RESEARCH
Creation of a Temperature Stability Database for Refrigerated Medications Sharon R Davis, Elizabeth A Anderson ABSTRACT Aim: To create a database of refrigerated medications along with comprehensive data on their stability when stored outside the recommended conditions; and to develop an educational tool for managing cold chain emergencies at the hospital. Method: Phase 1: a searchable database was created with fields on product stability, stored temperatures and storage conditions. Phase 2: the database was populated with the products’ stability data from various sources, such as literature searches, approved product information and pharmaceutical companies. Phase 3: focus groups were held with the hospital’s stakeholders (nurses, pharmacists, pharmacy technicians) to develop an educational tool for managing cold chain emergencies. Results: Of the 36 pharmaceutical companies contacted, 29 responded (response rate 81%) and provided ‘extra’ stability data for 28 products (n = 150; 19%). Pursuant to issues raised by the pharmaceutical companies about concerns of breaching the registration conditions of their products and misinterpretation of the provided in-house stability data, a stakeholder meeting was held with the Therapeutic Goods Administration. At the meeting, the need for short-term ‘end of shelf life’ real-time stability studies for refrigerated products was discussed. An educational tool was designed based on a survey of local practices at the hospital pertaining to monitoring refrigerators used to store medications. Conclusion: Creation of the database has resulted in a critical analysis of the existing stability data on refrigerated medications. Hospital staff lack guidance on the selection, monitoring and maintenance of refrigerators used to store medications, and to manage cold chain emergencies. There is an opportunity for professional pharmacy organisations to provide this guidance. J Pharm Pract Res 2010; 40: 31-5.
INTRODUCTION Maintaining pharmaceuticals at their recommended storage conditions is essential for medication safety. Variations in the ideal storage conditions of medicines do occur and health professionals often have to decide promptly whether a pharmaceutical stored inappropriately is suitable for patient use. This decision involves an assessment of whether the pharmaceutical has lost potency or is degraded to toxic by-products.1 In some cases, the inappropriately stored pharmaceutical may be the most clinically appropriate choice. There is a need for accurate and accessible data on the stability of medications stored at temperatures that differ from those recommended by the approved product information.
Sharon R Davis, BPharm, FSHP, Drug Information Pharmacist, Elizabeth A Anderson, BPharm, DipHospPharm, Principal Drug Information Pharmacist, Drug Information Unit, Westmead Hospital, Westmead, New South Wales Address for correspondence: Sharon Davis, Pharmacy Department, Westmead Hospital, Westmead NSW 2145, Australia. E-mail:
[email protected]
Although temperature variations from ideal storage conditions mostly tend to be higher, inadvertent freezing can also occur.2 Vaccines, insulin and biologicals can be inactivated by freezing or when stored at high temperatures.3 The stability of medications that require refrigeration when inadvertently stored at room temperature, has been an issue for over two decades.4,5 Most publications have reported on surveys of manufacturers to elicit information on the stability of medications when inadvertently stored at room temperature and some reports have provided a framework to manage refrigerator malfunction.4 In 1986, there were over 10 000 requests for this type of information in UK hospitals and since 2000 the UK Medicines Information has maintained a ‘Fridge Database’ for this purpose.3 Despite the widespread availability of guidance on vaccine storage in Australia, cold chain breaches of vaccine storage have been noted in an Australian hospital.6-8 Australian community pharmacies have a protocol for cold chain management, which includes specifications for refrigerators and their monitoring, but participation is optional. By contrast, there is no formal requirement for Australian hospitals to purchase a particular type of refrigerator, and guidance on monitoring refrigerators appears to vary between jurisdictions.9,10 The Society of Hospital Pharmacists of Australia has addressed the issue of medication storage outside of the pharmacy department: the refrigerator should be solely dedicated to the storage of medicines and no other goods should be stored in the refrigerator, it should be lockable, secure and the temperature monitored.11 The Drug Information Unit, Westmead Hospital is often consulted about the stability of medications that have been left out of the refrigerator or when refrigerators have been inadvertently switched off. (These inquiries have been collated for over ten years.) Other Australian drug information centres and pharmacy departments have also been gathering similar data. These valuable data are filed locally at the individual institutions without any opportunity to share them. The possibility of sharing these data was raised in 2006 at the Society of Hospital Pharmacists of Australia’s Drug Information Workshop and backed by the New South Wales Drug Information Special Interest Group. In 2006, 18 out of 911 inquiries (2%), to the Drug Information Unit, Westmead Hospital pertained to the usability of medications after refrigerator malfunction. This highlighted that there was a need for staff education on the steps to take when refrigerators malfunction, and the appropriate handling of medications contained therein.
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This study aimed to create a database of refrigerated medications along with comprehensive data on their stability when stored outside the recommended conditions; and to develop an educational tool for managing cold chain emergencies at the hospital. METHOD Phase 1 The Drug Information Unit, Westmead Hospital consulted the New South Wales Drug Information Special Interest Group to determine the relevant fields to be included when creating a searchable database for the stability data of refrigerated medications. They determined an arbitrary expiry of three years for information on temperature stability that was held by individual drug information units. An information technology specialist assisted in the creation of the database in Access. Phase 2 The newly created database was populated with 84 reports that been obtained by the Drug Information Unit, Westmead Hospital in response to queries on individual storage temperature variations. However, as the cut-off for information currency was set at three years, the 84 reports were subsequently reduced to 12 reports. A list was compiled of refrigerated medications stocked at Westmead Hospital. The approved product information and consumer medicines information of these medications were consulted to verify recommended storage conditions and any additional advice on storage temperature variations. A literature search in Medline and Embase databases was conducted for publications detailing experiences with collation of data on stability of refrigerated medications inadvertently stored at room temperature. Due to lack of human resources, a comprehensive literature search of the temperature stability data for specific refrigerated medications held at Westmead Hospital was not undertaken. In August 2007, letters were sent to 36 pharmaceutical companies requesting information on 150 medications requiring refrigeration with a request for reply within three weeks. The pharmaceutical companies were requested to provide the following stability data: • how long the medication can be stored outside of the refrigerator; and • how the expiry date of the medication will be affected if stored outside the refrigerator. Follow-up calls were made to non-responder companies four to six weeks after the initial letter. Phase 3 In August 2007, a focus group was set up at Westmead Hospital comprising nurses, pharmacists and pharmacy technician to develop an educational tool to manage cold chain emergencies. To inform the process and the focus group discussions, a survey was undertaken of the hospital’s nurse unit managers about their practices pertaining to the monitoring of refrigerators used to store medications on their ward areas. The Acting Director of Nursing e-mailed the survey to 50 ward areas.
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RESULTS Phase 1 The fields that were created in the database included the medication’s generic name, brand name, product strength, manufacturer, stability data provided by the manufacturers, revised expiry date (if applicable), stability data retrieved from other sources, person reviewing the data and date of review. Phase 2 Of the 36 pharmaceutical companies contacted, written responses were received from 29 companies (response rate 81%): ten provided stability data; four provided product information; 13 offered to provide information on a case–by–case basis; and two declined. Seven pharmaceutical companies did not respond. The pharmaceutical companies provided in-house stability data for 28 pharmaceuticals (n = 150; 19%). Some of the companies provided limited additional data on variations to their product’s shelf-life as a result of temperature deviations from those recommended in the approved product information. The quality of stability data provided by the companies was variable, with several companies only addressing the reasons for not providing the information. Comparative analysis of the data held by the Drug Information Unit, Westmead Hospital and responses received from the pharmaceutical companies revealed variations for several medications. For example, stability data that were previously supported by the company were no longer relevant, and there were significant changes in the stability and storage data for some of the medications. This discrepancy highlighted the need for a regular review of the stability and handling data contained in the database. Therefore, a decision has been made to archive earlier data and to review the database annually. Phase 3 Of the surveys sent to 50 nurse unit managers on refrigerators used to store medications on the wards, 29 responses were received (response rate 54%). Approximately, one-third of respondents (35%) indicated that there were two or more refrigerators for medication storage on their ward and the majority (26/33; 87%) of refrigerators were of the ‘bar fridge’ type. Twelve (46%) wards noted that their refrigerators were monitored – two with temperature activated alarms, six with temperature range recorders, and four with electronic thermometers mounted on the front of the refrigerator. All except one ward had a dedicated power point for the refrigerator and six (21%) wards had a sign on the power point advising ‘do not turn off or disconnect’. Only three wards indicated that they had a written procedure in place in case of refrigerator failure. Sixteen (55%) wards had a staff member responsible for cleaning and maintaining the refrigerators. Pursuant to the survey, one ward actioned placing a warning sign above the power point for their refrigerator advising ‘not to disconnect the power supply’. As a result of the survey, two flow charts describing the steps to take when a malfunctioning refrigerator is discovered on the ward, were designed by the authors and reviewed by the New South Wales Drug Information
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Special Interest Group and a sample of nurses at the hospital. An A4 chart suitable for display on refrigerators was created with the assistance of the Sydney West Area Health Multimedia Department (Figure 1). DISCUSSION Quality use of medicines involves the judicious selection of treatment options, appropriate choice of medicines (when required), and safe and efficacious use of medicines. In clinical situations, decisions about whether to administer a drug of choice that has been subjected to inappropriate storage for a determined period of time need to be balanced against the practicality of procurement of a therapeutic alternative at short notice. It is unlikely that the drug of choice would be used without data from the pharmaceutical companies, as efficacy may not be guaranteed. The Australian approved product information should be the primary source of information on product stability and storage in all but exceptional circumstances. The pharmaceutical companies are legitimately concerned about providing in-house stability data for their products. They are concerned about breaching the registration conditions of their products and misinterpretation of the provided in-house stability data. In this study, the majority of pharmaceutical companies were willing to assist with providing in-house stability data and useability advice on a case–by–case basis. Reasons given by the pharmaceutical companies for not providing in-house data on medication stability to populate the database, included: • in-house data are not approved by the Therapeutic Goods Administration and may be seen as violating registration conditions and endorsing the off-label use of their products; • information is commercially sensitive; • temperature excursions can be cumulative; • data provision may lead to erroneous assessments; • primary aim of stability studies is determination of shelf life, not temperature excursions; and • product formulations and manufacturing sites may be subject to change. Therapeutic Goods Administration The International Conference on Harmonisation guidelines do not include temperature excursion protocols.12 As the majority of excursions outside of recommended storage conditions in hospitals would not exceed three days, short-term stability data would be useful to assist with decisions to guide use or destruction of temperature labile medications. In October 2007, pursuant to the issues raised by the pharmaceutical companies about concerns of breaching the registration conditions of their products and misinterpretation of the provided in-house stability data, the authors contacted the Therapeutic Goods Administration to clarify some of these concerns. In May 2008, a stakeholder meeting was held between the authors, industry delegates and the Therapeutic Goods Administration. Some of the points discussed included issues facing hospital pharmacists with regard to stability of pharmaceuticals and the industry’s perspective on provision of in-house stability data.
After the stakeholder meeting, industry delegates agreed to meet with Medicines Australia to raise the issue of adding short-term ‘end of shelf-life’ real-time stability studies to the stability testing for products that are stored at 2 to 8 ºC. The intention being that these data would then be included in the approved product information. The stakeholders also agreed to raise with the International Conference on Harmonisation, that the inclusion of a three day assessment of stability at room temperature for refrigerated products at the end of their expiry period, would provide data on allowable accidental excursions. UK Medicines Information The issue of using products that have been stored outside of recommended temperatures has been addressed in the UK. The UK Medicines Information Fridge Database is password protected and only available to drug information pharmacists. As at 31 October 2007, 255 products had been listed in the UK Medicines Information Fridge Database with stability data on 157 (61%) products. Disclaimer One of the key barriers initially identified when creating the database was the development of an appropriate disclaimer for the information provided in the database. The UK Medicines Information Fridge Database contains a disclaimer, has assisted with provision of information by the pharmaceutical companies. Although the Sydney West Area Health Service Corporate Services, the NSW Health Department and Pharmaceutical Defence Limited were contacted there was no satisfactory resolution of the issue. It appears that in Australia a higher level of evidence on medication storage and stability advice is required from manufacturers than required internationally. Stability Data Stability information for some of the products that were not supplied by the pharmaceutical companies has been published in the USA by Cohen et al.13 The reaction from a sample of Australian companies was that the medications listed in the US publication were possibly different formulations to the ones available in Australia. Additionally, the times stated by Cohen et al.13 appeared to be cumulative, i.e. covering the manufacture, distribution (i.e. warehousing and transportation) and administration of the products. The New South Wales Drug Information Special Interest Group initially anticipated that the creation of the database would allow data collated by individual drug information sites to be shared. This would facilitate sharing data with other institutions at a national level. This expectation has required adjustment in accordance with information acquired during the study. The planned update of our local data on an annual basis has also not been actioned, due to resource implications. Refrigerator Maintenance The surveyed nurse unit managers confirmed previous reports that refrigerators on most wards did not have a policy for daily temperature checks and lacked the sophisticated monitoring devices possessed by the refrigerators in hospital pharmacy departments.14 It was identified that hospital staff lack guidance on the
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What to do when you discover that the drug fridge IS NOT COLD AND IS MALFUNCTIONING Correct fridge failure if possible
STEP 1 STEP 2
Door open? Unplugged/turned off? Broken?
Shut it Restart Contact engineering or maintenance departments
Notify NUM, Team Leader or Department Manager
Label stock “DO NOT USE”
STEP 3
Use alternative refrigerated storage if requiredseek advice if unsure Estimate fridge temperature and timing of malfunction
STEP 4
FRIDGE NOT MONITORED Note if fridge appears to be warmer, cooler, or about the same as room temperature Estimate and record timeframe details (ask other staff if necessary)
MONITORED* FRIDGE Call Maintenance on x.............. and give location details Record temperature and timeframe details Obtain email or printout of data if possible
* Monitored may include min/max thermometers or data loggers which are monitored on or off site
STEP 5
CONTACT PHARMACY: Have details from Step 4 ready: Ph:........................(daytime) After hours: Page the On-call pharmacist or After Hours Nursing Supervisor
An initiative of the SHPA NSW Drug Information Special Interest Group
Supported by DBL Development Fund Grant DBL 620
Figure 1. Flow chart describing the steps to take when a malfunctioning refrigerator is discovered in a ward area. 34
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selection, monitoring and maintenance of refrigerators as well as strategies for managing cold chain emergencies. The Strive for 5 guidelines note that vaccines are ‘delicate biological substances that can become less effective or destroyed if frozen, too hot or exposed to direct sunlight or fluorescent light’.6 Although other pharmaceuticals, such as antivenoms and immunoglobulins, fall into this category, no Australian advice has been issued. Ensuring cold chain management as part of medication integrity is of the utmost importance for biopharmaceuticals.14 A flow chart such as that shown in Figure 1 may assist nursing staff when confronted with a cold chain emergency. This could be supplemented with an education package on refrigerator temperature monitoring.
11. O’Leary K, Burke R, Kirsa S. SHPA standards of practice for the distribution of medicines in Australian hospitals. J Pharm Pract Res 2006; 36: 143-9. 12. International Conference on Harmonisation Expert Working Group. Stability testing of new drug substances and products Q1A (R2). Geneva: International Conference on Harmonisation; 2003. Available from . 13. Cohen V, Jellinek SP, Teperikidis L, Berkovits E, Goldman WM. Room temperature storage of medication labeled for refrigeration. Am J Health Syst Pharm 2007; 64: 1711-15. 14. Tredree R. The supply chain for biopharmaceuticals: maintaining the correct temperature. Eur J Hosp Pharm Pract 2007; 13: 52-4. Received: 27 May 2009 Revisions requested after external review: 10 August 2009 Revised version received: 12 November 2009 Accepted: 22 January 2010
Limitations A limitation of our study was that the pharmaceutical companies were not asked to provide stability data on refrigerated products that inadvertently freeze. Our questions to manufacturers were based on the UK Medicines Information model, which did not address the issue of inadvertent freezing of products. CONCLUSION Creation of the database has resulted in a critical analysis of existing stability data on refrigerated medications. Availability of this database will contribute to the quality use of medicines by maintaining optimisation of drug treatment, storage conditions and reduction of wastage. Hospital staff lack guidance on the selection, monitoring and maintenance of refrigerators used to store medications, and to manage cold chain emergencies. There is an opportunity for professional pharmacy organisations to provide this guidance. Acknowledgments New South Wales Drug Information Special Interest Group for their advice regarding construction of the database. Nursing unit managers at Westmead Hospital for completing the survey. SHPA Grants and Awards Program for providing the project funding. Paul Spindler for development of the database. Sydney West Area Health Multimedia Department for assistance with the educational chart. Competing interests: None declared References 1. Grabenstein JD. ImmunoFacts: vaccines and immunologic drugs. St Louis: Facts and Comparisons;: 1993. p. 26. 2. Matthias DM, Robertson J, Garrison MM, Newland S, Nelson C. Freezing temperatures in the vaccine cold chain: a systematic literature review. Vaccine 2007; 25: 3980-6. 3. Todd S. Refrigerated medicinal products: what pharmacists need to know. Pharm J 2008; 281: 449-52. 4. Longland PW, Rowbotham PC. Room temperature stability of medicines recommended for cold storage. Pharm J 1989; 240: 589-95. 5. Miller LG, Loomis JH. Advice of manufacturers about effects of temperature on biologicals. Am J Hosp Pharm 1985; 42: 843-8. 6. Australian Government Department of Health and Ageing. National vaccine storage guidelines: strive for 5. Canberra: Commonwealth of Australia; 2005. Available from . 7. Australian Technical Group on Immunisation. The Australian immunisation handbook. 9th ed. Canberra: Australian Government; 2008. Available from . 8. Dubrava S, Tait PA, Humphris MA. Identification of potential and actual breaches in the cold-chain within a tertiary hospital. J Pharm Pract Res 2007; 37: 16-18. 9. Queensland Health (Dispensary) Regulation 1993 (Qld). 10. NSW Health. Medication handling in NSW public hospitals. Sydney: NSW Health; 2007. Available from .
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