Pooled Sampling in Dissolution

USP <711> contains a couple references to pooled sampling for dissolution. What is pooled sampling and when is it appropriate? What risks are there with pooled sampling?

Pooled sampling is a procedure where each sample from a dissolution time point is combined into a single sample. Pooled sampling is only done for immediate-release dosage forms and is not allowed or appropriate for extended-release products.

The reason for pooled sampling in the USP is to help the analysis of immediate-release products where there is a challenge to running 6 individual samples instead of 1. At the time that most (if not all) pooled sampling monographs were written, the analysis of dissolution samples took longer, was more expensive, and involved more use of solvents, etc. When I first started working on dissolution testing, it wasn't uncommon to have a dissolution sample on HPLC take 15-30 minutes or longer. This could create a bottleneck in the lab where an immediate-release product has a 15 minute dissolution method and an analysis that would take several hours. For a lab with several dissolution methods in a day, it may take until the next day for those samples to be analyzed. These days, HPLC injections take a small fraction of the time and so pooled sampling is much less relevant today than in the past.

If you want to look into pooled sampling, be aware that it can only be used in specific situations. First, the product needs to be immediate-release. Second, the drug cannot have a narrow therapeutic index - since we are only looking at the average of 6 samples we lose the measure of variability and need to be mindful of risk. Going along with risk, the drug product should also be well understood. Manufacturing limits need to be understood with adequate controls in place to ensure quality.

Pooled sampling hides variability of samples, and this can be a risk if you have single tablets with very poor release. To try to compensate for that risk, you will notice that the Q values required for pooled sampling are higher than when sampling individually. Instead of Q+5% at the first time point, pooled sampling requires Q+10% which can be much more difficult to acheive.

If doing pooled sampling, ensure that you are combining equal volumes form each vessel. Micropipettes may be useful to perform this step.

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Resource Person: Ken Boda

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