As per FDA guidance on dissolution specification of extended release oral dosage form
In vitro dissolution specifications should generally be based on the performance of the clinical/bioavailability lots. These specifications may sometimes be widened so that scale-up lots, as well as stability lots, meet the specifications associated with the clinical/bioavailability lots. This approach is based on the use of the in vitro dissolution test as a quality control test without any in vivo significance, even though in certain cases (e.g., ER formulations), the rate limiting step in the absorption of the drug is the dissolution of the drug from the formulation.
When dissolution specifications is setting without an IVIVC
• The recommended range at any dissolution time point specification is ± 10% deviation from the mean dissolution profile obtained from the clinical/bioavailability lots.
• In certain cases, reasonable deviations from the ± 10 % range can be accepted provided that the range at any time point does not exceed 25%. Specifications greater than 25% may be acceptable based on evidence that lots (side batches) with mean dissolution profiles that are allowed by the upper and lower limit of the specifications are bioequivalent.
• Specifications should be established on clinical/bioavailability lots. Widening specifications based on scale-up, stability, or other lots for which bioavailability data are unavailable is not recommended.
• A minimum of three time points is recommended to set the specifications. These time points should cover the early, middle, and late stages of the dissolution profile. The last time point should be the time point where at least 80% of drug has dissolved. If the maximum amount dissolved is less than 80%, the last time point should be the time when the plateau of the dissolution profile has been reached.
• USP acceptance criteria for dissolution testing are recommended unless alternate acceptance criteria are specified in the ANDA/NDA.
As per EMA guideline on dissolution specification of extended release drug product
In general, a minimum of three points should be included in the specification on in vitro dissolution of an oral prolonged release product: an early time point to exclude dose dumping and/or to characterize a loading/initial dose (typically 20 to 30% dissolved), at least one point to ensure compliance with the shape of the dissolution profile (around 50% dissolved) and one to ensure that the majority of the active substance has been released (Q=80 %). If the maximum amount dissolved is less than 80%, the last time point should be the time when the plateau of the dissolution profile has been reached.
The acceptable variation allowed around each time-point (upper and lower limits), can be determined in different ways:
• Normally, the permitted range in release at any given time point should not exceed a total numerical difference of ±10% of the labelled content of active substance (i.e. a total variability of 20%: a requirement of 50±10% thus means an acceptable range from 40-60%), unless a wider range is supported by a bioequivalence study.
• When bioequivalence is based on in vivo data, the acceptance range for the maximum difference in comparative data is 80-125%, based on confidence intervals around the mean Cmax and the selected AUC parameter.
As per EMA guideline on dissolution specification of delayed release drug product
At least two points should be included in the specification on in vitro dissolution of a gastro-resistant product: an early time point to exclude release in the acidic medium (less than 10% dissolved after 2 hours) and one to ensure that the majority of the active substance has been released in a (near) neutral medium. It is emphasized that gastro-resistance must be demonstrated for two hours or more. With regard to acceptance criteria for continued testing, reference is made to the Ph. Eur.
