Abbreviations and Acronyms:
FDA (Food and Drug Administration), HCl (hydrochloride), SLEP (Shelf Life Extension Program)Since 1979, the US Food and Drug Administration (FDA) has required pharmaceutical companies to provide rigorous proof that their medication is stable over the course of months when submitting a New Drug Application or an Abbreviated Drug Application.
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, Expiration dating and stability testing for human drug products. US Food and Drug Administration website. http://www.fda.gov/ICECI/Inspections/InspectionGuides/InspectionTechnicalGuides/ucm072919.htm. Accessed July 23, 2015.
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A medication's shelf life, or expiration date, is the time frame in which a medication has been proven safe and effective despite exposure to various environmental factors including temperature, humidity, and light.International Conference on Harmonization. Guidance for industry Q1A(R2) stability testing of new drug substances and products. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm073369.pdf. Published November 2003. Accessed July 23, 2015.
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Although expiration dates guarantee a certain length of stability, the FDA has no requirement for long-term testing. Many medications may have much longer shelf lives than labeled.International Conference on Harmonization. Guidance for industry Q1A(R2) stability testing of new drug substances and products. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm073369.pdf. Published November 2003. Accessed July 23, 2015.
The best evidence indicating that medications can last longer than their labeled expiration date comes from the Shelf Life Extension Program (SLEP). Rather than disposing of billions of dollars of the military's stockpiled medications that were set to expire in the 1980s, the FDA tested various batches of the medications in their supplies to provide extensions in shelf life.
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In their studies of 122 different medication products, nearly 90% met the requirements for an extension. Table 1 includes medications for which all lots tested by SLEP when approaching their expiration dates met the criteria for initial shelf life extension, and Table 2 lists medications for which less than 50% of lots tested were initially extended. Whereas the shelf life of most medications in the United States is 1 to 5 years, the average additional extension length by SLEP was 5.5 years, and some lots were extended by more than 20 years.SLEP: The DOD/FDA shelf life extension program. https://slep.dmsbfda.army.mil/portal/page/portal/SLEP_PAGE_GRP/SLEP_HOME_NEW. Accessed July 23, 2015.
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Table 1SLEP Medication Stability Testing Results: All Lots Initially Extended
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| Medication | Form | Extension time (mo) mean |
|---|---|---|
| Triamterene and hydrochlorothiazide | Capsules | 19 |
| Amoxicillin sodium | Tablets | 23 |
| Acetaminophen pseudoephedrine | Capsules | 24 |
| Dextrose 10% | Injection solution | 25 |
| Doxycycline hyclate | Powder | 27 |
| Atropine sulfate pralidoxime chloride | Autoinjector | 31 |
| Morphine sulfate | Autoinjector | 32 |
| Ciprofloxacin | Suspension | 32 |
| Flurazepam HCl | Capsules | 35 |
| Metaraminol bitartrate | Syringe needles | 40 |
| Mepivacaine HCl | Cartridge needle | 41 |
| Cimetidine HCl | Injection solution | 42 |
| Hydrocortisone sodium succinate | Injection solution | 43 |
| Prochloroperazine edisylate | Injection solution | 43 |
| Hetastarch in sodium chloride | Injection solution | 44 |
| Benzonatate | Capsules | 44 |
| Cefoperzone sodium | Powder | 46 |
| Ephedrine sulfate | Injection solution | 46 |
| Dobutamine HCl | Injection solution | 47 |
| Enflurane | Liquid | 48 |
| Ampicillin | Capsules | 49 |
| Calcium glucepate | Injection solution | 49 |
| Bretylium tosylate | Injection solution | 49 |
| Sodium chloride | Injection solution | 50 |
| Tetracycline HCl | Capsules | 50 |
| Doxycycline hyclate | Capsules | 50 |
| Iothalamate meglumine | Injection solution | 51 |
| Promethazine HCl | Injection solution | 51 |
| Chlorpromazine HCl | Tablets | 52 |
| Ophthalmic irrigating | Solution | 52 |
| Naproxen | Tablets | 52 |
| Ringer's, lactated and dextrose | Injection solution | 53 |
| Thiopental sodium | Powder | 54 |
| Sodium polystyrene sulfonate | Powder | 55 |
| Ciprofloxacin | Tablets | 55 |
| Sodium bicarbonate | Injection solution | 55 |
| Oxacillin sodium | Powder | 56 |
| Sulfisoxazole | Tablets | 56 |
| Ampicillin sodium | Injection solution | 57 |
| Furosemide | Injection solution | 57 |
| Sulfadiazine silver | Cream | 57 |
| Cephalexin | Capsules | 57 |
| Mebendazole | Tablets | 58 |
| Amyl nitrite | Inhalant | 59 |
| Mafenide acetate | Cream | 59 |
| Tubocurarine chloride | Injection solution | 59 |
| Ceftriaxone sodium | Powder | 60 |
| Erythromycin lactobionate | Powder | 60 |
| Neostigmine methylsulfate | Injection solution | 60 |
| Phenylephrine HCl | Injection solution | 60 |
| Dexamethasone sodium phosphate | Syringe needle | 61 |
| Phenytoin sodium | Injection solution | 63 |
| Ketamine HCl | Injection solution | 64 |
| Chloroquine HCl | Injection solution | 64 |
| Dextrose and sodium chloride | Injection solution | 64 |
| Protamine sulfate | Powder | 64 |
| Dextrose (5%) | Injection solution | 65 |
| Povidone iodine | Ointment | 65 |
| Edrophonium chloride | Injection solution | 65 |
| Mannitol | Injection solution | 66 |
| Halothane | Liquid | 67 |
| Cimetidine HCl | Tablets | 67 |
| Undecylenic acid and zinc salt | Powder | 68 |
| Potassium iodide | Tablets | 69 |
| Penicillin G benzathine | Suspension | 70 |
| Succinylcholine chloride | Powder | 72 |
| Sodium chloride | Irrigation | 72 |
| Cephapirin sodium | Powder | 74 |
| Chlorpromazine HCl | Injection solution | 74 |
| Diphenhydramine HCl | Syringe needle | 76 |
| Naloxone HCl | Injection solution | 77 |
| Cellulose, oxidized, regenerated | Dermal | 79 |
| Pancuronium bromide | Injection solution | 79 |
| Calcium chloride | Injection solution | 81 |
| Hexachlorophene cleansing | Emulsion | 81 |
| Fentanyl citrate | Injection solution | 84 |
| Guaifenesin | Extended-release tablets | 85 |
| Bupivacaine HCl | Injection solution | 88 |
| Morhpine sulfate | Syringe needle | 89 |
| Sodium nitrite | Injection solution | 89 |
| Meperidine HCl | Injection solution | 89 |
| Sodium thiosulfate | Injection solution | 131 |
| Potassium iodide | Granules | 254 |
FDA = Food and Drug Administration; HCl = hydrochloride; SLEP = Shelf Life Extension Program.
Table 2SLEP Medication Stability Testing Results: <50% of Lots Initially Extended
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| Medication | Form | Extension time (mo), mean |
|---|---|---|
| Albuterol | Inhalant | NA |
| Diphenhydramine HCl | Spray | NA |
| Levarterenol bitartrate | Injection solution | 22 |
| Ergotamine tartrate and caffeine | Tablets | 24 |
| Lidocaine HCl and epineprhine | Injection solution | 29 |
| Physostigmine salicylate | Injection solution | 31 |
| Mefloquine HCl | Tablets | 36 |
| Isoproterenol HCl | Injection solution | 45 |
| Phenobarbital sodium | Cartridge needle | 56 |
| Penicillin G procaine | Powder | 70 |
HCl = hydrochloride; NA = not available; SLEP = Shelf Life Extension Program.
Cantrell et al,
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in another study, tested medications that had expired 28 to 40 years earlier that were discovered unopened and in their original containers at a retail pharmacy. Twelve of the 14 active ingredients were present in at least 90% of the labeled amount, meeting our standard of acceptable minimum potency. Given these data, it seems that many labeled expiration dates do not reflect true longevity.Despite extensive federal data on the long-term quality of many medications, shelf life extensions that occur in our national stockpiles do not transfer to state or local supplies, let alone hospitals, pharmacies, and those of individual patients, although more accurate expiration dates could reduce costs.
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As an example, Tufts Medical Center in Boston, Massachusetts, disposes of approximately $200,000 worth of expired medications per year (written personal communication, Department of Pharmacy at Tufts Medical Center, January 8, 2015).The current standards for shelf life assignment are especially troublesome when populations that are unable to afford medications are considered. Infrastructural obstacles can delay health care distribution in developing countries,
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but medications cannot be donated internationally if they do not meet the donor country's standards.8
A donated drug that reaches a developing country past its stated expiration date must be discarded, although SLEP evidence suggests longer-term stability. Furthermore, it is illegal to dispense expired medication to any American regardless of whether they can obtain it otherwise.World Health Organization. Guidelines for drug donations. http://www.who.int/hac/techguidance/guidelines_for_drug_donations.pdf. Revised 1999. Accessed July 23, 2015.
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Text of the Prescription Drug Marketing Act of 1987. US Food and Drug Administration website. http://www.fda.gov/RegulatoryInformation/Legislation/SignificantAmendmentstotheFDCAct/PrescriptionDrugMarketingActof1987/ucm201702.htm. Updated March 1, 2010. Accessed July 23, 2015.
Longer shelf lives could also play a role in decreasing medication shortages. Many medication shortages occur for an unknown reason and without warning.
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If we had evidence that medications were stable for longer periods, pharmacy operation managers might have more flexibility to avoid shortages and paying the higher prices that are often associated with medications in short supply.American Society of Health-Systems. Drug shortages summit summary report. http://www.ashp.org/drugshortages/summitreport. Published November 5, 2010. Accessed July 23, 2015.
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Of the 15 medications that SLEP determined to be top performers in shelf life extension, 12 (80%) are currently in shortage or have been in shortage since 2013.4
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Extending the expiration dates for these medications could possibly help some providers, pharmacists, and patients during medication shortages.Drug shortages. American Society of Health-System Pharmacists website. http://www.ashp.org/menu/DrugShortages. Accessed July 23, 2015.
Finally, it is possible that extending shelf lives could have a positive environmental effect. Scientists recently found evidence of contamination by many medications in water and sediment samples from Lake Michigan at concentrations that pose “medium or high ecological risk.”
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,p2120 If longer shelf lives could reduce medication disposal, perhaps such a measure could also abate harmful environmental consequences.How do we implement a policy to establish more accurate expiration date labeling? One option is to require all pharmaceutical companies to complete long-term stability testing. Just as pharmaceutical companies must conduct ongoing monitoring for adverse effects after releasing a new medication, they could continue efficacy testing to see how long their medications truly last. Expiration dates could be preliminary and then updated. A second option is to create noncommercial, independent testing for the true lengths of medication stability. SLEP has provided the chemistry and protocol for ongoing testing, and a similar protocol could be applied for civilian medications. Perhaps the FDA or the US Pharmacopeial Convention could preside over this initiative. These proposals would require funding, but the potential benefits of such initiatives at least deserve consideration of their feasibility.
Or, we could take the current data from SLEP and extend expiration dates for top-performing medications, before they are dispensed, that have already been monitored for years. If the ciprofloxacin in the federal supplies was active for more than 20 years, the FDA might consider granting this medication a shelf-life extension for the general public as well, at least in pharmacies that have maintained optimal storage conditions. At a minimum, individual states that keep supplies of medications in proper storage conditions so as to respond to a pandemic or terrorist attack before federal supplies arrive
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should be able to use SLEP data to extend the shelf lives of medications in their local stockpiles.Even the age-old adage of particular expired medications being toxic may no longer be true. Although degraded tetracycline is thought to cause renal tubular insufficiency, manufacturing was changed decades ago to substantially reduce the likelihood of tetracycline formulations breaking down.
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Of course, subsequent monitoring for and reporting of adverse effects in medications of extended shelf life would be essential for ensuring patient safety; however, controversies from decades ago may need to be revisited for their validity.For most medications, the concern is for loss of potency under imperfect conditions more than for degraded metabolites that are toxic. One could argue that people do not always keep their medications in ideal conditions, as occurred with our federal supplies. This is a valid concern given our currently limited understanding of long-term drug stability, but investment in rigorous testing and surveillance could resolve this uncertainty.
Whereas many decisions in health care must balance the competing interests of cost and quality, extending expiration dates to reflect the true amount of time that a medication is safe and effective might sacrifice neither. Implementing such a measure could decrease the amount of money spent on prescription medications in the United States due to reduced medication disposal and could also improve health care quality by improving access to pharmacologic treatment.
The logistics of implementing shelf life extensions for the general population would not be simple, but the remarkable evidence provided by SLEP indicates that careful consideration is deserved. It only makes sense.
Expiration dates guarantee a certain length of stability, but many drugs may have much longer shelf lives than is labeled because there is no requirement for long-term efficacy testing. SLEP, pioneered by the FDA to conserve drugs stockpiled by the military, provides convincing data about the safety and efficacy of many medications past their expiration dates. If we were to apply shelf life extensions more broadly, it might be possible to reduce national health care costs, reduce drug shortages, and provide medications to those who would otherwise be unable to afford them.
Acknowledgments
We thank Tiffany Lieu, MD, for her help with the literature search.
References
Expiration dating and stability testing for human drug products. US Food and Drug Administration website. http://www.fda.gov/ICECI/Inspections/InspectionGuides/InspectionTechnicalGuides/ucm072919.htm. Accessed July 23, 2015.
International Conference on Harmonization. Guidance for industry Q1A(R2) stability testing of new drug substances and products. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm073369.pdf. Published November 2003. Accessed July 23, 2015.
SLEP: The DOD/FDA shelf life extension program. https://slep.dmsbfda.army.mil/portal/page/portal/SLEP_PAGE_GRP/SLEP_HOME_NEW. Accessed July 23, 2015.
- Stability profiles of medication products extended beyond labeled expiration dates.J Pharm Sci. 2006; 95: 1549-1560
- Stability of active ingredients in long expired prescription medications.Arch Intern Med. 2012; 172: 1685-1687
- Maximizing state and local medical countermeasure stockpile investments through the Shelf-Life Extension Program.Biosecur Bioterror. 2009; 7: 101-107
- The role of pharmaceuticals in the total health care of developing countries.Am J Trop Med Hyg. 1983; 32: 437-446
World Health Organization. Guidelines for drug donations. http://www.who.int/hac/techguidance/guidelines_for_drug_donations.pdf. Revised 1999. Accessed July 23, 2015.
Text of the Prescription Drug Marketing Act of 1987. US Food and Drug Administration website. http://www.fda.gov/RegulatoryInformation/Legislation/SignificantAmendmentstotheFDCAct/PrescriptionDrugMarketingActof1987/ucm201702.htm. Updated March 1, 2010. Accessed July 23, 2015.
American Society of Health-Systems. Drug shortages summit summary report. http://www.ashp.org/drugshortages/summitreport. Published November 5, 2010. Accessed July 23, 2015.
- The drug shortage crisis in the United States: Causes, impact, and management strategies.P T. 2011; 36: 740-757
Drug shortages. American Society of Health-System Pharmacists website. http://www.ashp.org/menu/DrugShortages. Accessed July 23, 2015.
- Pharmaceuticals and personal care products found in the Great Lakes above concentrations of environmental concern.Chemosphere. 2013; 93: 2116-2123
- Complications of tetracycline therapy.Arch Dermatol. 1965; 91: 628-632
Article Info
Publication History
Published online: September 30, 2015
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© 2015 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.
