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 or 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 quality control (QC) test).
- Temperature of the dissolution medium: 37±1°C.
- Agitation: paddle apparatus - 50 revolutions per minute (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.
When high variability or coning is observed in the paddle apparatus at 50 rpm for both reference and test products, the use of the basket apparatus at 100 rpm is recommended.
Additionally, alternative methods (e.g., the use of sinkers or other appropriately justified approaches) may be considered to overcome issues such as coning, if scientifically substantiated. All experimental results should be provided.
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.
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 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.
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