This guideline for generic solid oral immediate release products. In the context of the EMA reflection paper immediate release is identified as at least 75% (Q) of the active substance is dissolved within 45 minutes. The Q derives from the Ph. Eur. (5.17.1) recommendation for conventional release dosage forms.
The dissolution specification is expressed in terms of the quantity (Q) of active substance dissolved in a specified time, expressed as a percentage of the content stated on the product label.
When the dissolution test conditions have been chosen a suitable dissolution specification should be set. The dissolution specification limit is defined by a Q value, i.e. mean value, at a given time point, which allows discrimination between acceptable and non-acceptable batches.
The discriminatory power is the ability of a test procedure to discriminate between batches manufactured with different critical process parameters and /or critical material attributes which may have an impact on the bioavailability.
Batch results showing compliance with stage S1, S2 and S3 (Ph. Eur. 2.9.3.) are acceptable. The specification should be set in such a way so that during routine manufacture and testing it would be expected that compliance with S2 is attained.
Before setting the Q value, the time range allowing discrimination should be considered from the dissolution profile of the bio-batch. Sampling time points should be sufficient to obtain a meaningful dissolution profile
Bio-batch is a batch used in a bioavailability study or in clinical testing.
Similar dissolution of two batches may be assumed in case of differences of less than 10% of the label claim in their mean results. Therefore, the Q value is recommended to be set on the basis of the biobatch dissolution result (mean value of 12 units) minus 10%.
The acceptance criterion Q value is usually set in the range between 75-85% (5% intervals) to demonstrate discriminatory power and satisfactory dissolution. A limit greater than 85% is not relevant. Usually the time points 15, 30 or 45 minutes would be sufficient, but other time points may be used if justified. It is not considered relevant to choose a time point before 15 minutes.
• If dissolution of the bio-batch is larger than or equal to 95% in 15 minutes, the specification may be set to Q=85% after 15 minutes.
• If dissolution of the bio-batch is less than 95% but larger than or equal to 85% in 15 minutes, the specification (Q) may be set to 75%, 80% or 85% whichever is closer to Q = (bio-batch result -10%) at 15 minutes.
• If dissolution of the bio-batch is larger than or equal to 85% only after 30 minutes, the specification (Q) may be set to 75%, 80% or 85% whichever is closer to Q = (bio-batch result -10%) at 30 minutes;
• If dissolution of the bio-batch is larger than or equal to 85% only after 45 minutes, the specification may be set to 75%, 80% or 85% after 45 minutes.
In case dissolution of the bio-batch is less than or equal to 85% after 45 minutes, a minimum of 75% at 45 minutes should be specified if possible. Otherwise, if the dissolution specification (Q) is less than 75% after 45 minutes, the dissolution specification should be based on more than one time point (see the below Decision tree for the principles for setting specifications).
Recommendation in case of BCS biowaiver
In case there is no bio-batch the specification limit with a fixed Q value within 15 min (for BCS class I and III) or 30 minutes (applicable only for human BCS class I products) can be established. This Q value should be at least 80% using discriminatory test conditions (i.e. the QC method applied for), irrespective of the dissolution results of the test batch observed in the study used to claim the BCS biowaiver. The conditions for the dissolution test in the specification should be chosen as the most discriminatory between those used in the comparative dissolution study.
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