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United States Food and Drug Administration and Department of Defense Shelf-Life Extension Program of Pharmaceutical Products: Progress and Promise
COMMENTARY
United States Food and Drug Administration and Department of Defense Shelf-Life Extension Program of Pharmaceutical Products: Progress and Promise SAEED R. KHAN,1 RAVIKANTH KONA,1 PATRICK J. FAUSTINO,1 ABHAY GUPTA,1 JEB S. TAYLOR,1 DONNA A. PORTER,2 MANSOOR KHAN1 1
United States Food and Drug Administration, Center for Drug Evaluation and Research, Division of Product Quality Research, Silver Spring, Maryland 20993 2 United States Food and Drug Administration, Office of Regulatory Affairs, Rockville, Maryland 20857 Received 2 December 2013; revised 6 February 2014; accepted 10 February 2014 Published online 12 March 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.23925
ABSTRACT: The Department of Defense (DoD)–United States Food and Drug Administration (FDA) shelf-life extension program (SLEP) was established in 1986 through an intra-agency agreement between the DoD and the FDA to extend the shelf life of product nearing expiry. During the early stages of development, special attention was paid to program operation, labeling requirements, and the cost benefits associated with this program. In addition to the substantial cost benefits, the program also provides the FDA’s Center for Drug Evaluation and Research with significant scientific understanding and pharmaceutical resource. As a result of this unique resource, numerous regulatory research opportunities to improve public health present themselves from this distinctive scientific database, which includes examples of products shelf life, their long-term stability issues, and various physical and chemical tests to identify such failures. The database also serves as a scientific resource for mechanistic understanding and identification of test failures leading to the development of new formulations or more robust packaging. It has been recognized that SLEP is very important in maintaining both national security and public welfare by confirming that the stockpiled pharmaceutical products meet quality standards after the “expiration date” assigned by the sponsor. SLEP research is an example of regulatory science that is needed to best ensure product performance past the original shelf life. The objective C 2014 Wiley of this article is to provide a brief history and background and most importantly the public health benefits of the SLEP. Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1331–1336, 2014 Keywords: stability; physical stability; chemical stability; spectroscopy; shelf life; formulation; shelf-life extension program; FDA; expiration date
INTRODUCTION The pharmaceutical product shelf life, also referred as the expiration date, is the time period during which the product is expected to retain its identity, purity, quality, and strength when properly stored as specified in the container label.1 Performance of the drug product beyond the manufacturer set shelf life has been a subject of study over past several decades. Studies have shown that many drug products retain their shelflife quality characteristics such as potency and efficacy, several years beyond the expiration date if stored properly.1–3 To estimate the drug product shelf life, stability tests are carried out under variety of stress conditions, such as temperature, humidity, and light, as described under the 21 CFR 211.137 and 211.166 documents.4 Based on the stability data, the pharmaceutical companies assign the expiration date for the drug products which is required documentation for new drug application (NDA) or the abbreviated new drug application (ANDA).3 Based on the accelerated and real-time stability data, the initial expiration date can be extended. Drug manufacturers are allowed to conduct long-term stability tests to prove that their Correspondence to: Saeed R. Khan (Telephone: +301-796-0051; Fax: +301796-9816; E-mail: [email protected]) Disclaimer: The findings and conclusions in this article have not been formally disseminated by the United States Food and Drug Administration and should not be construed to represent any Agency determination or policy. Journal of Pharmaceutical Sciences, Vol. 103, 1331–1336 (2014) C 2014 Wiley Periodicals, Inc. and the American Pharmacists Association
products are stable for long-term storage. But this is optional and there is little incentive for manufactures to extend the expiration date. However, the expiration date can be extended if the manufacturer demonstrates long-term stability of the product beyond the initial expiration date granted at the time of the drug approval. In 1981, the military services began purchasing large quantities of drugs and medical devices for stockpiling.5 Significant quantities of these products sit in the stockpiles around the world and are not rotatable for the peacetime use of the products. As the drug product approaches expiration date, these stockpiles are disposed of and replaced with new stocks. In 1987, Joel et al.5 reported that, of 1 billion dollar worth of medical supplies being procured, an estimated $300 million worth of material are shelf-life sensitive. The United States Food and Drug Administration (FDA) administers the shelf-life extension program (SLEP) for the United States Military as a comprehensive testing and evaluation program designed to justify an extension of the shelf life of stockpiled drug products. The program was initiated in 1985 as a result of an audit of Department of Defense (DoD) stockpiled drugs that documented the high cost associated with replacing the expired drug products. This article provides a brief overview of the SLEP background and its operations; with special focus on sample procurement procedures, evaluation, analysis, and the labeling requirements of the tested drug products. In addition, this article also discusses the associated cost benefits, and some of the challenges
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encountered in the effective implementation and expansion of the program.
SLEP BACKGROUND The Government Accountability Office (GAO) in 1985 reported that the $9 million worth of stockpiled drug product was about to reach its labeled expiration date and needed replacement.6 As there were no alternate measures available, it was standard practice to dispose the expired drug products and seek additional funds for the purchase of replacement drug products. This resulted in significant replacement cost each year. In an effort to defer the overall costs and reduce the taxpayer burden for replacing the expired drug stockpiles, organizations such as: the FDA, the defense medical standardization board US. Military branches, Defense Supply Center-Philadelphia, Strategic National Stockpile (SNS), and the veteran affairs (VA) emergency pharmacy services, joined together to develop the SLEP.5 A pilot project was initially initiated in 1985 to assess the feasibility of this program by the representatives of the Air Force Surgeon General’s office and the FDA. Fifty-six items were initially tested by the FDA. After 8 months of testing, 84% of the lots tested were extended for up to a period of 3 years or more past their labeled expiration date.5 After the success of the pilot program, in 1986, an agreement was reached to initiate the SLEP on a permanent basis. An interagency agreement was signed in 1986 between the FDA and the DOD to “conduct a comprehensive, scientifically sound testing and evaluation program that will determine whether there is justification for extending the shelf life of stored medical items owned by components of DOD or their authorized program partners.”6,7 Testing of the items began in Fiscal Year (FY) 87, and by FY 91, the program gained enough success that DOD and the FDA had to increase the monetary and laboratory resources to support the growing needs.
PROGRAM OPERATION The Office of Regulatory Affairs (ORA) within the FDA serves as an interphase between the program participants and the testing laboratories. Once a drug product has been identified as possible test candidate, the FDA gets the list of all possible pharmaceutical products in which category that are nominated as candidates for SLEP by the various program participants. The Defense Medical Material Program Office (DMMPO) maintains a database of the candidate items. The database is then used to select the products submitted for inclusion in a test project. Upon completion of testing, FDA field laboratory forwards the results to the ORA project manager who in turn sends it to the Center for Drug Evaluation and Research (CDER) SLEP chemist for a comprehensive evaluation of the submitted physical, chemical, and spectroscopic data and a final mathematical evaluation is made. Based on the final testing results and the evaluation, the FDA SLEP chemist decides whether to extend the shelf life of the product or not. Once the initial testing is carried out the product will be retested annually or biannually until it reaches its maximum extension when the product fails testing or when the stocks are depleted. The DoD database requires all users to enter their onhand inventory of Chemical, Biological, Radiological, and Nuclear (CBRN) medical material, pandemic influenza, and Khan et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:1331–1336, 2014
antimalaria pharmaceuticals as soon as they receive those items. They are then required to update their inventory once a quarter. Customer service point of contact (POC) now uses this data for budgeting, reporting, and management of CBRN and antimalaria material. Once a quarter, the SLEP program manager at the DMMPO pulls the on-hand inventories of all products expiring within the next 180 days. This list is cross-referenced against the total on-hand quantities and the original expiration date of the item. In order for the program to be cost effective, there should be at least $10,000 worth of stockpiled drugs on hand during the time of testing. However, there are exceptions, for example, if an item is in short supply and required for possible/actual event/operation, such stockpile are considered under this program. Also, it was originally established that no item will be extended beyond 10 years. However, some items such as silver sulfadiazine cream have shorter maximum extension date. Hence, great importance is placed on SLEP users to ensure that all stock is identified in the SLEP website to ensure testing decisions are based on the most accurate information. Once a lot has been identified as a possible test candidate, the FDA gets the list of all possible test lots that are approaching their labeled expiration date within the next 180 days and then the FDA requests samples. Samples are then requested through the automated system to the POC. Service POCs then provide the material to the FDA based on the lot and SNS number. The FDA requires the sample to be received within 45 days of the request. The items are then shipped to one of three FDA laboratory testing sites. Noncontrolled drugs are shipped to the FDA headquarters in Rockville, Maryland and controlled drugs are shipped to Detroit or Philadelphia or other FDA field laboratories. Figure 1 shows the SLEP operation flow that highlights the programs major activities. The CDER staff involved in the SLEP program assists with the evaluation of products for SLEP suitability by evaluating previous reviews of NDAs and ANDAs and related supplements for current release test procedures; evaluating tests for applicability as stability indicating assays; initiating and developing new procedures as needed; and forwarding the appropriate testing procedures to field laboratories. Upon receiving the test results from field laboratory, the CDER scientific staff reviews the data and is responsible for recommending or denying shelf-life extension for the specific product based on the quality attributes such potency (assay), impurities, water content, color, particulates, dissolution, pH, preservative content, and physical appearance. These attributes vary depending on the nature of the dosage form. For examples, oral solid dosage forms are tested for potency, physical attributes, water content, dissolution, and impurities, whereas injectable are tested for potency, impurities, pH, physical appearance, and preservatives. The test and their specifications are based on the United States Pharmacopeia (USP) Compendial methods or test specifications described in the NDA submission. When the FDA has received all the samples for the new testing period, or it has been 45 days since the request for samples was sent, the FDA assigns a project number, sends the list of products by lot numbers that will be tested and, a list of lot numbers that will not be tested to DMMPO. The DMMPO enters this information into the database system and then sends an email message out to all users of the SLEP system with affected inventory and service POCs. Any SLEP participating activity having those declared items in the database by lot DOI 10.1002/jps.23925
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Drug lot stored in military/SNS/VA stockpile
Samples
SLEP military/ SNS/VA contact
Samples Samples
FDA field laboratory “testing”
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New expiration date
FDA SLEP Coordinator
Test results Tests/test methods/location of standards/procedures/research (when needed)
Data evaluation, analysis, and estimations of new expiration date
FDA CDER Chemist analysis Figure 1. Shelf-life extension program (SLEP) operation of military, strategic national stockpile (SNS) and veteran affairs (VA) stockpiles.
number might extend that material to the new expiration date, but only if that material has been properly stored in accordance with the product labeling. Products tested under this program are maintained under controlled environmental conditions (humidity and temperature). In addition, items to be considered for testing must be placed stored in separate designated areas, away from the normal items. However, it is critical to note that under no circumstances can the data generated from these testing be extrapolated to others products or to other lots of the same product unless they are stored under identical conditions as specified in the product labeling. The SLEP program never considers individual prescriptions issued to patients for extension. An item once issued to the patients is never put back into the supply chain as it is difficult to assure the chain of custody, especially storage conditions.
EVALUATION AND STABILITY ASSESSMENT The Division of Field Science Laboratories of ORA, along with the Division of Product Quality Research (DPQR), which manages the program, provides an assurance that extended drug products meet the same stringent quality standards as the original product through laboratory testing. SLEP contains and maintains the most extensive source of long-term stability data available. This information is used to make science-based decisions regarding shelf-life extension of drug products. Drug products are tested for stability by FDA field laboratories based on the original NDA and USP procedures. The CDER laboratory personnel evaluate the results. Depending on the drug product, tests performed may include assay, impurities, dissolution, physical appearance, pH, preservative, and water content. Most of the products/lots selected for testing undergo two types of testing: accelerated stability (“stress”) testing and room-temperature (“unstressed”) testing. Stress testing is performed only the first time the product/lot is tested in SLEP for the initial extension and involves artificially accelerating the degradation of the drug product, using closely controlled International Conference on Harmonisation conditions of elevated DOI 10.1002/jps.23925
temperature, humidity, and time. The unstressed portions of a sample is called Sub A from a given lot of drug product is analyzed first and another portion of the sample called Sub B analyzed after it has been stressed. The Sub B is placed in an environmental chamber and maintained at 50◦ C/75% relative humidity (RH) for exactly 60 days. The Sub A is held until the 60-day stressing of Sub B is completed. After the testing is completed, the amount of stress-induced degradation is measured using stability-indicting methodology. With the accelerated data, a computer model employs the Arrhenius equation (1) and the equation for first order kinetics to extrapolate how long that lot can be stored under labeled storage conditions before it will reach the lower limit of its established potency specification. A degradation curve is created on a potency/time projection chart. The same lot is evaluated every year using the prestress battery of tests. This generates a regression line for each criterion. Based on these results, the target date for expiration is adjusted. Drug products can be extended past the expiration date only by continual testing and systematic evaluation.
CURRENT STATUS Currently this program is limited to DoD (Army, Air Force, Navy, and Marines) and the Center for Disease Control’s SNS since 2004 and the Veterans Administration since 2005. Nonfederal or Civilian agencies may not avail themselves to this program. Drugs that are: (1) manufactured specially for military use, for example, autoinjectors (2) the drugs that are purchased in very large quantities for specific contingency needs, and (3) those products which cannot be returned through return program are those currently considered for testing. In order for other drug products to be included in this program, factors such as product cost, product quantity, product shortage, and financial cost to test are considered for drug products on a case-by-case. Today the SLEP is mainly geared toward the testing military-unique products, with less or no commercial market, Khan et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:1331–1336, 2014
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and those high volume drugs that do not receive credit from the vendors upon expiration. However the direction of the program has changed significantly since its inception. The switch from a large DoD depot supply system to one that is supported predominantly by prime vendor suppliers and just-in-time deliveries for day-to-day requirements has reduced the need for centrally controlled warehousing of drugs which in turn reduced the pool of products that are eligible for testing. This enabled all medical treatment facilities in DoD to return goods for credit or replacement of expiring stocks with little or no cost to the facility.
SLEP RESEARCH CASE STUDIES There are several mechanisms by which a drug product degrades. They are broadly classified into chemical and physical pathways. The chemical pathways include degradation of the active pharmaceutical ingredient by the environmental conditions such as temperature, humidity, oxygen, free radicals, photolytic, and polymorphic changes. These can be detected using various chromatographic techniques such as HPLC, UPLC, GC, and so on. On the other hand, physical changes involve changes in crystallinity, solubility, dissolution, and so on of the active ingredient during storage. These changes could be detected by several techniques such as thermal analysis, X-ray diffraction, and spectroscopy. It has been recognized that SLEP is very important in maintaining national security readiness of the pharmaceutical stockpiles by ensuring that the products for which the expiration date has been extended continue to meet the quality standards after the “expiration date” assigned by the sponsor. By creating a scientific platform to conduct a comprehensive pharmaceutical evaluation using chemical, physical, and spectroscopic approaches to monitor changes or the elucidation of the mechanistic pathways, a wealth of scientific information can be collected by the FDA on the drug product stability and safety. Knowledge gained through participating in such research activities could help FDA in establishing a better regulatory oversight of the pharmaceutical product development based on low and high risk factors. In addition, information on product stability and the reasons for failure could provide the pharmaceutical companies the necessary knowledge to manufacture more robust formulations and stable products with less risk for failure. A set of case studies listed below provides insights on how this information can advance the FDA’s understanding of product quality. Case 1: In a study conducted by the ORA field laboratory, while evaluating the Mark 1 Nerve Agent Antidote Kits of atropine sulfate stability under SLEP, for five of every six atropine autoinjector tested that failed the stability testing, the observed brown particulate matter or the precursory cloudy brown solution was identified as the cause of the product failure and for one in six autoinjector failures was due to out of range of pH or out of specification of potency (unpublished FDA internal reports). It was believed that the observed brown particulate matter was formed via a complex polymerization reaction involving several major and minor ingredients of silicone oil lubricant, citrate, glycerin, atropine sulfate, and phenol (unpublished data). Further investigation revealed that discoloration was result of leaching of low levels of iron from the stopper. The atropine lots tested so far have expiration dates ranging from Khan et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:1331–1336, 2014
12 months to 135 months. The reasons behind this variation could be differences in analysts, environments, laboratory, or just the real differences due to excipients, process, or manufacturing changes. Case 2: Oseltamivir phosphate (Tamiflu) capsules that are part of SNS, where they are stored under controlled environment conditions. However, there have been instances of excursion beyond the approved storage conditions during moving and distribution of these drug products that have led to the deformation or increased brittleness of the Tamiflu capsule shell. Although the product met all other product specifications, the physical appearance was changed making the product visually unacceptable for consumption and compromising patient compliance. The primary goal of this research study conducted, by the DPQR/CDER under the SLEP program, was to investigate the influence of storage temperature on the gelatin shells of Tamiflu capsules packaged in HDPE bottles, a product packaging exclusive to the SNS, which had been extended past the manufacturer’s assigned expiration date after SLEP testing. Hence, one bottle from each Tamiflu batch was evaluated under 75% RH at the two study temperatures (45◦ C and 50◦ C). In this study, the seal of the HDPE bottle was broken at the start of the study and the bottle was without the original manufacturing seal for the rest of the study. The results showed that Tamiflu capsules stored at both conditions showed no physical change for 6 weeks. However, after 9 weeks, a significant flattening was observed for the capsules from both lots stored at 50◦ C. An increase in the flattening of these capsules was also observed at 13 weeks. The capsules stored at 45◦ C, however, did not show any flattening during the 13 weeks study period. The results are summarized in Table 1. In conclusion, flattening of Tamiflu capsule stored in closed HDPE bottles without the original manufacturer seal was observed after 9 weeks of storage at 50◦ C/75% RH, whereas storage at 45◦ C/75% RH for 13 weeks showed no such flattening of the capsules. This means that a few weeks exposure of Tamiflu drug product to higher temperature and RH conditions of up to 50◦ C and 75% RH would not impact the physical integrity of this drug product, if properly stored past the expiration date. The broader public health impact was incalculable. During the pandemic influenza scare of 2008–2009, FDA was able to assist in the release of 12 million doses of the highly needed of lots of Tamiflu capsule drug products from the SNS to the US public. Case 3: A study was conducted on diazepam autoinjectors to assess and to understand the degradation behavior and the critical stability attributes of this drug product. Several different lots were tested and the results were evaluated. Analytical
Table 1. Appearance of Tamiflu Capsules after Storage under Elevated Temperature Conditions Lot 1 Time 0 week 2 weeks 4 weeks 6 weeks 9 weeks 13 weeks
45◦ C
Lot 2 50◦ C
No change No change No change No change No change No change No change No change No change Some flattening No change Most capsules appear flat
45◦ C
50◦ C
No change No change No change No change No change No change No change No change No change Some flattening No change Most capsules appear flat
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evaluation studies have shown that lot-to-lot variability exists in extended shelf life of diazepam autoinjectors. These observations were based on the diazepam content, preservative content (benzyl alcohol), pH, low levels of degradants (carbostyril, 2methylamino-5-chloro-benzophenone), and the absence of particulates. It has been determined that the primary reason for failure to extend the shelf life of these products were the presence of excessive carbostyril (failing impurity specification) and the presence of drug crystals which can negatively impact quality of the drug product unacceptable for consumption, but not the loss of diazepam content. This study illustrates that pharmaceutical testing for content alone was not adequate to understand lot-to-lot variability and a more comprehensive testing protocol is warranted to understand the scientific and mechanistic pathways. In light of these results, it was concluded that certain drug products can be extended past the expiration date, but the stability of these drug products may differ from lot-tolot. In another issue related to the diazepam auto-injectors, two out of five injectors from one single lot had a mechanical failure, that is, shattered upon firing. The diazepam autoinjector (known as CANA) was originally developed and manufactured in the early 1990s by Solvay-Duphar for the US army, the holder of NDA. In the late 1990s, all the manufacturing responsibilities and supply to the army was carried out by Meridian Medical Technologies in order to prevent reoccurring of the crystals formation. Further investigation into the cause of breaking of the back of autoinjectors suggests some form of physical rough handling of the injectors or exposure to some rather harsh environmental conditions. Meridian technologies responded to this problem and corrected the design of the back of the Powerpaks outer tube by increasing the radius and shrinking of the tube. This case study is important in that it highlights that physical and chemical changes can both negatively impact the quality of a drug product.
FUTURE DIRECTIONS Extending SLEP to States Currently, FDA laboratories perform all the required shelf-life extension testing of drug products entered into SLEP. Analysis of drug products of different lots is an ongoing process. FDA does not have the residual capacity for expansion without receiving additional personnel, laboratory space and equipment resources. In 2006, the national strategy for pandemic influenza implementation plan explored the possibility of extending SLEP from its current participants (Army, Air Force, Navy, Marines, SNS, and Veteran Administration) to the state stockpiles. However, it was extremely difficult during that time to assess the feasibility and practicality of the program.8 Courtney et al.8 summarized the recommendations and statements from various agencies and health organizations over the eligibility and inclusion of the stockpiles of different states in to this program.9 The SNS holds many courses of antivirals such R) as neuraminidase inhibitors such as Oseltamavir (Tamiflu R ) in federal stockpiles.9 It was reand Zanamivir (Relenza ported that the State governments have purchased millions of doses and have stockpiled the antivirals. However, the current stockpiles of states are not eligible to participate in the SLEP forcing states to dispose of these units upon reaching the expiration dates assigned by the manufacturer. Since 1986, the FDA headquarters’ and field laboratories have developed the DOI 10.1002/jps.23925
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expertise to include several classes of drugs such as antivirals in their program. However, the states have to invest additional dollars to replace the expired stockpiles. By participating in the FDA sponsored SLEP, it would minimize the financial burden on state on restocking the stockpiles Food and Drug Administration has begun efforts to work with the states on this issue. In 2004, as an effort for the emergency preparedness against the radiation toxicity the FDA issued guidance document to state and local government on the shelf-life extension of the potassium iodide granting permission to extend the expiration dating period of these stockpiles for 7 years, provided the state ensures that theses lots have been stored as recommended by the product label and also maintain adequate record of the expiration date extension.10
CONCLUSIONS SLEP was primarily initiated by a GAO audit in 1985 to look into deferring the replacement cost of expiring DoD stockpiles. Since its inception, this program has enjoyed tremendous success and has saved the Federal Government, and the US taxpayer, significant money by extending the shelf life of drug products in national stockpiles beyond the expiration date as long as the product met the approved quality standards. In addition, participating in this program has provided CDER with significant knowledge on product stability and performance. SLEP has been beneficial for the military because of large stockpiles of medications necessary for use during contingencies ensuring readiness. However, as the program participants’ needs are unique, the program may not be fiscally feasible to others because of size and resources. The program has enjoyed a greater degree of success due to inclusion of those products that have a higher probability of shelf life being extended. In addition, participation in this program has also provided the FDA the necessary knowledge regarding the length of time the drug product can maintain the strength and efficacy. In summary, the progress and promise of SLEP has led to three substantial findings. The actual shelf life for many products is much longer than the labeled shelf life. The stability period can be variable from product to product or from lot-tolot with-in a product and only long-term and comprehensive scientific studies can provide understanding of this variability. The SLEP program and its database are a unique resource that may ultimately serve as a scientific platform for drug product research that has the potential to support FDA’s broader product quality initiatives and address US and global public health issues.
REFERENCES 1. Stark G, Fawcett JP, Tucker IG. 1997. A study of the stability of some commercial solid dosage forms beyond their expiration dates. Online Zocor Pharm J 6941:637–640. 2. Lyon RC, Taylor JS, Porter DA, Prasanna HR, Hussain AS. 2006. Stability profiles of drug products extended beyond labeled expiration dates. J Pharm Sci 95:1549–1560. 3. International Conference on Harmonization. 2003. Guidance for industry Q1A(R2) stability testing of new drug substances and products. Current Step 4 Version. U.S. Department of Health and Human Services. http://www.fda.gov/downloads/regulatoryinformation/ guidances/ucm128204.pdf. Accessed on Feb 2013. 4. 1985. Expiration dating and stability testing for human drug products. Department of Health, Education, and Welfare, Food and Drug Khan et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:1331–1336, 2014
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Administration. http://www.fda.gov/ICECI/Inspections/InspectionGui des/InspectionTechnicalGuides/ucm072919.htm. Accessed on Feb 2013. 5. Joel SD, Francis JF. 1987. Shelf life extension project project for the drug products stockpiled by the military. American Association of Pharmaceutical Scientists. Woodbridge, NJ. Unpublished speech. 6. 2012. Interagency agreement between Department of Defense and the Food and Drug Administration. 7. Leissa B. 2010. Shelf Life Extension Program (SLEP) Federal, State, and Local Public Health Preparedness Meeting, FDA, December.
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8. Courtney B, Easton J, Inglesby TV, SooHoo C. 2009. Maximizing states and local medical countermeasure stockpile investments through the shelf-life extension program. Biosecur Bioterror 7:101–107. 9. Committee on Implementation of Antiviral Medication Strategies for an Influenza Pandemic. 2008. Antivirals for pandemic influenza: Guidance on developing a distribution and dispensing program. Institute of Medicine, Washington, DC: National Academies. 10. Food and Drug Administration. 2004. Guidance for federal and states and local governments potassium idodide tablets shelf life extension, Rockville, MD.
DOI 10.1002/jps.23925
United States Food and Drug Administration and Department of Defense Shelf-Life Extension Program of Pharmaceutical Products: Progress and Promise SAEED R. KHAN,1 RAVIKANTH KONA,1 PATRICK J. FAUSTINO,1 ABHAY GUPTA,1 JEB S. TAYLOR,1 DONNA A. PORTER,2 MANSOOR KHAN1 1
United States Food and Drug Administration, Center for Drug Evaluation and Research, Division of Product Quality Research, Silver Spring, Maryland 20993 2 United States Food and Drug Administration, Office of Regulatory Affairs, Rockville, Maryland 20857 Received 2 December 2013; revised 6 February 2014; accepted 10 February 2014 Published online 12 March 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.23925
ABSTRACT: The Department of Defense (DoD)–United States Food and Drug Administration (FDA) shelf-life extension program (SLEP) was established in 1986 through an intra-agency agreement between the DoD and the FDA to extend the shelf life of product nearing expiry. During the early stages of development, special attention was paid to program operation, labeling requirements, and the cost benefits associated with this program. In addition to the substantial cost benefits, the program also provides the FDA’s Center for Drug Evaluation and Research with significant scientific understanding and pharmaceutical resource. As a result of this unique resource, numerous regulatory research opportunities to improve public health present themselves from this distinctive scientific database, which includes examples of products shelf life, their long-term stability issues, and various physical and chemical tests to identify such failures. The database also serves as a scientific resource for mechanistic understanding and identification of test failures leading to the development of new formulations or more robust packaging. It has been recognized that SLEP is very important in maintaining both national security and public welfare by confirming that the stockpiled pharmaceutical products meet quality standards after the “expiration date” assigned by the sponsor. SLEP research is an example of regulatory science that is needed to best ensure product performance past the original shelf life. The objective C 2014 Wiley of this article is to provide a brief history and background and most importantly the public health benefits of the SLEP. Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1331–1336, 2014 Keywords: stability; physical stability; chemical stability; spectroscopy; shelf life; formulation; shelf-life extension program; FDA; expiration date
INTRODUCTION The pharmaceutical product shelf life, also referred as the expiration date, is the time period during which the product is expected to retain its identity, purity, quality, and strength when properly stored as specified in the container label.1 Performance of the drug product beyond the manufacturer set shelf life has been a subject of study over past several decades. Studies have shown that many drug products retain their shelflife quality characteristics such as potency and efficacy, several years beyond the expiration date if stored properly.1–3 To estimate the drug product shelf life, stability tests are carried out under variety of stress conditions, such as temperature, humidity, and light, as described under the 21 CFR 211.137 and 211.166 documents.4 Based on the stability data, the pharmaceutical companies assign the expiration date for the drug products which is required documentation for new drug application (NDA) or the abbreviated new drug application (ANDA).3 Based on the accelerated and real-time stability data, the initial expiration date can be extended. Drug manufacturers are allowed to conduct long-term stability tests to prove that their Correspondence to: Saeed R. Khan (Telephone: +301-796-0051; Fax: +301796-9816; E-mail: [email protected]) Disclaimer: The findings and conclusions in this article have not been formally disseminated by the United States Food and Drug Administration and should not be construed to represent any Agency determination or policy. Journal of Pharmaceutical Sciences, Vol. 103, 1331–1336 (2014) C 2014 Wiley Periodicals, Inc. and the American Pharmacists Association
products are stable for long-term storage. But this is optional and there is little incentive for manufactures to extend the expiration date. However, the expiration date can be extended if the manufacturer demonstrates long-term stability of the product beyond the initial expiration date granted at the time of the drug approval. In 1981, the military services began purchasing large quantities of drugs and medical devices for stockpiling.5 Significant quantities of these products sit in the stockpiles around the world and are not rotatable for the peacetime use of the products. As the drug product approaches expiration date, these stockpiles are disposed of and replaced with new stocks. In 1987, Joel et al.5 reported that, of 1 billion dollar worth of medical supplies being procured, an estimated $300 million worth of material are shelf-life sensitive. The United States Food and Drug Administration (FDA) administers the shelf-life extension program (SLEP) for the United States Military as a comprehensive testing and evaluation program designed to justify an extension of the shelf life of stockpiled drug products. The program was initiated in 1985 as a result of an audit of Department of Defense (DoD) stockpiled drugs that documented the high cost associated with replacing the expired drug products. This article provides a brief overview of the SLEP background and its operations; with special focus on sample procurement procedures, evaluation, analysis, and the labeling requirements of the tested drug products. In addition, this article also discusses the associated cost benefits, and some of the challenges
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encountered in the effective implementation and expansion of the program.
SLEP BACKGROUND The Government Accountability Office (GAO) in 1985 reported that the $9 million worth of stockpiled drug product was about to reach its labeled expiration date and needed replacement.6 As there were no alternate measures available, it was standard practice to dispose the expired drug products and seek additional funds for the purchase of replacement drug products. This resulted in significant replacement cost each year. In an effort to defer the overall costs and reduce the taxpayer burden for replacing the expired drug stockpiles, organizations such as: the FDA, the defense medical standardization board US. Military branches, Defense Supply Center-Philadelphia, Strategic National Stockpile (SNS), and the veteran affairs (VA) emergency pharmacy services, joined together to develop the SLEP.5 A pilot project was initially initiated in 1985 to assess the feasibility of this program by the representatives of the Air Force Surgeon General’s office and the FDA. Fifty-six items were initially tested by the FDA. After 8 months of testing, 84% of the lots tested were extended for up to a period of 3 years or more past their labeled expiration date.5 After the success of the pilot program, in 1986, an agreement was reached to initiate the SLEP on a permanent basis. An interagency agreement was signed in 1986 between the FDA and the DOD to “conduct a comprehensive, scientifically sound testing and evaluation program that will determine whether there is justification for extending the shelf life of stored medical items owned by components of DOD or their authorized program partners.”6,7 Testing of the items began in Fiscal Year (FY) 87, and by FY 91, the program gained enough success that DOD and the FDA had to increase the monetary and laboratory resources to support the growing needs.
PROGRAM OPERATION The Office of Regulatory Affairs (ORA) within the FDA serves as an interphase between the program participants and the testing laboratories. Once a drug product has been identified as possible test candidate, the FDA gets the list of all possible pharmaceutical products in which category that are nominated as candidates for SLEP by the various program participants. The Defense Medical Material Program Office (DMMPO) maintains a database of the candidate items. The database is then used to select the products submitted for inclusion in a test project. Upon completion of testing, FDA field laboratory forwards the results to the ORA project manager who in turn sends it to the Center for Drug Evaluation and Research (CDER) SLEP chemist for a comprehensive evaluation of the submitted physical, chemical, and spectroscopic data and a final mathematical evaluation is made. Based on the final testing results and the evaluation, the FDA SLEP chemist decides whether to extend the shelf life of the product or not. Once the initial testing is carried out the product will be retested annually or biannually until it reaches its maximum extension when the product fails testing or when the stocks are depleted. The DoD database requires all users to enter their onhand inventory of Chemical, Biological, Radiological, and Nuclear (CBRN) medical material, pandemic influenza, and Khan et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:1331–1336, 2014
antimalaria pharmaceuticals as soon as they receive those items. They are then required to update their inventory once a quarter. Customer service point of contact (POC) now uses this data for budgeting, reporting, and management of CBRN and antimalaria material. Once a quarter, the SLEP program manager at the DMMPO pulls the on-hand inventories of all products expiring within the next 180 days. This list is cross-referenced against the total on-hand quantities and the original expiration date of the item. In order for the program to be cost effective, there should be at least $10,000 worth of stockpiled drugs on hand during the time of testing. However, there are exceptions, for example, if an item is in short supply and required for possible/actual event/operation, such stockpile are considered under this program. Also, it was originally established that no item will be extended beyond 10 years. However, some items such as silver sulfadiazine cream have shorter maximum extension date. Hence, great importance is placed on SLEP users to ensure that all stock is identified in the SLEP website to ensure testing decisions are based on the most accurate information. Once a lot has been identified as a possible test candidate, the FDA gets the list of all possible test lots that are approaching their labeled expiration date within the next 180 days and then the FDA requests samples. Samples are then requested through the automated system to the POC. Service POCs then provide the material to the FDA based on the lot and SNS number. The FDA requires the sample to be received within 45 days of the request. The items are then shipped to one of three FDA laboratory testing sites. Noncontrolled drugs are shipped to the FDA headquarters in Rockville, Maryland and controlled drugs are shipped to Detroit or Philadelphia or other FDA field laboratories. Figure 1 shows the SLEP operation flow that highlights the programs major activities. The CDER staff involved in the SLEP program assists with the evaluation of products for SLEP suitability by evaluating previous reviews of NDAs and ANDAs and related supplements for current release test procedures; evaluating tests for applicability as stability indicating assays; initiating and developing new procedures as needed; and forwarding the appropriate testing procedures to field laboratories. Upon receiving the test results from field laboratory, the CDER scientific staff reviews the data and is responsible for recommending or denying shelf-life extension for the specific product based on the quality attributes such potency (assay), impurities, water content, color, particulates, dissolution, pH, preservative content, and physical appearance. These attributes vary depending on the nature of the dosage form. For examples, oral solid dosage forms are tested for potency, physical attributes, water content, dissolution, and impurities, whereas injectable are tested for potency, impurities, pH, physical appearance, and preservatives. The test and their specifications are based on the United States Pharmacopeia (USP) Compendial methods or test specifications described in the NDA submission. When the FDA has received all the samples for the new testing period, or it has been 45 days since the request for samples was sent, the FDA assigns a project number, sends the list of products by lot numbers that will be tested and, a list of lot numbers that will not be tested to DMMPO. The DMMPO enters this information into the database system and then sends an email message out to all users of the SLEP system with affected inventory and service POCs. Any SLEP participating activity having those declared items in the database by lot DOI 10.1002/jps.23925
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Drug lot stored in military/SNS/VA stockpile
Samples
SLEP military/ SNS/VA contact
Samples Samples
FDA field laboratory “testing”
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New expiration date
FDA SLEP Coordinator
Test results Tests/test methods/location of standards/procedures/research (when needed)
Data evaluation, analysis, and estimations of new expiration date
FDA CDER Chemist analysis Figure 1. Shelf-life extension program (SLEP) operation of military, strategic national stockpile (SNS) and veteran affairs (VA) stockpiles.
number might extend that material to the new expiration date, but only if that material has been properly stored in accordance with the product labeling. Products tested under this program are maintained under controlled environmental conditions (humidity and temperature). In addition, items to be considered for testing must be placed stored in separate designated areas, away from the normal items. However, it is critical to note that under no circumstances can the data generated from these testing be extrapolated to others products or to other lots of the same product unless they are stored under identical conditions as specified in the product labeling. The SLEP program never considers individual prescriptions issued to patients for extension. An item once issued to the patients is never put back into the supply chain as it is difficult to assure the chain of custody, especially storage conditions.
EVALUATION AND STABILITY ASSESSMENT The Division of Field Science Laboratories of ORA, along with the Division of Product Quality Research (DPQR), which manages the program, provides an assurance that extended drug products meet the same stringent quality standards as the original product through laboratory testing. SLEP contains and maintains the most extensive source of long-term stability data available. This information is used to make science-based decisions regarding shelf-life extension of drug products. Drug products are tested for stability by FDA field laboratories based on the original NDA and USP procedures. The CDER laboratory personnel evaluate the results. Depending on the drug product, tests performed may include assay, impurities, dissolution, physical appearance, pH, preservative, and water content. Most of the products/lots selected for testing undergo two types of testing: accelerated stability (“stress”) testing and room-temperature (“unstressed”) testing. Stress testing is performed only the first time the product/lot is tested in SLEP for the initial extension and involves artificially accelerating the degradation of the drug product, using closely controlled International Conference on Harmonisation conditions of elevated DOI 10.1002/jps.23925
temperature, humidity, and time. The unstressed portions of a sample is called Sub A from a given lot of drug product is analyzed first and another portion of the sample called Sub B analyzed after it has been stressed. The Sub B is placed in an environmental chamber and maintained at 50◦ C/75% relative humidity (RH) for exactly 60 days. The Sub A is held until the 60-day stressing of Sub B is completed. After the testing is completed, the amount of stress-induced degradation is measured using stability-indicting methodology. With the accelerated data, a computer model employs the Arrhenius equation (1) and the equation for first order kinetics to extrapolate how long that lot can be stored under labeled storage conditions before it will reach the lower limit of its established potency specification. A degradation curve is created on a potency/time projection chart. The same lot is evaluated every year using the prestress battery of tests. This generates a regression line for each criterion. Based on these results, the target date for expiration is adjusted. Drug products can be extended past the expiration date only by continual testing and systematic evaluation.
CURRENT STATUS Currently this program is limited to DoD (Army, Air Force, Navy, and Marines) and the Center for Disease Control’s SNS since 2004 and the Veterans Administration since 2005. Nonfederal or Civilian agencies may not avail themselves to this program. Drugs that are: (1) manufactured specially for military use, for example, autoinjectors (2) the drugs that are purchased in very large quantities for specific contingency needs, and (3) those products which cannot be returned through return program are those currently considered for testing. In order for other drug products to be included in this program, factors such as product cost, product quantity, product shortage, and financial cost to test are considered for drug products on a case-by-case. Today the SLEP is mainly geared toward the testing military-unique products, with less or no commercial market, Khan et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:1331–1336, 2014
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and those high volume drugs that do not receive credit from the vendors upon expiration. However the direction of the program has changed significantly since its inception. The switch from a large DoD depot supply system to one that is supported predominantly by prime vendor suppliers and just-in-time deliveries for day-to-day requirements has reduced the need for centrally controlled warehousing of drugs which in turn reduced the pool of products that are eligible for testing. This enabled all medical treatment facilities in DoD to return goods for credit or replacement of expiring stocks with little or no cost to the facility.
SLEP RESEARCH CASE STUDIES There are several mechanisms by which a drug product degrades. They are broadly classified into chemical and physical pathways. The chemical pathways include degradation of the active pharmaceutical ingredient by the environmental conditions such as temperature, humidity, oxygen, free radicals, photolytic, and polymorphic changes. These can be detected using various chromatographic techniques such as HPLC, UPLC, GC, and so on. On the other hand, physical changes involve changes in crystallinity, solubility, dissolution, and so on of the active ingredient during storage. These changes could be detected by several techniques such as thermal analysis, X-ray diffraction, and spectroscopy. It has been recognized that SLEP is very important in maintaining national security readiness of the pharmaceutical stockpiles by ensuring that the products for which the expiration date has been extended continue to meet the quality standards after the “expiration date” assigned by the sponsor. By creating a scientific platform to conduct a comprehensive pharmaceutical evaluation using chemical, physical, and spectroscopic approaches to monitor changes or the elucidation of the mechanistic pathways, a wealth of scientific information can be collected by the FDA on the drug product stability and safety. Knowledge gained through participating in such research activities could help FDA in establishing a better regulatory oversight of the pharmaceutical product development based on low and high risk factors. In addition, information on product stability and the reasons for failure could provide the pharmaceutical companies the necessary knowledge to manufacture more robust formulations and stable products with less risk for failure. A set of case studies listed below provides insights on how this information can advance the FDA’s understanding of product quality. Case 1: In a study conducted by the ORA field laboratory, while evaluating the Mark 1 Nerve Agent Antidote Kits of atropine sulfate stability under SLEP, for five of every six atropine autoinjector tested that failed the stability testing, the observed brown particulate matter or the precursory cloudy brown solution was identified as the cause of the product failure and for one in six autoinjector failures was due to out of range of pH or out of specification of potency (unpublished FDA internal reports). It was believed that the observed brown particulate matter was formed via a complex polymerization reaction involving several major and minor ingredients of silicone oil lubricant, citrate, glycerin, atropine sulfate, and phenol (unpublished data). Further investigation revealed that discoloration was result of leaching of low levels of iron from the stopper. The atropine lots tested so far have expiration dates ranging from Khan et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:1331–1336, 2014
12 months to 135 months. The reasons behind this variation could be differences in analysts, environments, laboratory, or just the real differences due to excipients, process, or manufacturing changes. Case 2: Oseltamivir phosphate (Tamiflu) capsules that are part of SNS, where they are stored under controlled environment conditions. However, there have been instances of excursion beyond the approved storage conditions during moving and distribution of these drug products that have led to the deformation or increased brittleness of the Tamiflu capsule shell. Although the product met all other product specifications, the physical appearance was changed making the product visually unacceptable for consumption and compromising patient compliance. The primary goal of this research study conducted, by the DPQR/CDER under the SLEP program, was to investigate the influence of storage temperature on the gelatin shells of Tamiflu capsules packaged in HDPE bottles, a product packaging exclusive to the SNS, which had been extended past the manufacturer’s assigned expiration date after SLEP testing. Hence, one bottle from each Tamiflu batch was evaluated under 75% RH at the two study temperatures (45◦ C and 50◦ C). In this study, the seal of the HDPE bottle was broken at the start of the study and the bottle was without the original manufacturing seal for the rest of the study. The results showed that Tamiflu capsules stored at both conditions showed no physical change for 6 weeks. However, after 9 weeks, a significant flattening was observed for the capsules from both lots stored at 50◦ C. An increase in the flattening of these capsules was also observed at 13 weeks. The capsules stored at 45◦ C, however, did not show any flattening during the 13 weeks study period. The results are summarized in Table 1. In conclusion, flattening of Tamiflu capsule stored in closed HDPE bottles without the original manufacturer seal was observed after 9 weeks of storage at 50◦ C/75% RH, whereas storage at 45◦ C/75% RH for 13 weeks showed no such flattening of the capsules. This means that a few weeks exposure of Tamiflu drug product to higher temperature and RH conditions of up to 50◦ C and 75% RH would not impact the physical integrity of this drug product, if properly stored past the expiration date. The broader public health impact was incalculable. During the pandemic influenza scare of 2008–2009, FDA was able to assist in the release of 12 million doses of the highly needed of lots of Tamiflu capsule drug products from the SNS to the US public. Case 3: A study was conducted on diazepam autoinjectors to assess and to understand the degradation behavior and the critical stability attributes of this drug product. Several different lots were tested and the results were evaluated. Analytical
Table 1. Appearance of Tamiflu Capsules after Storage under Elevated Temperature Conditions Lot 1 Time 0 week 2 weeks 4 weeks 6 weeks 9 weeks 13 weeks
45◦ C
Lot 2 50◦ C
No change No change No change No change No change No change No change No change No change Some flattening No change Most capsules appear flat
45◦ C
50◦ C
No change No change No change No change No change No change No change No change No change Some flattening No change Most capsules appear flat
DOI 10.1002/jps.23925
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evaluation studies have shown that lot-to-lot variability exists in extended shelf life of diazepam autoinjectors. These observations were based on the diazepam content, preservative content (benzyl alcohol), pH, low levels of degradants (carbostyril, 2methylamino-5-chloro-benzophenone), and the absence of particulates. It has been determined that the primary reason for failure to extend the shelf life of these products were the presence of excessive carbostyril (failing impurity specification) and the presence of drug crystals which can negatively impact quality of the drug product unacceptable for consumption, but not the loss of diazepam content. This study illustrates that pharmaceutical testing for content alone was not adequate to understand lot-to-lot variability and a more comprehensive testing protocol is warranted to understand the scientific and mechanistic pathways. In light of these results, it was concluded that certain drug products can be extended past the expiration date, but the stability of these drug products may differ from lot-tolot. In another issue related to the diazepam auto-injectors, two out of five injectors from one single lot had a mechanical failure, that is, shattered upon firing. The diazepam autoinjector (known as CANA) was originally developed and manufactured in the early 1990s by Solvay-Duphar for the US army, the holder of NDA. In the late 1990s, all the manufacturing responsibilities and supply to the army was carried out by Meridian Medical Technologies in order to prevent reoccurring of the crystals formation. Further investigation into the cause of breaking of the back of autoinjectors suggests some form of physical rough handling of the injectors or exposure to some rather harsh environmental conditions. Meridian technologies responded to this problem and corrected the design of the back of the Powerpaks outer tube by increasing the radius and shrinking of the tube. This case study is important in that it highlights that physical and chemical changes can both negatively impact the quality of a drug product.
FUTURE DIRECTIONS Extending SLEP to States Currently, FDA laboratories perform all the required shelf-life extension testing of drug products entered into SLEP. Analysis of drug products of different lots is an ongoing process. FDA does not have the residual capacity for expansion without receiving additional personnel, laboratory space and equipment resources. In 2006, the national strategy for pandemic influenza implementation plan explored the possibility of extending SLEP from its current participants (Army, Air Force, Navy, Marines, SNS, and Veteran Administration) to the state stockpiles. However, it was extremely difficult during that time to assess the feasibility and practicality of the program.8 Courtney et al.8 summarized the recommendations and statements from various agencies and health organizations over the eligibility and inclusion of the stockpiles of different states in to this program.9 The SNS holds many courses of antivirals such R) as neuraminidase inhibitors such as Oseltamavir (Tamiflu R ) in federal stockpiles.9 It was reand Zanamivir (Relenza ported that the State governments have purchased millions of doses and have stockpiled the antivirals. However, the current stockpiles of states are not eligible to participate in the SLEP forcing states to dispose of these units upon reaching the expiration dates assigned by the manufacturer. Since 1986, the FDA headquarters’ and field laboratories have developed the DOI 10.1002/jps.23925
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expertise to include several classes of drugs such as antivirals in their program. However, the states have to invest additional dollars to replace the expired stockpiles. By participating in the FDA sponsored SLEP, it would minimize the financial burden on state on restocking the stockpiles Food and Drug Administration has begun efforts to work with the states on this issue. In 2004, as an effort for the emergency preparedness against the radiation toxicity the FDA issued guidance document to state and local government on the shelf-life extension of the potassium iodide granting permission to extend the expiration dating period of these stockpiles for 7 years, provided the state ensures that theses lots have been stored as recommended by the product label and also maintain adequate record of the expiration date extension.10
CONCLUSIONS SLEP was primarily initiated by a GAO audit in 1985 to look into deferring the replacement cost of expiring DoD stockpiles. Since its inception, this program has enjoyed tremendous success and has saved the Federal Government, and the US taxpayer, significant money by extending the shelf life of drug products in national stockpiles beyond the expiration date as long as the product met the approved quality standards. In addition, participating in this program has provided CDER with significant knowledge on product stability and performance. SLEP has been beneficial for the military because of large stockpiles of medications necessary for use during contingencies ensuring readiness. However, as the program participants’ needs are unique, the program may not be fiscally feasible to others because of size and resources. The program has enjoyed a greater degree of success due to inclusion of those products that have a higher probability of shelf life being extended. In addition, participation in this program has also provided the FDA the necessary knowledge regarding the length of time the drug product can maintain the strength and efficacy. In summary, the progress and promise of SLEP has led to three substantial findings. The actual shelf life for many products is much longer than the labeled shelf life. The stability period can be variable from product to product or from lot-tolot with-in a product and only long-term and comprehensive scientific studies can provide understanding of this variability. The SLEP program and its database are a unique resource that may ultimately serve as a scientific platform for drug product research that has the potential to support FDA’s broader product quality initiatives and address US and global public health issues.
REFERENCES 1. Stark G, Fawcett JP, Tucker IG. 1997. A study of the stability of some commercial solid dosage forms beyond their expiration dates. Online Zocor Pharm J 6941:637–640. 2. Lyon RC, Taylor JS, Porter DA, Prasanna HR, Hussain AS. 2006. Stability profiles of drug products extended beyond labeled expiration dates. J Pharm Sci 95:1549–1560. 3. International Conference on Harmonization. 2003. Guidance for industry Q1A(R2) stability testing of new drug substances and products. Current Step 4 Version. U.S. Department of Health and Human Services. http://www.fda.gov/downloads/regulatoryinformation/ guidances/ucm128204.pdf. Accessed on Feb 2013. 4. 1985. Expiration dating and stability testing for human drug products. Department of Health, Education, and Welfare, Food and Drug Khan et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:1331–1336, 2014
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Administration. http://www.fda.gov/ICECI/Inspections/InspectionGui des/InspectionTechnicalGuides/ucm072919.htm. Accessed on Feb 2013. 5. Joel SD, Francis JF. 1987. Shelf life extension project project for the drug products stockpiled by the military. American Association of Pharmaceutical Scientists. Woodbridge, NJ. Unpublished speech. 6. 2012. Interagency agreement between Department of Defense and the Food and Drug Administration. 7. Leissa B. 2010. Shelf Life Extension Program (SLEP) Federal, State, and Local Public Health Preparedness Meeting, FDA, December.
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8. Courtney B, Easton J, Inglesby TV, SooHoo C. 2009. Maximizing states and local medical countermeasure stockpile investments through the shelf-life extension program. Biosecur Bioterror 7:101–107. 9. Committee on Implementation of Antiviral Medication Strategies for an Influenza Pandemic. 2008. Antivirals for pandemic influenza: Guidance on developing a distribution and dispensing program. Institute of Medicine, Washington, DC: National Academies. 10. Food and Drug Administration. 2004. Guidance for federal and states and local governments potassium idodide tablets shelf life extension, Rockville, MD.
DOI 10.1002/jps.23925