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The Effect of High Storage Temperature on the Stability and Efficacy of Lyophilized Tenecteplase

Published online by Cambridge University Press:  20 July 2020

Emily Henkel Open the ORCID record for Emily Henkel [Opens in a new window] ,
Rebecca Vella  and
Andrew Fenning
Emily Henkel*
Affiliation:
Central Queensland University, School of Health, Medical and Applied Sciences, Rockhampton, Queensland, Australia
Rebecca Vella
Affiliation:
Central Queensland University, School of Health, Medical and Applied Sciences, Rockhampton, Queensland, Australia
Andrew Fenning
Affiliation:
Central Queensland University, School of Health, Medical and Applied Sciences, Rockhampton, Queensland, Australia
*
Correspondence: Emily Henkel, BSc (Hons) Central Queensland UniversitySchool of Health, Medical and Applied Sciences 554-700 Yaamba Road Rockhampton, Queensland4701Australia E-mail: [email protected]
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Abstract

Introduction:

Tenecteplase is a thrombolytic protein drug used by paramedics, emergency responders, and critical care medical personnel for the prehospital treatment of blood clotting diseases. Minimizing the time between symptom onset and the initiation of thrombolytic treatment is important for reducing mortality and improving patient outcomes. However, the structure of protein drug molecules makes them susceptible to physical and chemical degradation that could potentially result in considerable adverse effects. In locations that experience extreme temperatures, lyophilized tenecteplase transported in emergency service vehicles (ESVs) may be subjected to conditions that exceed the manufacturer’s recommendations, particularly when access to the ambulance station is limited.

Study Objective:

This study evaluated the impact of heat exposure (based on temperatures experienced in an emergency vehicle during summer in a regional Australian city) on the stability and efficacy of lyophilized tenecteplase.

Methods:

Vials containing 50mg lyophilized tenecteplase were stored at 4.0°C (39.2°F), 35.5°C (95.9°F), or 44.9°C (112.8°F) for a continuous period of eight hours prior to reconstitution. Stability and efficacy were determined through assessment of: optical clarity and pH; analyte concentration using UV spectrometry; percent protein monomer and single chain protein using size-exclusion chromatography; and in vitro bioactivity using whole blood clot weight and fibrin degradation product (D-dimer) development.

Results:

Heat treatment, particularly at 44.9°C, was found to have the greatest impact on tenecteplase solubility; the amount of protein monomer and single chain protein lost (suggesting structural vulnerability); and the capacity for clot lysis in the form of decreased D-dimer production. Meanwhile, storage at 4.0°C preserved tenecteplase stability and in vitro bioactivity.

Conclusion:

The findings indicate that, in its lyophilized form, even relatively short exposure to high temperature can negatively affect tenecteplase stability and pharmacological efficacy. It is therefore important that measures are implemented to ensure the storage temperature is kept below 30.0°C (86.0°F), as recommended by manufacturers, and that repeated refrigeration-heat cycling is avoided. This will ensure drug administration provides more replicable thrombolysis upon reaching critical care facilities.

Keywords

drug stabilitydrug storageEmergency Medical Servicesprehospital emergency caretenecteplase
Type
Original Research
Information
Prehospital and Disaster Medicine , Volume 35 , Issue 5 , October 2020 , pp. 501 - 507
Copyright
© World Association for Disaster and Emergency Medicine 2020

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