Revision of the BCS waivers Guidance has been on FDAs agenda since last year. A new draft guidance issued May 5th. As long promised, this draft addresses waivers for BCS Class 3 compounds in addition to BCS Class 1 compounds that have been eligible for BA/BE study waiver since 2000.
Waivers of the need to perform Bioavailability/Bioequivalence studies based on a drug's BCS Classification and the dosage form has been a topic of discussion for many years. The BCS system classifies drugs and drug products according to 2 drug properties, in vivo solubility and in vivo permeability. There are 4 classes in the BCS system as follows.
Class 1 – High solubility, High permeability
Class 2 – Low solubility, High permeability
Class 3 – High solubility, Low permeability
Class 4 – Low solubility, Low permeability
There is little that formulators can do to change a drug’s permeability. Permeability is the rate at which the drug is absorbed across the intestinal mucosa. Some excipients can affect the rate of permeability but mostly to slow it down. Now as formulators we can affect the rate of drug dissolution. We can formulate delayed-release dosage forms, extended-release dosage forms or we might make API complexes to increase the rate of dissolution. However, if we formulate immediate-release dosage forms, then we do not control the rate of dissolution, we design a dosage form that disintegrates quickly in the stomach so releasing the drug which then dissolves according to the API solubility properties.
In considering this situation, if a drug has high solubility it will quickly and completely dissolve and the rate of absorption into the body will depend only on the drug’s permeability. Or to put it another way – “once the drug is dissolved, whatever happens next just happens”. So from this perspective, if a drug has a high solubility and the dosage form does nothing to affect solubility, then these drug products will all behave the same, that is they will all give the same blood level profiles. This means that they will all have the same bioavailability or bioequivalence if Reference and Test are being compared.
The draft guidance defines “high solubility” as meaning the API of the highest strength immediate-release dosage form dissolves completely in 250 mL of aqueous solution with pHs between 1 and 6.8. It suggests using pH 1 (the lowest pH of a fasting stomach), pH 4.5 (the pH immediately after passing from the stomach into the top of the small intestine), and pH 6.8 (the pH at the distal end of the small intestine). The 250 mL comes from the “8 ounce glass of water” taken with the dose in single dose bioequivalence studies (8 oz is about 240 mL). The immediate-release dosage form dissolution must meet a Q of 85% in 30 minutes in 500 mL of medium with a pH of 1, 4.5, and 6.8 for Apparatus I at 100 rpm or Apparatus 2 at 50 rpm of 75 rpm. If these conditions are met, then you have a BCS 1 or BCS 3 product depending on permeability.
The draft guidance provides 4 ways of measuring permeability, the most usual way being in vitro using a monolayer of epithelial cells. If the drug is 85% absorbed across the gut wall (or model system) it is classified as highly permeable, less than 85% is low permeability.
There are many conditions given in the “fine print” which you have to be aware of. So you need to read the whole guidance thoroughly. However, assuming your BCS 1 or BCS 3 product is not one of the many exception situations, then you can follow the BCS waiver path. Why do this? Well it is cheaper (no fasting and fed studies required) and once you have established a waiver you can make changes in the future which might have required biostudies without having to do them, assuming you still meet the solubility and dissolution requirements.
The conditions that must be met are as follows.
BCS 1
The drug substance is highly soluble
The drug substance is highly permeable
The drug product (both Test and Reference) is rapidly dissolving
The product does not contain any excipient that will affect the rate or extent of absorption of the drug
BCS 3
The drug substance is highly soluble
The drug product (both Test and Reference) is very rapidly dissolving (Q in 15 mins)
The Test product formulation is qualitatively the same and quantitatively very similar to the Reference formulation. That is it must contain the same inactive ingredients as the Reference product and the amounts must be within the range allowed by SUPAC IR guidance for level 1 or level 2 changes
The formulation similarity requirement for BCS 3 is to ensure that if there is any “interference” in permeability from the excipients. This seems to me to be highly unlikely but as the saying goes, FDA is not paid to take a chance – on anything!
MOST IMPORTANTLY, remember this is a draft guidance. If you are thinking of trying a BCS 3 waiver, consult FDA first. DO NOT RISK doing anything with a BCS 3 drug without consulting FDA FIRST (first means before you start, not before you file!!).
Remember the adage – “if a draft guidance means you can do less work, wait until it is final (or ask first), if a draft guidance requires you to do more work, then do it immediately”.
