Setting Clinically Relevant Tolerances for IR Products – A Simple and Rationale Approach

For clinically relevant tolerances, perhaps the most important consideration is that the tolerance should reflect consistent and reproducible delivery of an expected dose (amount of the drug) to the patient. Commonly, dosage or strength of a tablet/capsule reflects the expected amount of drug to be released or delivered.  Therefore, for clinical relevance, the amount of drug to be released is fixed, i.e. 100% (at least on average). The only variable which needs to be determined is the time, i.e., how long would it take for the drug to be released. For IR products, this duration of drug release is usually an hour or less. However, in exceptional cases, based on experimental evidence, this time duration may be adjusted as required.

The setting of tolerances, therefore, should be based on the duration of time required for the release of all drug present in the product.

It is to be noted that at present, tolerances are set (e.g. see USP) based on two parameters (values) i.e. amount of drug released at a certain time.

The amount (%age of drug) released is often referred to as the Q-value. Although, the Q-value is set based on the product behavior at the product development stage, it is still chosen arbitrarily rather than based on any scientific/clinical relevance. It is not clear why this Q-value is chosen arbitrarily and set at less than 100%, usually 80% or lower, when it should be 100%. The practice of setting tolerances at 80% or less may not be clinically relevant and require reconsideration.

In short, clinically relevant tolerances should only be based on the time duration, i.e., how long would it take for 100% of the drug to be released from a product.

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