Comparative dissolution testing

Comparative dissolution testing on the higher strength of the test and reference products is submitted and found to be appropriate. 

The information requirements for products such as prolonged-release oral dosage forms will depend on whether or not it has been possible, during the development of the product, to establish an in vivo-in vitro correlation between clinical data and dissolution studies. In vivo-in vitro correlations should be attempted using product at different stages of development, but bioavailability and pharmacokinetics data from pivotal clinical studies using at least pilot-scale production materials and possibly routine production material are particularly important. Where it is not possible to establish an in vivo-in vitro correlation, additional data will be required to compare the bioavailability of product developed at laboratory scale, pilot scale, and production scale. In the absence of an in vivo-in vitro correlation, the dissolution test will be a quality control tool rather than a surrogate marker for in vivo performance of the product. 

Product bioavailability is mentioned, especially where it is low. Where there are differences between the formulations tested for bioavailability during the development process and the formulation to be marketed, there is considerable discussion of the data provided on the bioequivalence of the different products and/or formulations. This is particularly so where, for example, early clinical studies were undertaken with capsules but the marketed dosage form is to be a tablet. Bioequivalence data and pharmacokinetic data (e.g., in crossover studies) and comparative dissolution studies are usually reported. This is particularly significant where the different strengths of the final products are not achieved by using different quantities of the same granulate formulation. Process optimization may also be addressed in such cases. 

Choice of Dissolution Tests to Compare Formulations During Development... 

In such cases, it is obviously advantageous to use biorelevant dissolution tests to characterize the drug substance, to compare formulations and to make a preliminary assessment of possible food effects. However, for routine quality control work, the manufacture of media containing bile components is not only rather time-consuming but may also present difficulties in terms of quality assurance and validation of the raw materials, as is the case with many chemicals obtained from natural sources. 

The dissolution test was carried out using the European Pharmacopoeia apparatus at a paddle speed of 100 rev min-1. The dissolution medium was 900 ml of hydrochloric acid (0.05 N) (pH 1. 6). Temperature was maintained at 37°C ( 0.5°C). Samples of 10 ml were automatically withdrawn, filtered and analysed by UV spectophotometry. Four or six samples were analysed for each test. A study was conducted to assess the dependence of the dissolution rate on the pH tests were conducted comparatively at pH 2, 5 and 7.4 with drug A and at pH 1.6 and 6.8 with drug B. 

Notification and updated batch record Stability Application/ compendial requirements plus multipoint dissolution profiles in three other media (e.g., water, 0.1/VHC1, and USP buffer media at pH 4.5 and 6.8) until >80% of drug released or an asymptote is reached Apply some statistical test (f2 test) for comparing dissolution profiles No biostudy... 

Notification and updated batch record Stability Dissolution requirements case A, case B, or case C Apply some statistical test (f2 test) for comparing dissolution profiles No biostudy... 

Apply some statistical test (f2 test) for comparing dissolution profiles No biostudy... 

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