Following is a collection of scholarly articles shared with us by David B. Volkin, PhD., Pharmaceutical Chemistry Professor at the University of Kansas School of Pharmacy, who has both academic and industry experience with temperature exposures of temperature-sensitive healthcare products. These articles all focus on the impact of “poor handling” on temperature-sensitive medications and biologic products in the hospital or pharmacy, during transport and in patients’ homes. Poor handling includes the environmental stress factors of heat and freeze exposures, and inappropriate storage.
The Impact of Inadequate Temperature Storage Conditions on Aggregate and Particle Formation in Drugs Containing Tumor Necrosis Factor-Alpha Inhibitors
Vlieland ND1, Nejadnik MR2, Gardarsdottir H3,4, Romeijn S2, Sediq AS2, Bouvy ML5, Egberts ACG1,5, van den Bemt BJF6,7,8, Jiskoot W2
Purpose: To measure aggregate and particle formation in tumor necrosis factor-alpha (TNF-α) inhibitors etanercept, adalimumab and certolizumab pegol product samples after exposure to freezing temperature conditions similar to storage conditions previously observed in patients’ homes.
Methods: TNF-α inhibitors in their original primary and secondary packaging were exposed to 32 freeze-thaw cycles (-10°C for 120min/5°C for 60 min) or continuous low storage temperature (-20°C for 96 h) before thawing at 2-8°C. Non-stressed products were used as controls. The products were analyzed by high pressure size exclusion chromatography (HP-SEC), dynamic light scattering (DLS), nanoparticle tracking analysis (NTA), micro-flow imaging (MFI) and second derivative ultraviolet (UV) spectroscopy.
Results: Ten out of twenty-one stressed product samples (47.6%) showed increased particle numbers in the submicron and micron size range when compared to controls. For each product, DLS, MFI and NTA detected an increase in particle level in at least one stressed syringe (both continuous freezing and freeze-thaw), whereas HP-SEC and UV spectroscopy showed no differences between stressed and non-stressed products.
Conclusion: TNF-α inhibitors are relatively resistant to freezing temperatures similar to storage conditions previously observed in patients’ homes. However, almost half of the stressed product samples showed formation of particles in the submicron and micron size range
Postproduction Handling and Administration of Protein Pharmaceuticals and Potential Instability Issues
Nejadnik MR1, Randolph TW2, Volkin DB3, Schöneich C4, Carpenter JF5, Crommelin DJA6, Jiskoot W7
The safety and efficacy of protein pharmaceuticals depend not only on biological activity but also on purity levels. Impurities may be process related because of limitations in manufacturing or product related because of protein degradation occurring throughout the life history of a product. Although the pharmaceutical biotechnology industry has made great progress in improving bulk and drug product manufacturing as well as company-controlled storage and transportation conditions to minimize the level of degradation, there is less control over the many factors that may subsequently affect product quality after the protein pharmaceuticals are released and shipped by the manufacturer. Routine handling or unintentional mishandling of therapeutic protein products may cause protein degradation that remains unnoticed but can potentially compromise the clinical safety and efficacy of the product. In this commentary, we address some potential risks associated with (mis)handling of protein pharmaceuticals after release by the manufacturer. We summarize the environmental stress factors that have been shown to cause protein degradation and that may be encountered during typical handling procedures of protein pharmaceuticals in a hospital setting or during self-administration by patients. Moreover, we provide recommendations for improvements in product handling to help ensure the quality of protein pharmaceuticals during use.
Jiskoot W1, Nejadnik MR2, Sediq AS
A master student, who surveyed the procedures in a hospital pharmacy with regard to the handling of biologicals, identified several issues that might have jeopardized product quality. This case may be a tip of the iceberg and illustrates the urgent need for a better education of end-users about how to handle biologicals.
The medicines refrigerator is a common piece of equipment found in clinical areas. It is used to ensure specific medicines are safely stored within a narrow temperature range in line with manufacturers’ instructions; this is usually between +2˚C and +8˚C, and ideally +5˚C. Drugs stored in the medicines refrigerator include: vaccines; insulin; chemotherapy drugs; topical preparations, such as some types of eye drops; and other treatments such as glucagon, which is used to manage severe hypoglycemia. This article reviews the function of the medicines refrigerator and the checks required by healthcare practitioners to ensure that medicines remain safely stored and their effectiveness is maintained. It also outlines the medicines refrigeration procedure known as the ‘cold chain’, which includes the use of cold boxes or vaccine carriers to maintain the required temperature of medicines during transport from the manufacturer to user, or between healthcare departments.
Vlieland ND1, van den Bemt B2,3,4, van Riet-Nales DA5, Bouvy ML6, Egberts A1,6, Gardarsdottir H1,6
Background: Substantial quantities of unused medicines are returned by patients to the pharmacy each year. Redispensing these medicines would reduce medicinal waste and health care costs. However, it is not known if medicines are stored by patients as recommended in the product label. Inadequate storage may negatively affect the medicine and reduce clinical efficacy whilst increasing the risk for side effects.
Objective: To investigate the proportion of patients storing oral anticancer medicines according to the temperature instructions in the product label.
Methods: Consenting adult patients from six Dutch outpatient hospital pharmacies were included in this study if they used an oral anticancer medicine during February 2014 – January 2015. Home storage temperatures were assessed by inclusion of a temperature logger in the original cancer medicines packaging. The primary outcome was the proportion of patients storing oral anticancer medicines as specified in the Summary of Product Characteristics, either by recalculating the observed temperature fluctuations to a single mean kinetic temperature or by following the temperature instructions taking into account a consecutive 24-h tolerance period.
Results: Ninety (81.1%) of the 111 included patients (47.8% female, mean age 65.2 (SD: 11.1)) returned their temperature loggers to the pharmacy. None of the patients stored oral anticancer medicines at a mean kinetic temperature above 25℃, one patient stored a medicine requiring storage below 25℃ longer than 24 h above 25℃. None of the patients using medicines requiring storage below 30℃ kept their medicine above 30℃ for a consecutive period of 24 h or longer.
Conclusion: The majority of patients using oral anticancer medicines store their medicines according to the temperature requirements on the product label claim. Based on our results, most oral anticancer medicines will not be negatively affected by temperature conditions at patients’ homes for a maximum of three months and are likely to be suitable for redispensing.
Kumar N1, Jha A1
Quality of pharmaceutical product largely depends upon the environment controls during its storage and handling. Each pharmaceutical product should be handled and stored under specified storage condition labelled on product information data sheet or product pack. Hence the temperature excursions during receipt of raw materials, manufacturing of pharmaceutical products and distribution should be managed during entire product life cycle with holistic approach. The research is based on primary data and exploratory study through literature review. The temperature excursion may be observed during transportation of raw materials manufacturing as well as distribution of pharmaceutical products, which have potential to deteriorate the product quality. Temperature excursion in pharmaceutical industry should be recorded and reported to the manufacturer for further investigation and risk analysis. The concept of temperature excursions, its reasons, consequences and handling mechanism should be well understood to ensure the concerted efforts under the aegis of Quality Management System. Based on the reasons and consequences of temperature excursions during pharmaceutical operations, a system based quality management has been envisaged through this study. The concept and procedure to handle temperature excursion have evolved after this study which shall be useful to pharmaceutical industry as well as to medicine distributors and consumers.
The majority of patients do not store their biologic disease-modifying antirheumatic drugs within the recommended temperature range
Vlieland ND1, Gardarsdottir H2, Bouvy ML3, Egberts TC2, van den Bemt BJ4
Objective: To monitor whether biologic DMARD (bDMARD) home storage temperatures comply with the manufacturers’ Summary of Product Characteristics (SmPC) recommendations.
Methods: This observational study included consenting adult patients from eight Dutch pharmacies who received their bDMARDs with a validated temperature logger. Patients were instructed to store their packages according to standard label instructions and to return the temperature logger(s) after use. Primary outcome was defined as the proportion of patients that stored their bDMARDs within the SmPC recommended temperature range. In addition, the proportion of patients storing bDMARDs below 0°C or above 25 °C for longer than two consecutive hours was estimated.
Results: A total of 255 (87.0%) patients (mean age 53.2 (s.d.; 13.1) years, 51.4% female) returned their temperature logger(s) to the pharmacy. Of these, 17 patients (6.7%) stored their bDMARD within the recommended temperature range. The proportion of the patients that stored their bDMARD for more than 2 h consecutive time below 0°C or above 25°C was respectively 24.3% (median duration: 3.7 h (IQR 2.2 h; range 2.0-1,097.1 h) and 2.0% (median duration: 11.8 h (IQR 44.3 h; range 2.0-381.9 h).
Conclusion: The majority of patients do not store their bDMARDs within the SmPC-recommended temperature range.