A biowaiver is applicable when the drug substance(s) in test and reference products (RLD) are
identical.
BCS-based biowaivers are applicable to drug products where the drug substance or substances exhibit high solubility and, either high permeability (BCS Class I) or low permeability (BCS Class III).
In order for a drug product to qualify for a BCS-based biowaiver, criteria with respect to the composition (excipients) and in vitro dissolution performance of the drug product should be satisfied.
Ideally, the composition of the test product should mimic that of the reference product. However, where excipient differences exist, they should be assessed for their potential to affect in vivo absorption. This should include consideration of the drug substance properties as well as excipient effects.
When applying the BCS based biowaiver approach, comparative in vitro dissolution tests should be conducted using one batch representative of the proposed commercial manufacturing process for the test product relative to the reference product. The test product should originate from a batch of at least 1/10 of production scale or 100,000 units, whichever is greater, unless otherwise justified.
To qualify for a BCS-based biowaiver for BCS Class I drug substances, both the test product and reference product should display either very rapid (≥85% for the mean percent dissolved in ≤ 15 minutes) in vitro dissolution characteristics, or rapid (≥85% for the mean percent dissolved in ≤ 30 minutes) and similar in vitro dissolution characteristics (i.e., based on f2 comparison), under all of the defined conditions as below:
– Apparatus: paddle or basket.
– Volume of dissolution medium: 900 mL or less (it is recommended to use the volume selected for the quality control (QC) test).
– Temperature of the dissolution medium: 37±1°C.
– Agitation: for paddle apparatus – 50 revolutions per minute (rpm)and for basket apparatus – 100 rpm.
– At least 12 units of reference and test product should be used for each dissolution profile determination.
– Three buffers: pH 1.2, pH 4.5, and pH 6.8. Pharmacopoeial buffers should be employed. Additional investigation may be required at the pH of minimum solubility (if different from the buffers above).
– Organic solvents are not acceptable, and no surfactants should be added.
– Samples should be filtered during collection, unless in situ detection methods are used.
– For gelatin capsules or tablets with gelatin coatings where cross-linking has been demonstrated, the use of enzymes may be acceptable, if appropriately justified.
Two dissolution profiles are considered similar when the f2 value is ≥50. When both test and reference products demonstrate that ≥85% of the labeled amount of the drug is dissolved in 15 minutes, comparison with an f2 test is unnecessary, and the dissolution profiles are considered similar. When the coefficient of variation is too high, f2 calculation is considered inaccurate and a conclusion on similarity in dissolution cannot be made.
Reference: M9 Biopharmaceutics Classification System Based Biowaivers