Comparative Dissolution Profile Guideline

Comparative Dissolution Profile

Comparative dissolution profile is a dissolution profile comparison between reference product and test product for biowaiver considerations and SUPAC after the product is approved.

Comparative Dissolution as per USP

In vitro drug dissolution and release testing can be related to in vivo drug performance, such as BA. The comparisons of dissolution profiles are gaining importance as a means of documenting comparative BA studies—that is, BE. A biowaiver is the replacement or waiver of in vivo BE studies by an in vitro test.

F2 Calculation

A model independent mathematical approach is used to compare the dissolution profiles of two products: 1) to compare the dissolution profile between the (T) test product and (R) reference product in biowaiver considerations; 2) to compare the dissolution profile between the two strengths of products from a given manufacturer; and 3) for SUPAC after the product is approved. For comparing the dissolution profile, the similarity factor f2 should be computed using the equation:

Where, Rt and Tt are the cumulative percentage of the drug dissolved at each of the selected n time points of the R  and T product, respectively. 

  • An f2 value of 50 or greater (50–100) ensures dissolution profile similarity and thus equivalence of the performance of the two products.
  • FDA guidance recommends that, at a minimum three points, NMT 1 point exceeding 85% of the label claim dissolved, should be used for similarity profile comparison. 
  • For products that dissolve very rapidly (≥85% dissolution in 15 min), a profile comparison is not necessary.

Comparative Dissolution Profile Guideline

As per FDA Guidance,

  • The dissolution measurements of the test and reference batches should be made under exactly the same conditions. The dissolution time points for both the profiles should be the same (e.g., 15, 30, 45, 60 minutes). The reference batch used should be the most recently manufactured product.
  • Only one measurement should be considered after 85% dissolution of both the products.

As per TGA Guideline,

When dissolution profiles or a similar term is used in this guidance, data should be generated in a comparative manner as follows:

  • At least 12 dosage units (e.g. tablets, capsules) of each batch must be tested individually, and mean and individual results reported.
  • The percentage of nominal content released are measured at a minimum of three (3) suitably spaced time points (excluding zero time point) to provide a profile for each batch (e.g. at 5, 15, 30 and 45 minutes, or as appropriate to achieve virtually complete dissolution).
  • The batches are tested using the same apparatus and, if possible, on the same day.
  • The stirrer used is normally a paddle at 50 rpm for tablets and a basket at 100 rpm for capsules. However, other systems or speeds may be used if adequately justified and validated.
  • Test conditions are those used in routine quality control or, if dissolution is not part of routine quality control, any reasonable, validated method.
  • The similarity factor, f2, is calculated using the equation and conditions stated in Appendix I of the European Medicines Agency (EMA) Guideline on the investigation of bioequivalence to demonstrate the similarity of two dissolution profiles. The f2 value must be between 50 and 100.
  • If more than 85 per cent of the active substance is dissolved within 15 minutes in all tested batches, dissolution profiles are considered to be similar without the need to calculate the similarity factor.
  • If there are insufficient quantities of recently manufactured batches available to meet this requirement, then both:
    • test retention batches
    • explain in the test report why this was done, stating the age and storage history of the samples.

As per EMA Guideline,

Dissolution profile similarity testing and any conclusions drawn from the results (e.g. justification for a biowaiver) can be considered valid only if the dissolution profile has been satisfactorily characterized using a sufficient number of time points.

For immediate release formulations, further to the guidance given in section 1 above, comparison at 15 min is essential to know if complete dissolution is reached before gastric emptying.

Where more than 85% of the drug is dissolved within 15 minutes, dissolution profiles may be accepted as similar without further mathematical evaluation.

The evaluation of the similarity factor is based on the following conditions:

  • A minimum of three time points (zero excluded)
  • The time points should be the same for the two formulations
  • Twelve individual values for every time point for each formulation
  • Not more than one mean value of > 85% dissolved for any of the formulations.
  • The relative standard deviation or coefficient of variation of any product should be less than 20% for the first point and less than 10% from second to last time point.

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