How to Document Temperature Excursions and Set Up A Stability Budget

It is the responsibility of every pharmaceutical manufacturer to guarantee every medicine they deliver to a patient is of the highest quality. Maintaining the quality of a pharmaceutical product requires adhering to strict precautions, including storing or transporting the medication at specified temperatures.

Document Temperature Excursions

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However, glitches are bound to happen regardless of all precautions put in place, and manufacturers have had to come up with contingency plans.

A temperature excursion could result in patients ending up with unsafe products that may cause adverse reactions. Therefore, every pharmaceutical manufacturer must ensure all products are kept in the specified conditions until they reach the patient.

So, what are the right tools to use to guarantee that patients are getting the right quality and, most importantly, safe medicine?

What Are Temperature Excursions and Why Do They Even Matter?

Under the WHO Model Guidance, temperature excursion is “an excursion event in which a Time Temperature Sensitive Pharmaceutical Product (TTSPP) is exposed to temperatures outside the range(s) prescribed for storage and/or transport. Temperature ranges for storage and transport may be the same or different, as they are based on individual product stability data”.

Like many products, some medicinal products are sensitive to temperature and need to be stored and transported within a limited temperature range until expiry. However, unlike a flower that one can see has lost the vibrancy and aromas, it isn't easy to tell when pharmaceutical products have lost their quality or efficacy.

Whenever temperature-sensitive pharmaceutical products are exposed to temperatures above or below the specified range, they experience temperature excursions.

These excursions can affect their potency or result in an adverse reaction to the patient’s health. A temperature excursion may occur at the manufacturing site, in transit, or at the repository.

The Role of Regulators

Both the European and United States Pharmacopeia outline that pharmaceutical manufacturers are accountable for a product’s quality until it reaches the patient. While temperature conditions at manufacturing and packaging sites are usually under strict control (GMP regulation), this control is likely to decrease as soon as the product is dispatched for transportation.

As such, manufacturers should guarantee the safety, efficacy, and quality of the product until its final use. And when temperature excursions occur, they have to take the required measures.

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How to Document Temperature Excursions

Manufacturers should have procedures in place to document, investigate and handle temperature excursions. The approach outlined below entails best practices for the documentation of temperature excursions at the manufacturing site, during transportation or warehouse storage:

  • Document details of the person completing the report

  • Date and time of the temperature excursion

  • Inventory of affected products

  • Storage unit temperature (including minimum/maximum temperatures during the time of the event, if available)

  • Room temperature (if available)

  • General description of the event-what happened

  • The length of the exposure if using a digital data logger (DDL)

  • List of other items in the unit

  • Any problems with the storage unit or affected products before the event

  • Other relevant information

The distributor and recipient of the affected product(s) should receive a notification should a temperature excursion happen.

What Is A Stability Budget?

Most (bio)pharmaceuticals are subject to change as they age. Nevertheless, they remain stable as long as they retain their properties or potency.

This stability period is what is known as shelf life. Each product’s shelf life will vary depending on the data collected in the stability tests.

A product’s stability budget is determined by its stability profile. The stability budget combines relevant information from temperature studies with available data from the stability testing to determine the amount of time a product can spend out of its specified storage conditions without risk to its quality, safety, or efficacy.

Throughout the product’s cycle, it will move through multiple ‘legs’ in the supply chain. As there is always the risk of temperature excursions in each ‘leg’, a stability budget could help support the product’s safety at the end of the chain.

Furthermore, a stability budget also prevents expensive, time-consuming investigations with CROs and LSP, which avoids delays, and reduces the cost of unnecessary discards. Most importantly, a stability budget could prevent drug shortages and ensure critical drugs reach patients in time.

How to Set Up A Stability Budget

Many pharmaceutical manufacturers use data from the extensive product stability studies to determine the minimum and maximum allowed temperatures and time out of storage during transport.

Determining the product’s thermal stability (the product's ability to resist, under specified conditions, irreversible changes in its identity, strength, quality, and purity at various temperatures above and below the specified storage range) is the first step.

As one can imagine, time is of the essence, especially when developing a new drug substance. Therefore, instead of solely relying on real-time stability tests that may take years, most pharmaceutical manufacturers also choose to conduct accelerated stability studies and predict the shelf life using the Arrhenius equation.

In these accelerated tests, the products are exposed to defined sets of elevated temperatures, for example, (25°C, 30°C, 40°C), and potency tested after defined periods (e.g., six days, 28 days, three months, 12 months, 24 months, and 36 months).

The impact of temporary lower or elevated temperatures on drug degradation is then studied using these simulations. The idea here is to run the worst-case scenario.

The stability budget concept is a practical management tool to allocate time out of storage (TOS) to each supply chain partner for the manufacturing, packaging, storage, and distribution of (bio)pharmaceutical products.

The budget can apply to all pharmaceuticals, including those with storage conditions at -20°C, 2-8°C, and 15-25°C.

However, in as much as a stability budget makes it possible to guarantee the product's safety and efficacy to the patient, success is only possible with the commitment of every partner involved in the supply chain.