BCS Classification
BCS classification system is a scientific framework to differentiate the drug substances on the basis of solubility and permeability under prescribed condition.
Highly soluble
A drug substance is classified as highly soluble if the highest single therapeutic dose is completely soluble in 250 ml or less of aqueous media over the pH range of 1.2–6.8 at 37±1°C.
Highly permeable
A drug permeability can be concluded as high when the absolute bioavailability is ≥85%. High permeability can also be concluded if ≥85% of the administered dose is recovered in urine as unchanged (parent drug), or as the sum of parent drug, Phase 1 oxidative and Phase 2 conjugative metabolites.
Significance
The BCS (Biopharmaceutics Classification System) based biowaiver apply to reduce in-vivo bioequivalence studies and it is applicable to drug products where the drug substance(s) exhibit high solubility and high permeability (BCS Class I) or low permeability (BCS Class III).
For BCS class 1 drug products, the following should be demonstrated:
- the drug substance is highly soluble
- the drug substance is highly permeable
- the drug product (test and reference) is rapidly dissolving, and
- the product does not contain any excipients that will affect the rate or extent of absorption of the drug
For BCS class 3 drug products, the following should be demonstrated:
- the drug substance is highly soluble
- the drug product (test and reference) is very rapidly dissolving, and
- the test product formulation is qualitatively the same and quantitatively very similar
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. During a (clinical) development phase, smaller batch sizes may be acceptable, if justified.
The comparative in-vitro dissolution experiments should use compendial apparatus and suitably validated analytical method(s). The following conditions should be employed in the comparative dissolution studies to characterize the dissolution profile of the product:
- 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: paddle apparatus - 50 rpm, 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.
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. In cases where one product has rapid dissolution and the other has very rapid dissolution, similarity of the profiles should be demonstrated as below.
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 products.
- Mean of the individual values for every time point for each product.
- Not more than one mean value of ≥85% dissolved for either of the products.
- To allow the use of mean data, the coefficient of variation should not be more than 20% at early time-points (up to 10 minutes), and should not be more than 10% at other time points.
Two dissolution profiles are considered similar when the f2 value is ≥50. When both test and reference products demonstrate that ≥85% of the labelled 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.
To qualify for a BCS-based biowaiver for BCS Class III drug substances both the test product and reference product should display very rapid (≥85% for the mean percent dissolved in ≤15 minutes) in vitro dissolution characteristics under the defined conditions.
For FDC formulations, dissolution profiles should meet the criteria for all drug substances in the FDC to be considered. FDC formulations containing only BCS Class I drugs should meet dissolution criteria for a BCS Class I drug. FDC formulations containing only BCS Class III drugs should meet dissolution criteria for a BCS Class III drug. For FDCs containing both BCS Class I and BCS Class III drugs the dissolution criteria for the applicable BCS class for each component should be applied.
For products with more than one strength, the BCS approach should be applied for each strength, i.e., it is expected that test and reference product dissolution profiles are compared at each strength.
References
- ICH M9 Guideline
