Bailey Rubin, Technical Sales Representative
Temperature Excursions
What happens to your compounded preparations after they leave your pharmacy? During transit, compounding preparations can experience shipping delays, which may result in temperature changes. Even the most carefully packaged preparations can be exposed to unexpected environmental changes. Without supporting data to demonstrate that a product remains stable under these conditions, a pharmacy could face compliance consequences, and patients could receive compromised medications.
Understanding Stability Studies and Temperature Excursions
Stability studies are required to demonstrate the stability of compounded preparations. They test how a preparation's physical and chemical integrity performs under its intended storage condition(s) over time and provide data needed to support a Beyond-Use-Date (BUD). During the stability study, samples are stored in stability chambers that must be maintained within specifications that allow only very small changes in temperature and humidity. As stability samples are held under defined and controlled environmental conditions, stability studies are not intended to, nor can they, demonstrate the stability of compounded preparations under temperature excursions or conditions not included in the validated study parameters.
Temperature excursion studies are designed to evaluate how a compounded preparation responds when exposed to short-term temperature or humidity fluctuations outside its labeled storage range, such as 40°C ± 2°C / 75% RH ± 5% for 24 or 48 hours. After exposure to the higher temperature and humidity, the compounded preparations are then tested for stability using a stability-indicating method.
Why Temperature Excursion Studies Matter
Some compounds, such as GLP-1 (semaglutide, tirzepatide) and trimix formulations, can be highly susceptible to degradation when exposed to temperatures higher than those for which they are intended to be stored. Even just a few hours at room temperature or higher can lead to degradation, potentially compromising product quality. Regulatory authorities and quality standard organizations like the Food and Drug Administration (FDA), United States Pharmacopeia (USP), and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) expect supporting data demonstrating that compounded preparations remain stable during a deviation from their labeled storage condition(s).
The FDA has repeatedly issued 483s and warning letters for failing to investigate temperature fluctuations. Examples of these observations include:
Firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).
- “During the inspection, firm personnel indicated that this lot had experienced high temperature excursions while in storage.”
- “You had prolonged problems assuring maintenance of the required temperatures of the refrigerated storage unit in which this API was stored.”
Firm failed to establish a written testing program designed to assess the stability characteristics of drug products and determine appropriate storage conditions and expiration dates. Firm also failed to have buildings used in the manufacture, processing, packing, or holding of drug products with adequate space for the orderly placement of equipment and materials to prevent mix-ups and contamination (21 CFR 211.166(a) and 21 CFR 211.42(b)).
- Inadequate Material Storage - “Bulk totes of ethanol hand sanitizer gel were stored outdoors, and you informed our investigator that these totes had been stored outdoors since April 2020. Labeling for the bulk ethanol hand sanitizer gel lists a temperature storage range of (b)(4) F. The totes are exposed to temperature excursions that often exceed the specified temperature storage range, which could compromise the quality of the drug product therein.”
Firm failed to review and investigate production and QC laboratory deviations.
- “The inspection documented that, despite the fact that your firm has an uninterrupted power supply used by the QC laboratories, power failures have impacted the QC stability chambers. However, in each case, no investigation was conducted to determine the impact of the power loss on the samples kept within the chambers.”
Firm’s quality unit is not involved in quality related matters; the unit fails to review deviations from established specifications or procedures and does not adequately assess the need for corrective actions for deviations it is made aware of.
- “No follow-up or investigations were conducted for the excursions … to determine the root cause and potential impacts on the products and stability studies.”
Written procedures are lacking, which describe in sufficient detail the storage of components, drug product containers, and closures.
- “Specifically, there is no temperature monitoring in the warehouse where raw material and blended drug products are stored.”
Be Proactive
ARL Bio Pharma offers complete stability and temperature excursion testing that meets USP, FDA, and ICH standards. Our studies show how preparations hold up under different temperature and humidity conditions and provide the data needed to support beyond-use dates and quality claims.
Contact ARL Bio Pharma at 800-393-1595 or info@arlok.com today to see how a temperature excursion study can strengthen your stability program, protect patients, and keep your pharmacy compliant.
References:
- Food and Drug Administration
- ICH Stability Testing of New Drug Substances and Products Q1A(R2)
- USP 659 – Packaging and Storage Requirements
- USP 797 – Pharmaceutical Compounding – Sterile Preparations
- USP 1079 – Risks and Mitigation Strategies for the Storage and Transportation of Finished Drug Products
- USP 1149 – Guidelines for Assessing and Controlling the Physical Stability of Chemical and Biological Pharmaceutical Raw Materials, Intermediates and Dosage Forms