expectations for applying the f2 test vary significantly, posing challenges for pharmaceutical companies. Harmonizing these criteria would streamline the regulatory process, reduce unnecessary testing, and facilitate quicker patient access to medications. As the pharmaceutical landscape continues to evolve, ongoing dialogue and collaboration are essential to achieve this goal.

References

European Medicines Agency. Committee for medicinal products for human use. Guideline on the investigation of bioequivalence CPMP/EWP/QWP/1401/98 Rev.1/Corr**. 2010.

FDA Guidance for Industry. SUPAC-IR. Immediate release solid oral dosage forms. Scale-up and post approval changes. Chemistry, manufacturing and controls. In vitro dissolution testing and in vivo bioequivalence documentation. 1995.

Freitag G. Guidelines on dissolution profile comparison. Drug Inform J. 2001;35:865–74.

Gupta E, Barends DM, Yamashita E, et al. Review of global regulations concerning biowaivers for immediate release solid oral dosage forms. Eur J Pharm Sci. 2006;29:315–24.

Liu Q, Davit BM, Cherstniakova SA, et al. Common deficiencies with bioequivalence submissions in abbreviated new drug applications assessed by FDA. AAPS J. 2012;14(1):19–22.

Pharmaceuticals and Medical Devices Agency, Japan. Guideline for bioequivalence studies for formulation changes of oral solid dosage forms. English translation of Attachment 3 of Division-Notification 0229 No. 10 of the Pharmaceutical and Food Safety Bureau. 2012 February.

Rohilla S, Rohilla A, Nanda A. Biowaivers: criteria and requirements. Int J Pharmaceut Biol Arch. 2012;3(4):727–31.

Sathe P, Tsong Y, Shah P. In vitro dissolution profile comparison: statistics and analysis, model dependent approach. Pharm Res. 1996;13(12):1799–803.

Shah V, Cecil T, Srinivassan S, Williams R. Progressively reducing regulatory burden. AAPS J. 2014;16(4):621–4.

Xie F, Ji S, Cheng Z. In vitro dissolution similarity factor (f2) and in vivo bioequivalence criteria, how and when do they match? using a BCS class II drug as a simulation example. Eur J Pharm Sci. 2015;66:163–72.

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Disclaimer: The opinions and views expressed in this blog are strictly those of the author and do not reflect the stance of their employers or any affiliated organizations. This content is for informational purposes only, not as professional advice. The author is not liable for any inaccuracies, losses, or damages arising from the use of this information. Always seek direct advice from qualified professionals for specific situations. The inclusion of external links does not imply endorsement. Information is provided as-is, and it's the reader's responsibility to ensure its accuracy and applicability to their situation. Regulatory guidelines are everchanging; please refer to the latest guidelines and regulatory thought at the time of reading. While all latest regulatory guidelines are referred to here, check the current guidelines.