Is the presence of f2 in Multimedia a reliable measure of bioequivalence?
In the realm of pharmaceutical development, the F2 similarity factor plays a significant role in comparing the dissolution profiles of a test product and its reference listed drug. This mathematical tool, while useful, has its limitations as a bioequivalence surrogate in multimedia dissolution testing.
F2 reflects the rate and extent of drug absorption, which is influenced by various physiological factors such as gastrointestinal motility, enzyme activity, permeability, food effects, and first-pass metabolism. However, it does not account for these complex human physiological variables that affect drug absorption and metabolism.
For drugs classified as BCS Class I or III, F2 in multimedia can be used to support biowaiver applications, provided all other regulatory criteria are met. A calculated F2 value of ≥ 50 indicates that the two profiles are similar under the tested conditions. However, it is essential to note that a consistent F2 value across multiple media does not guarantee bioequivalence.
The F2 factor provides a model-independent single value to compare dissolution profiles based on percentage dissolved over time. However, its use is subject to certain conditions, such as a limited number of time points (usually up to 12) and low variability in dissolution data. The sampling distribution of F2 is not well-defined, preventing exact confidence intervals, and uncertainty quantification relies on resampling (bootstrap) methods.
Despite these limitations, F2 can still be supportive in regulatory submissions and formulation development. When its validity criteria are met, F2 can indicate similarity in dissolution profiles, especially for biowaivers and demonstrating formulation robustness. Confidence intervals for F2 derived via bootstrap are regarded as an improved method and can strengthen the statistical case for similarity.
It is crucial to remember that F2 is not a substitute for clinical bioequivalence. It offers no direct evidence of in vivo equivalence and hence cannot replace pharmacokinetic (PK) studies. Therefore, an in vivo bioequivalence study remains essential to truly establish therapeutic equivalence between the test and reference products.
Regulatory agencies such as the USFDA, EMA, and WHO accept the F2 threshold as a valid measure of similarity, but only within certain boundaries. Dissolution testing is often extended to multiple media (pH 1.2, 4.5, and 6.8) to mimic the changing pH environments of the human gastrointestinal tract.
In summary, while F2's use as a surrogate for bioequivalence is limited by its inability to fully capture in vivo performance and its statistical constraints, it remains a valuable comparative tool in vitro when carefully applied and interpreted with supporting data and justified methodology. Moinuddin Syed, Ph.D, PMP® is the resource person for this article.
This is especially critical for BCS Class II or IV drugs, where solubility or permeability may limit absorption. Therefore, while F2 in multimedia provides valuable insights into the consistency of drug release across varying pH environments, an in vivo bioequivalence study remains essential unless biowaiver conditions are clearly fulfilled.
- In science and medical-conditions, the rate and extent of drug absorption are subject to various factors like gastrointestinal motility, enzyme activity, permeability, food effects, and first-pass metabolism, which are not accounted for by the F2 factor.
- For drugs classified as BCS Class II or IV, while F2 in multimedia can offer valuable insights into the consistency of drug release, it is crucial to conduct an in vivo bioequivalence study to establish therapeutic equivalence, due to challenges in solubility or permeability that may limit absorption.
- When studying health-and-wellness, especially in the context of pharmaceuticals, it is important to recognize that the F2 factor, though useful and accepted by regulatory agencies, has limitations in serving as a bioequivalence surrogate and providing direct evidence of in vivo equivalence, necessitating pharmacokinetic studies and specific conditions for its application.
