A drug product is eligible for a BCS based biowaiver provid ed that the drug substance(s) satisfy the criteria regarding solubility and permeability (BCS Class I and III), the drug product is an immediate release oral dosage form with systemic action , and the drug product is a dosage form that is pharmaceutically equivalent to the reference product.
In cases where the highest single therapeutic dose does not meet th e high solubility criterion but the highest strength of the reference product is soluble under the required conditions, BCS based biowaiver s can be support ed based on additional data. An example of such additional data is demonstration of dose proportional pharmacokinetics (i.e. AUC and C max ) over a dose range that includes the highest therapeutic dose.
Drug products with buccal or sublingual absorption are not eligible for a BCS based biowaiver application. As such, an orodispersible product is eligible for a biowaiver application only if there is no buccal or sublingual absorption and the product is labelled to be taken with water only.
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. The drug product acceptance criteria are described in below.
Excipients
Excipient differences between the proposed test and the reference products 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. To be eligible for a BCS based biowaiver, the applicant should justify why the proposed excipient differences will not affect the absorption profile of the drug substance under consideration, i.e., rate and extent o f absorption, using a mechanistic and risk based approach.
The possible effects of excipients on aspects of in vivo absorption such as solubility, gastrointe stinal motility, transit time and intestinal permeability including transporter mechanisms, should be considered. Excipients that may affect absorption include sugar alcohols e.g. mannitol, sorbitol, and surfactants e.g. sodium lauryl sulfate The risk that a given excipient will affect the absorption of a drug substance should be assessed mechanistically by considering
- the amount of excipient used
- the mechanism by which the excipient may affect absorption
- absorption properties (rate, exten t and mechanism of absorption) of the drug substance
The amount of excipients that may affect absorption in the test and reference formulations should be addressed during product development, such that excipient changes are kept to a minimum. Small amoun ts included in the tablet coating or levels below documented thresholds of effect for the specific drug substance are of less concern.
By definition, BCS Class I drugs are high ly absorbed, and have neither solubility nor permeability limited absorption. Therefore they generally represent a low risk group of compounds in terms of the potential for excipients to affect absorption, compared to other BCS classes. Consideration of excipient effects for BCS Class I drug products should focus on potential chang es in the rate or extent of absorption. For example, if it is known that the drug has high permeability due to active uptake, excipients that can inhibit uptake transporters are likely to be of concern. For BCS Class I drugs that exhibit slow absorption, the potential for a given excipient to increase absorption rate should also be considered.
For BCS Class I drugs, qualitative and quantitative differences in excipients are permitted, except for excipients that may affect absorption, which should be qualitatively the same and quantitatively similar i.e. within 10 .0 % of the amount of excipient in the reference.
For FDC formulations containing only BCS Class I drugs, criteria regarding excipients should follow that for a BCS Class I drug. For FDC formulations containing only BCS Class III drugs, or BCS Class I and BCS Cla ss III drugs, criteria regarding excipients should follow that for a BCS Class III drug. This is applicable to FDCs which are pharmaceutically equivalent.
In vitro Dissolution
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 one batch of the reference product. The test product should originate from a batch of at least 1/10 of p roduction 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 es and validated analytical methods.
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 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. Pharmacopoeia l buffers should be employed Additional investigation may be required at the pH of minimum solubility if different from the buffers above) P urified water may be used as an additional dissolution medium in some regions.
- Organic solvents are not acceptable and no surfactants should be added.
- Samples should be filtered during collection.
- For gelatin capsules or tablets with gelatin coatings where cross linking has been demonstrated , the use of enzymes may be acceptable, if appropriately.
- When high variability or coning is observed in the paddle apparatus at 50 rpm, the use of the basket apparatus at 100 rpm is recommended. Additionally, use of sinkers in the paddle apparatus to overcome issues such as coning may be considered with justification.
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 mea n percent dissolved in ≤15 minutes) or rapid 85% for the mean percent dissolved in ≤30 minutes) and similar in vitro dissolution characteristics under all of the defined conditions.
In cases where one product has rapid dissolution and the other has very rapid dissolution, statistical similarity of the profiles should be demonstrated as below.
Read also: Biowaiver and Multiple Strengths