Selection Criteria for Dissolution Profile Evaluation
Two principal methods used for statistical evaluation of dissolution which in turn gives confidence for BE study are the F2 similarity factor and the bootstrap approach.
F2 Similarity Factor
The F2 similarity factor is a model-independent, log-transformed mathematical calculation that assesses the closeness between the average dissolution profiles of a test and reference product.
Here, and denote the percentage of drug dissolved at each time point for the reference and test formulations, respectively, and is the number of time points, usually 3 to 4.
F2 value ranging from 50 to 100 indicates that the two profiles are similar. This method typically requires dissolution data from 12 units of both test and reference products and is applicable when variability is controlled. The F2 method assumes:
- No more than 85% drug release at the first time point,
- ≤ 20% coefficient of variation (CV) at earlier time points, and
- ≤ 10% CV at later time points.
It is simple to apply and widely accepted by regulatory authorities for immediate-release formulations with low variability. However, it becomes unsuitable when dissolution profiles are highly variable, when data are missing, or when fewer than 12 units are available.
Bootstrap Approach
The bootstrap approach, on the other hand, is a resampling-based statistical technique designed to estimate the uncertainty around the similarity factor (F2) in conditions where classical F2 assumptions are not met. This method involves generating thousands of pseudo-samples from the original dataset by sampling with replacement, calculating F2 values for each sample, and then determining the confidence interval for the distribution of F2 values.
If the lower bound of the 90% confidence interval (CI) is ≥ 50, the profiles are considered similar.
This method is especially useful in cases involving:
- High inter-unit variability (CV > 20%),
- Highly variable drug products (HVDPs),
- Incomplete or non-uniform data, or
- Modified-release dosage forms with complex profiles.
The bootstrap approach is supported by both USFDA and EMA when adequately justified, and it offers a statistically robust alternative when the classical F2 method fails despite apparent visual similarity.
F2 vs. Bootstrap: Practical Considerations
When dissolution profiles are consistent and within specification limits, the F2 method is efficient and preferred. However, when the data show significant variability or irregularity, the bootstrap method provides a more reliable and scientifically sound analysis.
In practice:
Use F2 when the product is immediate-release, has low variability, and the standard requirements (12 units, consistent profiles) are met.
Use Bootstrap when there is high variability, fewer units, or borderline F2 results, particularly in modified-release or biowaiver contexts.
Read also:
- Comparative Dissolution Profile Guideline
- Global Regulatory Requirements for Multimedia Dissolution Testing
- Does an F2 Similarity Value of 50 Mean the Two Dissolution Profiles are Only 50% Similar?
