Drug Product Stability

The Stability of Drug Products Through a Temperature Profile Study

Shaundrea Rechsteiner, Business Development

Deena Conrad-Vlasak, Business Development

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Study Purpose
Impact Analytical recently worked with a government body to study the effects of different shipping packaging on drug stability through simulated transit studies. The purpose of this study was to evaluate the transit temperature profiles, mean kinetic temperatures (MKTs), and the potency after simulated exposure of four drug products. The packaged drugs were analyzed in four types of shipping containers exposed to simulated Summer and Winter profiles.

Overview
The client serves patients all over the country by dispensing and shipping prescriptions to patients’ residences. Environmental changes occur regularly in response to carriers’ delivery programs, including standard delivery procedures, redelivery attempts, and seasonal temperatures at both the shipper’s location and the delivery destination. According to the United States Pharmacopeia (USP), the acceptable tolerance to shipping conditions for packages containing medications is measured using mean kinetic temperatures (MKT) to monitor temperature fluctuations relative to the manufacturer’s accepted storage conditions. The MKT measures the effects of temperature fluctuations during storage and/or transit of drug products. Packages at ambient temperatures are assigned an MKT of 20-25° C, and shipments may experience brief exposure to temperatures ranging from 15 to 40° C. Refrigerated shipments are assigned an MKT of 2-8° C. Temperature ranges are not provided for fluctuations at refrigerated temperatures as MKTs were initially used for room temperature storage. The transit temperature profiles, mean kinetic temperatures, and long-term storage of drug products in both insulated and non-insulated containers exposed to simulated Summer and Winter profiles have been evaluated. The previous study determined that all samples met USP-specified limits and retained product stability regardless of shipping conditions or packaging. The study reported here performed transit comparisons of the drug product using four types of shipping containers during Summer and Winter temperature conditions, as well as a continuation that includes drug product potency over 120 days after each transit.

Temperature Profiles
For the purpose of this study the following temperature profiles were used:

Profiles 1 

Profiles 2

Packaging Configurations
For the purpose of this study the following temperature profiles were used:

Container Summer (May-Sept) Winter (Dec-Feb)
Extra Small (XS) Cooler   
2 frozen 8oz gels 
1 frozen 8oz gel
Small Cooler     3 frozen 12oz gels 1 Paper   
(8.5” x 11” white) 
   1 frozen 12oz gel 1 Paper     
(8.5” x 11” white) 
Medium Cooler  4 frozen 12oz gels 1 Paper
(8.5” x 11” white) 
2 frozen 12oz gels 1 Paper
(8.5” x 11” white) 
Mylar Bag  0 frozen gels  0 frozen gels 

Mean Kinetic Temperature of Packages Calculation
Mean Kinetic Temperature (MKT) Values: 

MKT Values

ΔH = 83.14472 kJ/mole
R (Gas Constant) = 0.008314472 kJ/mole/degree
Tk = MKT
T1 = temperature recorded at the first time interval
T2 = temperature recorded at the second time interval
Tn = the value for the temperature recorded during the nth time interval
Note: All temperatures, T, are absolute temperatures in Kelvin (K), reported values are converted to °C using TC = TK-273.

High-Performance Liquid Chromatography Assay
The Drug products were analyzed using an optimized method derived from the validated assay procedure published in The Journal of Chemical and Pharmaceutical Research. Samples were prepared in triplicate. The drug samples were gently mixed and directly transferred into individual autosampler vials for analysis by HPLC-UV. Samples were also observed using optical microscopy for any aggregation or changes.

Results Transit Temperature Profiles and MKT
Representative temperature profiles of the environmental chamber and shipping containers are shown on the following page and were used to calculate the MKT. The solid line shows the temperature profile of the chamber while the dotted line represents the temperature within the test container. During a programmed temperature shift, the test chamber will adjust to the programmed conditions.
The more robust the insulative effect of the test chamber, the bigger the deviation from the chamber trace. If the test container follows the chamber traces closely, then insulation isn’t effective.

It can be seen that the Mylar Bag temperature line closely follows the temperature profile of the test chamber, while the Medium Cooler temperature line largely deviating from the test chamber temperature profile. This indicates a higher insulating property for the Medium Cooler versus a lower insulating property for the Mylar Bag.

The medium and small coolers displayed a much lower MKT and temperature profile than the mylar bags and extra small coolers during the Summer transits. At the initial point of each transit, there was a temperature reduction in the MKT for the coolers due to the cooling effect of the ice packs.

When comparing the MKTs, the medium and small coolers provided the closest acceptable MKT tolerance per the USP’s acceptable tolerance level when compared to the mylar bags in all transits. The medium and small coolers were found to provide closer acceptable MKT tolerance levels than the extra small cooler in the 48-hour Summer transit, when compared. The medium cooler results were comparable to the small cooler. The MKTs for the medium cooler reported at ~32°C for 120-hour Summer transits, ~27°C for 48-hour Summer transits.

Discussion
The Drug Product maintained potency within ±7% of the initial T-1 time point (95%), regardless of packaging material, when stored under
the experimental temperature conditions. Average label potency ranged between 88-98%. See the following table for the average assay results at T-1 (control) and time points up to day 120.

Avg Assay Table

Conclusion
When comparing the MKTs, the medium and small coolers provided the closest acceptable MKT tolerance per the USP’s acceptable tolerance level. Per Chandler et. al., at 18-20 hours the gel refrigerant packs no longer regulated the samples’ temperature during the Summer transit, which was characterized by an increase in the MKT when comparing the 24 hour transit MKT to the 72 hour MKT.1 Transits in this study were all significantly longer than 24 hours and comparisons of MKT showed no significant changes between the coolers containing gel packs. The Drug Product maintained potency within ±7% of the initial T-1 time point (95%) when stored in programmable environmental chambers simulating Summer and Winter 48 and 120 hour delivery conditions, regardless of packaging material. The calculated t-values at all time points for Latanoprost at each testing condition are less than the statistical table value3 at an alpha level of 0.05 (95% confidence level). It was concluded that there is no statistical difference between the control potency averages and the sample potency averages that underwent transit and storage at 95% confidence level.