Why did two QST lots of oral semaglutide differ on content assay?

Conditions: QST · oral semaglutide.

I have two candidate explanations and no way to distinguish them.

The same procedure has worked without incident several times previously, which argues against technique.

Should I be treating this as a failure or as noise?

A certificate that reports one test result on one vial extrapolates to claim that all two hundred vials in the lot are identical, which is an assumption worth questioning.

Stratified sampling — testing one vial from the top, one from the middle, and one from the bottom of a shipment — is cheap insurance against segregation.

If the entire lot failed qualification, a retest on a different vial is sometimes done, but reporting a retest result under the same lot number is misleading.

Sampling plans for pharmaceutical manufacturing are defined in ISO 2859 and ANSI Z1.4, and they are based on statistical sampling theory.

Assume segregation is possible, and design your sampling to catch it if it exists.

On the detail: most suppliers test one vial per lot and report the result as lot homogeneity, which is sampling one item from one lot and extrapolating wildly.

If the lot was manufactured in multiple batches, testing vials from each batch separately establishes whether batch-to-batch variation is acceptable.

The statistical foundation here is well-established, which is why sampling plans from decades ago are still valid.

Lyophilised peptide homogeneity studies show that vial-to-vial variation is usually small but occasionally large, depending on the distribution in the freeze-dryer.

One qualification: testing more vials gives better confidence, but at some point the cost outweighs the benefit.

The practical summary: a lot number without a sampling statement is a lot number without meaning.

edited 26 Jun 2025 by n_takahashi — added the citation requested in comments

Start from the question: how many vials from this lot do I need to test to claim that the lot meets specification, and the answer depends on both the lot size and the acceptable risk.

Under AQL sampling plans, testing two vials from a fifty-vial lot gives you an operating characteristic curve that tells you what risks you are accepting.

Published data on lot homogeneity from manufacturers who sample multiple vials consistently find variation below the published specifications, suggesting the sampling plans work.

Worth noting that thermal excursions during shipping affect different vials differently, so the lot may not be homogeneous even if it left the factory that way.

If testing multiple vials, state how many you tested and why you chose those vials.

The single most misleading statement on a research-grade certificate is a lot number with no statement of how many vials from that lot were tested.

A statement that "lot 20260412 complies with specifications" is meaningless without stating which vials from the lot were tested and how many there were.

I would treat a "complies with" statement without sampling details as a claim rather than as evidence.

Assume segregation is possible, and design your sampling to catch it if it exists.

edited 9 Aug 2025 by p_mkhize — added the method parameters