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Extending Shelf Life Just Makes Sense

Published:September 30, 2015DOI:https://doi.org/10.1016/j.mayocp.2015.08.007

      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.

      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.

      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.

      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.
      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.

      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.

      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.
      • Lyon R.C.
      • Taylor J.S.
      • Porter D.A.
      • Prasanna H.R.
      • Hussain A.S.
      Stability profiles of medication products extended beyond labeled expiration dates.
      Table 1SLEP Medication Stability Testing Results: All Lots Initially Extended
      • Lyon R.C.
      • Taylor J.S.
      • Porter D.A.
      • Prasanna H.R.
      • Hussain A.S.
      Stability profiles of medication products extended beyond labeled expiration dates.
      MedicationFormExtension time (mo) mean
      Triamterene and hydrochlorothiazideCapsules19
      Amoxicillin sodiumTablets23
      Acetaminophen pseudoephedrineCapsules24
      Dextrose 10%Injection solution25
      Doxycycline hyclatePowder27
      Atropine sulfate pralidoxime chlorideAutoinjector31
      Morphine sulfateAutoinjector32
      CiprofloxacinSuspension32
      Flurazepam HClCapsules35
      Metaraminol bitartrateSyringe needles40
      Mepivacaine HClCartridge needle41
      Cimetidine HClInjection solution42
      Hydrocortisone sodium succinateInjection solution43
      Prochloroperazine edisylateInjection solution43
      Hetastarch in sodium chlorideInjection solution44
      BenzonatateCapsules44
      Cefoperzone sodiumPowder46
      Ephedrine sulfateInjection solution46
      Dobutamine HClInjection solution47
      EnfluraneLiquid48
      AmpicillinCapsules49
      Calcium glucepateInjection solution49
      Bretylium tosylateInjection solution49
      Sodium chlorideInjection solution50
      Tetracycline HClCapsules50
      Doxycycline hyclateCapsules50
      Iothalamate meglumineInjection solution51
      Promethazine HClInjection solution51
      Chlorpromazine HClTablets52
      Ophthalmic irrigatingSolution52
      NaproxenTablets52
      Ringer's, lactated and dextroseInjection solution53
      Thiopental sodiumPowder54
      Sodium polystyrene sulfonatePowder55
      CiprofloxacinTablets55
      Sodium bicarbonateInjection solution55
      Oxacillin sodiumPowder56
      SulfisoxazoleTablets56
      Ampicillin sodiumInjection solution57
      FurosemideInjection solution57
      Sulfadiazine silverCream57
      CephalexinCapsules57
      MebendazoleTablets58
      Amyl nitriteInhalant59
      Mafenide acetateCream59
      Tubocurarine chlorideInjection solution59
      Ceftriaxone sodiumPowder60
      Erythromycin lactobionatePowder60
      Neostigmine methylsulfateInjection solution60
      Phenylephrine HClInjection solution60
      Dexamethasone sodium phosphateSyringe needle61
      Phenytoin sodiumInjection solution63
      Ketamine HClInjection solution64
      Chloroquine HClInjection solution64
      Dextrose and sodium chlorideInjection solution64
      Protamine sulfatePowder64
      Dextrose (5%)Injection solution65
      Povidone iodineOintment65
      Edrophonium chlorideInjection solution65
      MannitolInjection solution66
      HalothaneLiquid67
      Cimetidine HClTablets67
      Undecylenic acid and zinc saltPowder68
      Potassium iodideTablets69
      Penicillin G benzathineSuspension70
      Succinylcholine chloridePowder72
      Sodium chlorideIrrigation72
      Cephapirin sodiumPowder74
      Chlorpromazine HClInjection solution74
      Diphenhydramine HClSyringe needle76
      Naloxone HClInjection solution77
      Cellulose, oxidized, regeneratedDermal79
      Pancuronium bromideInjection solution79
      Calcium chlorideInjection solution81
      Hexachlorophene cleansingEmulsion81
      Fentanyl citrateInjection solution84
      GuaifenesinExtended-release tablets85
      Bupivacaine HClInjection solution88
      Morhpine sulfateSyringe needle89
      Sodium nitriteInjection solution89
      Meperidine HClInjection solution89
      Sodium thiosulfateInjection solution131
      Potassium iodideGranules254
      FDA = Food and Drug Administration; HCl = hydrochloride; SLEP = Shelf Life Extension Program.
      Table 2SLEP Medication Stability Testing Results: <50% of Lots Initially Extended
      • Lyon R.C.
      • Taylor J.S.
      • Porter D.A.
      • Prasanna H.R.
      • Hussain A.S.
      Stability profiles of medication products extended beyond labeled expiration dates.
      MedicationFormExtension time (mo), mean
      AlbuterolInhalantNA
      Diphenhydramine HClSprayNA
      Levarterenol bitartrateInjection solution22
      Ergotamine tartrate and caffeineTablets24
      Lidocaine HCl and epineprhineInjection solution29
      Physostigmine salicylateInjection solution31
      Mefloquine HClTablets36
      Isoproterenol HClInjection solution45
      Phenobarbital sodiumCartridge needle56
      Penicillin G procainePowder70
      HCl = hydrochloride; NA = not available; SLEP = Shelf Life Extension Program.
      Cantrell et al,
      • Cantrell L.
      • Suchard J.R.
      • Wu A.
      • Gerona R.R.
      Stability of active ingredients in long expired prescription medications.
      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.
      • Courtney B.
      • Easton J.
      • Inglesby T.V.
      • SooHoo C.
      Maximizing state and local medical countermeasure stockpile investments through the Shelf-Life Extension Program.
      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,
      • Hoekenga M.T.
      The role of pharmaceuticals in the total health care of developing countries.
      but medications cannot be donated internationally if they do not meet the donor country's standards.

      World Health Organization. Guidelines for drug donations. http://www.who.int/hac/techguidance/guidelines_for_drug_donations.pdf. Revised 1999. Accessed July 23, 2015.

      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.

      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.

      American Society of Health-Systems. Drug shortages summit summary report. http://www.ashp.org/drugshortages/summitreport. Published November 5, 2010. Accessed July 23, 2015.

      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.
      • Ventola C.L.
      The drug shortage crisis in the United States: Causes, impact, and management strategies.
      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.
      • Lyon R.C.
      • Taylor J.S.
      • Porter D.A.
      • Prasanna H.R.
      • Hussain A.S.
      Stability profiles of medication products extended beyond labeled expiration dates.

      Drug shortages. American Society of Health-System Pharmacists website. http://www.ashp.org/menu/DrugShortages. Accessed July 23, 2015.

      Extending the expiration dates for these medications could possibly help some providers, pharmacists, and patients during medication shortages.
      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.”
      • Blair B.D.
      • Crago J.P.
      • Hedman C.J.
      • Klaper R.D.
      Pharmaceuticals and personal care products found in the Great Lakes above concentrations of environmental concern.
      ,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
      • Courtney B.
      • Easton J.
      • Inglesby T.V.
      • SooHoo C.
      Maximizing state and local medical countermeasure stockpile investments through the Shelf-Life Extension Program.
      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.
      • Clendenning W.E.
      Complications of tetracycline therapy.
      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

      1. 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.

      2. 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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