US Pharm. 2021;46(6):30-38.
ABSTRACT: Storage conditions are vitally important to the overall integrity and quality of medications, and the United States Pharmacopeial Convention, the FDA, and drug manufacturers provide guidelines for proper storage. However, this factor is often overlooked, ultimately impacting the quality of the drug products patients use. The increase in the use of medication mail-order and delivery services magnifies the importance of strict adherence to recommended storage criteria from the point of manufacture to distribution of the medication to the patient. Pharmacists can play an integral role in educating patients and finding ways to overcome barriers preventing their adherence to storage protocols; additionally, pharmacists are best suited to monitoring and advising on the many factors that could impact the quality of the drug products their patients use.
From the point of manufacture to the distribution of a medication to a patient, many factors can directly impact the integrity of a drug product, which may result in an avoidable decrease in treatment efficacy or even cause harm.1 One of the most easily overlooked factors that can directly impact the quality of a drug product is the condition in which medications are stored.1 From fluctuating temperatures to improper sealing to potential contamination during transportation from place to place, medications are often subjected to conditions that are less than optimal.2,3 Most drugs require specific storage conditions in order to ensure that their integrity remains intact.4,5 The manufacturer’s package insert specifies the conditions that must be met in order to ensure that the medication does not degrade, break down, or undergo a reduction in overall quality.6
Good-practice protocols for drug manufacturing, handling, and distribution are established by the United States Pharmacopeial Convention (USP), and the many chapters of the United States Pharmacopeia stress the importance of proper storage techniques.7 Additionally, the FDA has drafted and enacted legislation to preserve medication integrity through tracing of the drug-supply chain, ensuring that the points of contact an individual product makes are carefully recorded.6,8 Despite measures for monitoring medication integrity, many factors continue to be barriers to the storage of drugs under proper conditions.
The USP’s Role in Drug-Supply Safety
The mission of the USP, a scientific nonprofit organization, is to set official standards for the handling and use of pharmaceutical products, including generics.7 These standards are necessary to ensure the quality and integrity of a pharmaceutical product from time of manufacture up to when a patient uses it.7 USP Chapter <659> defines the key terms used in discussing medication storage and containment guidelines, and other chapters outline proper storage and shipping practices in further detail.9
The USP often expands on the storage requirements outlined in a medication’s monograph to ensure that the product’s unique needs are properly met; for example, USP Chapter <1079> discusses temperature regulation in storage locations (e.g., warehouses) in order to establish a temperature profile that preserves medication integrity.10 Chapter <1079> further explains that in addition to the need for strict observation, temperatures must be checked every 24 hours for required “cool,” “cold,” “refrigerated,” or “freezing” storage conditions.10 Through the establishment of nationwide standards for the handling and storage of medications, drug integrity can be preserved via the required drug pedigree (discussed in the next section).11
Drug Pedigree
A drug pedigree is a complete record of each distribution of a prescription drug, from its sale by a manufacturer through its acquisition and sale by any wholesale distributor to its final sale to a pharmacy or other authorized healthcare professional administering or dispensing the drug.11 The purpose of the drug pedigree is to maintain the efficacy and integrity of a medication before it reaches the consumer’s hands, with the tangible record of traceable events intended to prevent the medication from exposure to conditions that are below its standards.11
All prescription medications, including generics, are subject to pedigree requirements. An e-pedigree is often used to catalogue the necessary documentation for each drug product.11,12 This electronic form of documentation must subscribe to the requirements that satisfy a pedigree. While basic information including lot number, potency, and expiration dates may be included in an original e-pedigree, the most essential component of a pedigree is the sequential chain of distributors, wholesalers, and companies that have been involved in the handling of a medication.11,12
Whereas a drug pedigree provides a snapshot of the entities that handled a medication rather than the manner in which the medication was handled, the FDA’s Drug Supply Chain Security Act (DSCSA) defines distribution of a medication as “the sale, purchase, trade, delivery, handling, storage, or receipt of a product.”13 Legislation is in place to monitor the important facets of drug integrity, but storage is a challenge throughout the transportation process.2 It is important to consider the effects that subpar storage conditions may have on the overall quality of the product by the time it reaches the patient’s hands.1
Legislation
As of January 1, 2015, the pedigree provision of the Federal Food, Drug, and Cosmetic (FD&C) Act is no longer in effect.14 Although the provision calling for the identification of each prior sale, purchase, and trade of a drug is no longer stated in formal terms in the FD&C Act, language discussing updated requirements for product tracing was added to section 582. This section states that “a dispenser…prior to, or at the time of, each transaction in which the dispenser transfers ownership of a product (but not including dispensing to a patient or returns) shall provide the subsequent owner with transaction history, transaction information, and a transaction statement for the product, except that the requirements of this clause shall not apply to sales by a dispenser to another dispenser to fulfill a specific patient need.”14
Additionally, the DSCSA details the steps the federal government will take to properly track, assess, and record the movement of medications in order to enhance transparency throughout the drug’s chain of events from the point of manufacture to patient distribution.6 In this way, drugs are monitored closely to ensure that integrity and quality are preserved until the patient receives the medication. This step is intended to safeguard the pedigree of each drug that is manufactured and distributed.11
The DSCSA is intended to help protect consumers from exposure to drugs that may be counterfeit, stolen, contaminated, or otherwise harmful.6 The law focuses specifically on transitions within the supply chain rather than the conditions in which a medication is stored.15 If a medication is discovered to be of substandard quality, provisions of the law allow for a retrospective analysis to identify where in the medication’s distribution a loss of integrity may have occurred. However, these regulations do not clearly define the appropriate environmental conditions for medication storage.16
Medication storage has become especially important given the many rapid changes that the pharmacy field is currently undergoing.17 Novel methods of delivering medications to patients outside of brick-and-mortar pharmacies are quickly gaining popularity, leading to concerns about new threats to medication stability and integrity.17,18 Despite the detailed record keeping mandated by federal regulations and the heavy emphasis on maintaining the drug pedigree, a gap remains in ensuring that a medication is stored and transported in conditions that meet the criteria established by its individual monograph, the specifications laid out by the USP, and the standards required by the FDA.19
Mail-Order Pharmacy
A growing area of pharmacy practice is mail-order pharmacy.17 Many insurance companies now contract their own mailing services, whereas other entities have crafted their own form of competition, such as Amazon’s pharmaceutical endeavor, PillPack.20 The coronavirus disease 2019 (COVID-19) pandemic has further spurred patients and pharmacies to use contactless options such as mail-order and prescription-delivery services to reduce the risk of contracting COVID-19.21
Although the ability to avoid in-person visits to the pharmacy—which involves direct interaction with others and carries the risk of potential exposure—may give patients and pharmacists some peace of mind, the fact that delivery options may pose problems for medication storage cannot be ignored.19,21 Unless extreme care is exercised, the methods used to transport a medication from the manufacturer to the patient may be subject to fluctuating storage conditions that do not meet the standards established by entities such as manufacturers and the USP.2,19
Medications that are delivered to the patient’s door may be left outside, where the temperature and other weather conditions may interfere with the medication’s integrity.16 Although many delivery services package medications that require refrigeration in ice packs, it may be necessary to take additional steps or precautions to protect products that are left outside in environmental conditions that would be detrimental to the medication.19 Extreme weather, such as drought and excessive heat, may render ice packs useless, and for temperature-sensitive medications this can result in a poor-quality product that fails to meet established standards.2 Other conditions that can cause potential problems for medications left outside upon delivery include intense precipitation and unpredictable weather.16
Storage Requirements
A medication’s quality, integrity, and efficacy are often dependent on the conditions in which it is stored, including temperature, moisture, and light.1 Temperature control varies based on the medication, ranging from storage at room temperature to storage in the freezer.10 For example, insulin is optimally stored long-term in the refrigerator within a range of +2°C/36°F to +8°C/46°F, and once opened it should be stored within a range of +2°C/36°F to +25°C/77°F or +30°C/86°F.4 Most oral medications must be stored in a dry place away from moisture, and some products require protection from light or other specific storage conditions.22 For example, sublingual nitroglycerin must be stored tightly capped in the original glass vial and protected from direct light exposure.1,23 These storage requirements are essential for preserving the active ingredient in order to prevent loss of potency.22
A small number of studies have evaluated whether patients are able to maintain storage requirements of medications.4,5 These studies generally have found that a sizable number of medications are not stored properly by the patient.5 Biologics are better studied than most therapeutics, likely owing to their complexity and high cost as well as the fact that they require stringent storage conditions to prevent denaturation, which would render them less efficacious and increase the risk of adverse reactions.5 In a prospective, observational follow-up study using validated temperature loggers to assess storage conditions, 50% to 58% of patients stored their biological medications in conditions that did not meet storage requirements.5
It is essential for patients to understand the importance of proper medication storage. Unfortunately, patients with low health literacy may experience barriers that prevent them from meeting the necessary requirements.24 For example, some individuals with lower socioeconomic status may not have consistent access to a refrigerator or may try to conserve medications for a longer period of time.25,26 Patients without a permanent address may face additional challenges.
It is important to note that generics may be more readily affected by improper storage techniques.22 Although generics must demonstrate equal efficacy to the brand-name product, the excipients used in manufacturing may be different and may inherently result in accelerated degradation of the drug in question.23 Ultimately, the improper storage of medications may be ineffective at best and harmful at worst.1
Solutions to Storage Problems
A study of advanced life-support vehicles that transported approved medications requiring a controlled temperature in accordance with USP standards revealed that despite the use of equipment to regulate and ensure that storage temperatures for medications met requirements, actual temperatures inside the vehicles—in both summer and winter—far exceeded the thresholds established by the USP.2 According to the USP, the proper range for controlled room temperature is between 15°C and 30°C.10 However, the temperature inside the vehicles reached as high as 53°C in some instances.2 Deviation from the established standards may reduce the shelf life of a drug from years to several months or less, impacting its quality and efficacy.2
What steps can be taken to prevent these types of storage problems? Because temperature is one of the most easily disrupted facets of storage conditions and many medications require different temperature levels to meet manufacturer standards, temperature loggers may be installed where medications are stored in order to constantly record conditions.2 Retrospectively reviewing the recorded data allows pharmacists, manufacturers, and delivery services to identify any problematic areas in their chain of distribution.6 If records indicate fluctuating temperatures for extended periods of time, the installation of new technology may be considered in order to maintain the stringent range required by the USP.9 Additionally, problem behaviors (e.g., delivery vehicle parked without the engine running on an excessively hot day) may be pinpointed.2 Identifying such barriers to proper storage enables the initiation of specific training and protocols to mitigate negative effects and prevent problematic behaviors in the future.27
The Pharmacist’s Role
Pharmacists possess a deep knowledge of therapeutics, including an understanding of the profound impact storage conditions may have on medications and the importance of ensuring that individual medications’ requirements are met.27 This knowledge is important for ensuring that medication standards established by manufacturers, lawmakers, and USP protocols are achieved so that all products are safe for patients to use.28 Therefore, pharmacists are best suited to monitoring and advising on the many factors that could potentially impact the quality of the drug products their patients use.27,28
Most importantly, pharmacists can share their wealth of knowledge with patients, including educating them on the importance of proper storage techniques and adherence to quality-control measures.25,28 Through direct patient interactions, pharmacists can uncover barriers that prevent patients from storing their medications in suitable conditions and can propose potential solutions for patients to follow.28
Conclusion
Storage conditions are vitally important to medications’ overall integrity and quality.1 The growing reliance on mail-order and prescription-delivery services serves as a reminder that all entities follow necessary standards and regulation to ensure good drug pedigree and medication quality.11 It is important to recognize that some patients do not have the health literacy or means to adhere to stringent storage requirements for their medications.24 Pharmacists can play an integral role in educating patients and finding ways to overcome any barriers that prevent them from adhering to storage protocols.29 Pharmacists are ideally positioned to ensure that medications’ integrity is preserved in something so easily overlooked as the conditions in which they are stored.27
REFERENCES
1. Charter Home Health. Why proper medicine storage is essential. https://charterhomehealth.net/family-caregivers/why-proper-medicine-storage-is-essential/. Accessed March 31, 2021.
2. Allegra JR, Brennan J, Lanier V, et al. Storage temperatures of out-of-hospital medications. Acad Emerg Med. 1999;6(11):1098-1103.
3. Huntley GD. Caution: storage temperature may alter drug’s efficacy. Acad Med. 2017;92(2):221.
4. Braune K, Kraemer LA, Weinstein J, et al. Storage conditions of insulin in domestic refrigerators and when carried by patients: often outside recommended temperature range. Diabetes Technol Ther. 2019;21(5):238-244.
5. Vlieland ND, Gardarsdottir H, Bouvy ML, et al. The majority of patients do not store their biologic disease-modifying antirheumatic drugs within the recommended temperature range. Rheumatology (Oxford). 2016;55(4):704-709.
6. FDA. Drug Supply Chain Security Act (DSCSA). www.fda.gov/drugs/drug-supply-chain-integrity/drug-supply-chain-security-act-dscsa. Accessed February 26, 2021.
7. U.S. Pharmacopeia. About USP. www.usp.org/about. Accessed March 31, 2021.
8. FDA. DSCSA Pilot Project Program. www.fda.gov/drugs/drug-supply-chain-security-act-dscsa/dscsa-pilot-project-program. Accessed February 26, 2021.
9. U.S. Pharmacopeia-National Formulary. General Chapters: <659> Packaging and Storage Requirements, <661> Plastic Packaging Systems and Their Materials of Construction, <661.1> Plastic Materials of Construction, <661.2> Plastic Packaging Systems for Pharmaceutical Use. www.uspnf.com/notices/general-chapters-plastic. Accessed March 31, 2021.
10. U.S. Pharmacopeia. <1079> Good storage and shipping practices. http://ftp.uspbpep.com/v29240/usp29nf24s0_c1079.html. Accessed March 8, 2021.
11. Swichtenberg B. Drug pedigree standard established. www.pharmamanufacturing.com/articles/2007/041/. Accessed February 28, 2021.
12. Gintzler International. What is e-pedigree and why is it important? www.gintzlerinternational.com/blog/2016/12/07/what-is-e-pedigree-and-why-is-it-important. Accessed March 31, 2021.
13. Drug Supply Chain Security Act. 21 USC 360eee: definitions. (5) Distribute or distribution. https://uscode.house.gov/view.xhtml?req=granuleid:USC-prelim-title21-section360eee&num=0&edition=prelim. Accessed March 31, 2021.
14. FDA. Drug Supply Chain Security Act product tracing requirements frequently asked questions. www.fda.gov/drugs/drug-supply-chain-security-act-dscsa/drug-supply-chain-security-act-product-tracing-requirements-frequently-asked-questions. Accessed March 31, 2021.
15. FDA. Drug Supply Chain Security Act (DSCSA) implementation plan. www.fda.gov/drugs/drug-supply-chain-security-act-dscsa/drug-supply-chain-security-act-dscsa-implementation-plan. Accessed February 28, 2021.
16. Pilz J. Can extreme weather affect how your medications work? https://wexnermedical.osu.edu/blog/can-extreme-weather-affect-how-your-medications-work. Accessed March 31, 2021.
17. Lyle A. Opinion: mail-order pharmacy market to grow significantly. www.managedhealthcareexecutive.com/view/opinion-mail-order-pharmacy-market-grow-significantly. Accessed March 31, 2021.
18. Smith A. Extreme temperatures may pose risks to some mail-order meds. www.npr.org/sections/health-shots/2019/01/07/673806506/extreme-temperatures-may-pose-risks-to-some-mail-order-meds. Accessed March 2, 2021.
19. Graedon J. How was your medicine stored, shipped and delivered? www.peoplespharmacy.com/articles/proper-storage-of-medicine. Accessed February 26, 2021.
20. Business Wire. Global Mail Order Pharmacy Market 2020-2027—COVID-19 impact and analysis by drug type, product, mode of order, and geography—ResearchAndMarkets.com. www.businesswire.com/news/home/20201102005554/en/Global-Mail-Order-Pharmacy-Market-2020-2027---COVID-19-Impact-and-Analysis-by-Drug-Type-Product-Mode-of-Order-and-Geography---ResearchAndMarkets.com. Accessed March 31, 2021.
21. Hopkins JS. Mail-order drug delivery rises during coronavirus lockdowns. www.wsj.com/articles/mail-order-drug-delivery-rises-during-coronavirus-lockdowns-11589281203. Accessed March 31, 2021.
22. Sumners C. Drug stability: how storage conditions affect their performance. https://vitalrecord.tamhsc.edu/drug-stability-storage-conditions-affect-performance/. Accessed March 31, 2021.
23. Nitrostat (nitroglycerin sublingual tablets) package insert. New York, NY: Pfizer Inc; May 2011.
24. Curtis LM, Wolf MS, Weiss KB, Grammer LC. The impact of health literacy and socioeconomic status on asthma disparities. J Asthma. 2012;49(2):178-183.
25. Yin HS, Dreyer BP, Vivar KL, et al. Perceived barriers to care and attitudes towards shared decision-making among low socioeconomic status parents: role of health literacy. Acad Pediatr. 2012;12(2):117-124.
26. Constance J, Lusher JM. Diabetes management interventions for homeless adults: a systematic review. Int J Public Health. 2020;65(9):1773-1783.
27. Alkhawajah AM, Eferakeya AE. The role of pharmacists in patients’ education on medication. Public Health. 1992;106(3):231-237.
28. Mansur JM. Medication safety systems and the important role of pharmacists. Drugs Aging. 2016;33(3):213-221.
29. Mullins CD, Blatt L, Gbarayor CM, et al. Health disparities: a barrier to high-quality care. Am J Health Syst Pharm. 2005;62(18):1873-1882.
The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.
To comment on this article, contact rdavidson@uspharmacist.com.
