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Leveraging Dissolution Testing to Meet Regulatory Guidelines

Dissolution testing is a standard tool in a formulation scientist’s arsenal. When companies make changes to drug products (particle size, excipients, manufacturing process, equipment, etc), health authorities often require comparing dissolution profiles to determine if the reference and test products are equivalent. Generic drug developers are also required to show bioequivalence between the branded drug (reference product) and the generic version (test product). Comparison tests are also required, when the dissolution is not very rapid, to compare dissolution curves for biowaivers. The F2 statistical test is often used to make this comparison. In this blog post, I’ll discuss some important considerations for performing dissolution and F2 tests and explain how they can inform your drug development program.

Considerations for dissolution tests

Dissolution tests are required for all, non-liquid, drug dosage forms containing an active ingredient that is absorbed systemically to have systemic activity. Thus, dissolution tests can be used for tablets, implants containing hormones, injectable formulations, and some medical devices such as stents. The results of dissolution tests are plotted as the percent dissolved vs. time― the dissolution curve.

The dissolution sampling times depend on the drug’s formulation. An immediate-release (IR) formulation requires taking many samples over a short time period. For an extended-release formulation, the sampling time will be spread out over hours. For drug-containing implants, dissolution can take up to several days or longer.

The F2 test and regulatory considerations

The F2 test is a statistical test used to compare dissolution profiles. This test was developed by scientists in collaboration with U.S. FDA. While, the FDA requires pharma companies to use both the F2 and F1 test, the EMEA and other regulatory agencies only require the F2 test.

Numerous regulatory guidances have been written about comparing dissolution profiles. You may want to read the European and American guidances on this topic:

These two papers describe the F2 test:

Comparing dissolution profiles

When comparing drug dissolution profiles, you need to consider your drug’s pharmaceutical properties. If the drug is more than 85% dissolved within 15 minutes, the test and reference profiles can be considered similar without further statistical evaluation.

If dissolution takes more than 15 minutes, you must use statistical tests (either F2 or F1/F2) to show that the two dissolution profiles are equivalent. The F1 test measures the relative error between curves. The F2 is a similarity function over the full profile. It’s a more complicated calculation than the F1 test. To consider the profiles similar, each F1 value must be less than 10-15% and for F2, the final F2 value must be greater than 50%.

Prerequisites for using the F1/F2 test

To perform F1/F2 tests, you need to first determine whether your data fits the prerequisites. You need data from at least 12 dissolution experiments. That means plotting 12 dissolution curves of the reference and 12 dissolution curves for the test. For each sampling time point, calculate the mean value of the 12 tests. No more than one mean time point can show greater than 85% dissolution. In Europe, this applies to either the test or reference; in the U.S., it’s for both the test and reference. In addition, you must measure drug dissolution during at least three time points. Likewise, the coefficient of variation (CV) must be less than 20% for the first time point and less than 10% for later time points. Finally, F1/F2 tests do not apply to fast release formulations, i.e., those showing greater than 85% drug release in 15 minutes. If these prerequisites are not met (mainly variability), you should use an alternative test.

Caveats of F1/F2 tests

Be aware of these caveats before using F1/F2 tests. While the mean and CV are simple statistics, they can potentially mask outliers. Also, small deviations in the sampling time― especially for the first time point― have a huge impact on the F1 value, with a smaller impact on the F2 value. Thus, the F1 test is considered to be overly conservative, which is why this test is not used in Europe or Japan.

Example of a use for dissolution testing: BCS-based biowaivers

Dissolution testing has multiple practical applications. For example, you can use it to attain a BCS biowaiver for clinical study of BCS class I or III drugs formulated as solid IR dosage forms. For class III IR drugs, you must have more than 85% dissolution in 15 minutes or less. For class I drugs, they must either be like class III IR drugs or show a slower dissolution― greater than 85% dissolution between 15-30 minutes.

Thus, the in vitro dissolution tests will use dissolution media with the following pH levels: 1.2, 4.5, and 6.8. You also need to perform a QC dissolution test. In this case, compare the dissolution between test and reference under these conditions. If you have more than one strength for a BCS-based biowaiver, compare the reference to the test formulation for each strength.

Example of a use for dissolution testing: Seeking a biowaiver for other drug strengths

If you’ve demonstrated bioequivalence (BE) using a BE study on the highest strength for a drug, you can seek a biowaiver for demonstrating bioequivalence for the other strengths. The test drug must meet several conditions in this case:

  • linear pharmacokinetics
  • proportional composition or the drug substance (DS) comprising less than five percent of the tablet core or capsule content or bracketing approach
  • Same manufacturing process + dissolution data

Proportional composition means that the percentage of the active ingredient and excipients in all strengths is constant; only the mass of the tablet changes. Perform dissolution in pH 1.2, 4.5, 6.8, plus QC, unless otherwise justified. The drug must be more than 85% dissolved in 15 minutes or less. If that is not the case, the F2 test must be used.

The F2 test will be applied to the product series between additional strengths and the strength/batch used for bioequivalence. At some pH values, sink conditions may not be achievable for all strengths for low solubility drugs. In this case, show that the dissolution profiles are similar at the same dose (two tablets at 5mg strength vs one tablet at 10mg strength) or between test and reference product.

Dissolution testing is also used before BE studies to compare the test and the reference formulation. The F2 test can be used to show that the reference formulation used in the BE study is representative of the reference formulation on the market.

Key Takeaways

Dissolution testing is an important tool in drug development. The dissolution test can be used before a BE study to show that the reference is representative of the batches which are on the market. It can also be used as a surrogate for in vivo studies to attain a biowaiver of strength and a BCS-based biowaiver.

During drug development, dissolution tests can be used for QC to accept or reject production batches. Data from dissolution testing comprises an important part of your dossier. For example, you can present dissolution test data in the CTD Part 2.7.1 for a biowaiver of strength.

To help you analyze your dissolution test data, I’ve created a template that can be used to perform the F2 test in Phoenix. Please watch my webinar to learn more!

About the author

By: Jean-Michel Cardot

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