BCS Class 1 & 3 drugs are highly soluble across the physiological pH range and so are eligible for biowaiver in conventional IR dosage forms (mainly tablets and capsules) provided the dosage form rapidly releases these highly soluble drugs. The solubility characteristics of the dosage form must be demonstrated as detailed in the biowaiver guidance. This new draft guidance addresses routine dissolution testing, that is the so-called “QC Test” for dissolution.
The draft guidance begins by defining “eligible products”. There are 6 criteria that must be met for a dosage form to be considered “eligible”. These are:
It must be an orally administered (swallowed) IR dosage form. Note that chewable and orally disintegrating dosage forms are not covered by this guidance.
The drug substance must meet the “highly soluble” criteria of the highest dosage strength dissolving in 250 mL or less of aqueous media over the pH range 1 to 6.8. The drug substance must also be chemically stable for 24 hours under these conditions
This guidance does not apply to narrow therapeutic index drugs. As an interesting aside it states that NTI classification is described in the Warfarin Sodium bioequivalence guidance issued December 2012. You would think with over 1300 people someone could get that into an NTI guidance.
If the “time to maximum plasma concentration” is critical to the intended use then this guidance does not apply. I guess BCS 1 & 3 is not necessarily BCS 1 & 3. They have already excluded everything except a standard swallowed IR tablet, how special can it be?
The manufacturing and testing history, including stability, should demonstrate that the product will meet dissolution specifications.
Excipients should be “consistent with the design of IR drug products”. Excipients should be in “normal quantities that are consistent with the product’s labeled function”. “Large quantities of excipients, such as sweeteners and surfactants, may be problematic”. Since we have already established that these dosage forms are swallowed and contain highly soluble drug substances, this shouldn’t be a problem.
If the drug and its dosage form meet these conditions, then the dissolution test is defined as one of two possibilities.
USP Apparatus 1, 100 rpm, 500 mL, 0.01 M HCL, 37±0.5°C (No Surfactant)
These seem very reasonable methods to use. The stirring speeds are chosen to minimize artifacts such as cone formation in the unstirred “dead space” directly under the basket or paddle. Although the volume of media used to determine that the drug substance is highly soluble is 250 mL (related to the glass of water used in biostudies), 500 mL is the minimum volume that allows normal functioning of the dissolution apparatus.
The specifications to be used are as follows.
For BCS 1 products, a single point of Q=80% in 30 minutes
For BCS 3 products, a single point of Q=80% in 15 minutes
As was foreshadowed in the biowaiver draft guidance, the tighter criteria is required for BCS 3 products because FDA is not certain that all BCS 3 situations will be bioequivalent and therefore qualify for the biowaiver. In any case it should not be a problem with the dissolution tests given in this guidance.
Finally the draft guidance allows the replacement of the dissolution test with a disintegration test. The test would use the USP disintegration apparatus and 0.01 M HCl and the dosage form should disintegrate completely in 5 minutes. The dissolution test must be retained as the primary method with the disintegration test as an alternate method. This will allow much quicker testing than the dissolution test for routine product release testing, it could even be done in-process.
Overall a positive draft guidance which proposes sensible and simple dissolution tests and has an added gift of a disintegration test option for routine finished product testing.
