The Overlap Nobody Talks About: Packaging Decisions And Stability Budgets

By Dr. Muhammad Suffyan, medical advisor

Vials don't break in the warehouse. But where do they really fall short? Between the loading dock and the last mile, in the hours no one is looking. That gap is the beginning of most trial supply problems. Validity testing is performed on the same clock as drug stability. Creatinine and specific gravity readings deteriorate with heat in the same manner as a biologic deteriorates outside of the labeled range. After a sample or a drug product falls outside of its window, the number on the label is meaningless.

Manufacturing And Packaging Are One Decision, Not Two

Sponsors tend to treat manufacturing schedules and packaging design as separate line items. The thing is, in practice they are the same decision made twice. Imagine a batch that is scheduled to ship in January and a container that is scheduled to ship in July. They're tackling different challenges, and as the calendar turns, the packaging is seldom revisited.

In 2024, the AAPS Journal published a paper that suggested a tiered approach to temperature excursions in oral solid dosage products.¹ Tier 1 is for excursions that are observed every week, a shipment that is 2 degrees out of range for 20 minutes during a courier handoff, and clears them on the spot with a preestablished range. Tier 2 includes excursions that are further away, but within data the company already has. Only Tier 3 is a cause for concern. It indicates that the excursion occurred in a place for which the current data does not have an answer, and someone has to do a complete statistical review before the batch can be moved again.

Sponsors are more likely to develop these criteria following the receipt of the first bad excursion report, rather than prior to the study. That's the wrong order. The time delay in excursion handling is not due to the review but to whether an event requires review.

Stability Budgets Are Not Widely Used.

Thus, each drug product has a “stability budget.” which is an accumulation of hours that it can spend outside of the label parameters without being affected. It decreases with each transfer of ownership of the product. A CMO release, a customs hold, and a depot transfer all draw on the same account and few sponsors sum it up along the entire route.

BMC Public Health published a study in 2022 that simulated mean kinetic temperature for oral dosage products during various excursions.² The method transforms a variable temperature history into a single number that reflects the total thermal stress that a product has experienced, rather than asking if it has exceeded the range at any one time. That distinction matters. A product that was 1 degree over range for 6 hours can be worse off than a product that spiked 5 degrees for 10 minutes, and a simple pass/fail excursion log would not even detect the first excursion.

This is the discovery to sit with. Products are thrown away after an excursion without a proper risk assessment, as it takes longer for the manufacturer to get a real read on stability than the supply chain can wait. So, the safe call becomes the automatic call, and material that might still be fine is thrown out anyway.

The True Risk Lies Where?

In trial supply, risk is hardly ever manifested as a dramatic failure. It manifests as the silent space between what a spec sheet promises and what a delivery route can actually fit to. Imagine a packaging specification that specifies a temperature range of 2 to 8 degrees. It does not have any knowledge of a customs delay in a country where there is no cold storage at the airport. The spec is right on paper and wrong in transit, and that's two problems that need two fixes.

Operational teams that fill this gap are not doing anything exotic. They are creating excursion levels prior to a shipment going out, not after it arrives damaged. They are monitoring the stability budget on a leg-by-leg basis rather than relying on the container to hold. These are little, mundane decisions, taken earlier than usual and taken before the pressure sets in.

References:

1. Temperature Excursion Management: A Tier-Based Approach for Commercial Oral Solid Dosage Forms | The AAPS Journal | Springer Nature Link
2. Mean kinetic temperature evaluations through simulated temperature excursions and risk assessment with oral dosage usage for health programs | BMC Public Health | Springer Nature Link

About The Author:

Muhammad Suffyan is a medically trained advisor with a background in clinical medicine, specializing in the scientific review of urinalysis and drug testing information. He leads medical content evaluation, ensuring published materials are accurate, evidence-based, and aligned with current clinical and laboratory standards.

His work focuses on interpreting the science behind workplace and forensic urine drug testing, with particular expertise in urine specimen validity testing, detection window science, and laboratory markers such as creatinine, pH, and specific gravity. In addition to reviewing emerging research, Dr. Suffyan translates complex medical and laboratory concepts into practical, accessible information for both professionals and the public, with an emphasis on accuracy, scientific integrity, and responsible health communication.