Shelf-Life Extension Program (SLEP) as a Significant Contributor to Strategic National Stockpile Maintenance: The Israeli Experience with Ciprofloxacin

Abstract

In the past decade, the 2001 anthrax incident in the U.S. and the 2003 SARS epidemic have highlighted the biological threat to civilian populations. The risk posed by the natural or manmade spread of biological agents among the population dictates a need for better national preparedness. One key component of this preparation is the establishment of a Strategic National Stockpile (SNS) of pharmaceuticals that would provide appropriate medical countermeasures in case of an outbreak. However, to reduce the expense of such a stockpile and to make it worthwhile, there is also a need for a shelf-life extension program (SLEP) through which pharmaceuticals could be extended beyond manufacturer-ascribed shelf life, as long as they meet regulation standards. In this article, we review the Israeli experience with the national ciprofloxacin stockpile procurement and shelf-life extension program.

One component of preparedness is a pharmaceutical stockpile. To reduce the expense of such a stockpile, the Israeli government has instituted a shelf-life extension program. In this article, the authors review the processes for procuring and maintaining the ciprofloxacin supply.

In the past 2 decades, we have witnessed an increase in the CBRN (chemical, biological, radiological, nuclear) terrorism threat, climaxing with the Sarin attacks in Japan in the 1990s and the 2001 U.S. anthrax incident. The potential for nonconventional agents to inflict mass disruption in public life is regarded as a serious and possibly imminent threat. Bioterrorism is possibly the most challenging of these threats, incorporating potentially extensive and prolonged damage to human life as well as functional continuity of critical infrastructure.

These assumptions have been reviewed in the past by several authors, including Henderson et al. in 1999¹ and Rotz et al. in 2002,² but it is difficult to define a broadly accepted approach to bioterrorism risk assessment, since different nations take different considerations into account, many of which are restricted from open public discussion due to classification issues. Therefore, the best option for portraying the potential consequences of a contagious disease outbreak on society is through the model of pandemic influenza. In a previous review in 2009,³ we summarized different predictions of the burden on society caused by a pandemic influenza outbreak, including estimations of 25% morbidity and 2–3% mortality rates (in the general public) and 25–30% absence from workplaces at the peak of the outbreak. A 1999 review of the economic burden of a pandemic influenza outbreak in the U.S. performed by Meltzer et al. estimated the economic impact in the U.S. alone to be US$71.3 billion to US$166.5 billion, not including disruptions to commerce and society.⁴

One can rightfully argue that this model does not reflect the outcomes of all bio incidents. However, given that the above mentioned scenario is possible, it is understandable that many countries are engaged in constructing national preparedness and response plans to “bioemergencies.” And we argue that strategic stockpiles of pharmaceuticals and medical supplies are one of the most important components in such national response plans.

Importance of a Strategic National Stockpile (SNS)

The U.S. Strategic National Stockpile (SNS) is an excellent example of a national effort to mitigate potential consequences of a biological outbreak. The SNS is designed to supplement U.S. state and local public health authorities with medical equipment and pharmaceuticals whenever there is a public health emergency severe enough to cause local supplies to run out (eg, terrorist attack, flu outbreak, earthquake).⁵ Formerly known as the National Pharmaceutical Stockpile, this important component of the U.S. National Response Framework (NRF) (formerly known as the National Response Plan, or NRP) was established by congressional order in 1999 by the Department of Health and Human Services (HHS) and the U.S. Centers for Disease Control and Prevention (CDC). Within 4 years of its establishment, the SNS has grown in size from assets of US$50 million to more than US$600 million, and it has been broadened to include anti-infectives, chemical antidotes, antitoxins, life support medications, IV administration supplies, airway maintenance supplies, surgical items, and other medical supplies. This rapid expansion mostly occurred after the 2001 anthrax attacks.^5–7

According to a report published in October 2011 by the U.S. Bipartisan WMD Terrorism Research Center entitled Bio-Response Report Card: 21st Century Biological Threats, the current U.S. SNS includes:

• more than 300 million doses of FDA-approved smallpox vaccine;

• an unreported amount of attenuated smallpox vaccine for immune-compromised individuals and close contacts;

• oral antibiotics against anthrax exposure covering approximately 60 million individuals with a 60-day course each;

• FDA-approved Anthrax Vaccine Adsorbed (AVA) for 4.4 million adults, with another 6.3 million courses on order;

• an unreported amount of additional antibiotics for treatment of other likely bacterial agents such as Yersinia pestis (plague) and Francisella tularensis (tularemia); and

• sufficient quantities of antitoxin to respond to more than 100,000 cases of botulinum poisoning.⁸

Several other nations, including Australia,⁹ Canada,¹⁰ the Republic of Korea,¹¹ Israel,¹² and France,¹³ have publicly discussed having national strategic stockpiles for CBRN emergencies. In 2005, these and other nations openly discussed their smallpox vaccine stockpile during “Atlantic Storm,” a tabletop exercise. Among the countries who reported having such stockpiles in 2005 were Germany, the United Kingdom, the Netherlands, the Czech Republic, Denmark, Singapore, South Africa, Malaysia, Switzerland, Japan, Greece, and Spain.¹⁴ This list illustrates that some countries share the view that stockpiles are needed as a biosecurity measure against contagious diseases, at least for those with a high threat profile. However, stockpiling and maintaining medical countermeasures, especially against a broad spectrum of agents, can be costly and difficult to administer.

Past attempts to tackle this problem by creating a joint strategic stockpile in the European Union, for example, faced many difficulties, both fiscal and political, and to date only some European countries maintain such stockpiles for their own projected needs.^15,16 Furthermore, the decision to invest in a national strategic stockpile for civil protection purposes generates substantial logistical difficulties, of which maintenance costs are predominant, because initial and ongoing investments in procurement and disposal of stockpile components are always needed even if the stockpile is never put into use in an emergency.¹⁷ In order to reduce the costs of replacing expired pharmaceuticals, there is a need for long-lasting and highly effective drugs as well as a shelf-life extension program.

Ciprofloxacin: Key Component of Biological Strategic Stockpiles

Widely used nowadays, ciprofloxacin was first introduced in the 1980s as a broad spectrum antibacterial drug belonging to the fluoroquinolone family. Currently, several commercial brands are available, and all are effective in combating most gram-negative pathogens, as well as many gram-positive disease-causing agents, in a variety of infections.^18–20 The drug successfully distributes in many body tissues and fluids, including bile and renal, liver, prostate, and lung tissues.^18,19 Oral administration of the drug has shown some economic advantage in treating some infections that would otherwise require parenteral therapy, allowing overall treatment cost reductions in 2 aspects: basic drug procurement expenses and early discharge from hospital.¹⁸

With its broad antibacterial spectrum and ability to achieve therapeutic concentrations in most body fluids and tissues, ciprofloxacin has proved useful in treating a wide variety of infections, making it a preferred drug for treatment of many bacterial-related respiratory diseases, including several of those caused by bacterial agents listed on the CDC's Category A list of potential bioterrorism agents.^16,21,22 In August 2000, ciprofloxacin hydrochloride was the first antimicrobial drug ever approved by the U.S. Food and Drug Administration (FDA) for postexposure treatment of infections caused by intentional release of anthrax in a bioterrorism scenario. In October 2001 the FDA published a Federal Register notice clarifying that doxycycline and penicillin G procaine were also approved for inhalational anthrax (postexposure), and these were later followed by Levaquin (levofloxacin) and amoxicillin.²³ Nevertheless, the initial decision in 2000 to approve ciprofloxacin for the treatment of postexposure inhalational anthrax proved to be very important in the anthrax incident in 2001.²⁴ For these and other reasons, some nations have established stockpiles of ciprofloxacin as a first-choice antimicrobial drug for mass prophylaxis treatment of relevant diseases in cases of a biological emergency, caused either naturally or intentionally.

Shelf-Life Extension Programs

Getting the Most Out of Your Stockpile

Despite its many advantages, ciprofloxacin (like other pharmaceuticals) suffers a major drawback: Its manufacturer-assigned shelf life is generally 3 years.²⁵ Adherence to manufacturer guidelines may lead to excessive renewal expenditures—that is, proper disposal of expired pharmaceuticals and repurchasing of new batches—that might put in doubt the cost-effectiveness of the strategic stockpile.

This dilemma was first raised in the U.S. when the U.S. Air Force asked the FDA to examine the possibility of safely extending the expiration dates of some of the drugs that it had stockpiled in the mid-1980s. This appeal led in 1986 to the establishment of the Shelf-Life Extension Program (SLEP), which aimed at extending the useful shelf life of pharmaceuticals of “military significance” or which are stockpiled in large quantities by the U.S. government.²⁵

The extension of medicine shelf life by SLEP is subject to vigorous stability examinations consisting of real-time and accelerated tests of the drug products. Shelf-life extension is approved only if a specific batch meets minimum requirements, such as 95% bioavailability of the pharmaceutical chemicals, and only then is a new expiration date issued by the FDA. The batch will be retested annually or biannually until it fails testing or stocks of the product become depleted.²⁵

In 2006 a comprehensive study examining SLEP's data found that 88% of examined lots were extended for at least 1 year beyond the original date and that average batch extension was 66 months. The authors concluded that the results support the assertion that the shelf life of many drug products, if properly stored, can be extended past their official expiration date.²⁶ Overall the SLEP program in the U.S. has enabled a dramatic cut in inventory expenses. For example, SLEP made possible savings of up to US$135 and US$154 in expenditures for every dollar invested in testing in FY1997 and FY1998, respectively.²⁷

Courtney et al. surveyed several relevant publications and found that ciprofloxacin provides a strong example of the significant benefits of the U.S. SLEP.²⁵ Through this program, the Department of Defense (DoD) reportedly added an average of 10 years to the shelf life of the U.S. military ciprofloxacin stockpile, for a total of 13 years (including the manufacturer's 3-year initial claim).²⁵

Shelf-life extension programs, which are subject to high quality control and assurance standards, hold profound implications for maintenance of strategic stockpiles while allowing major reductions in cost. These cuts could subsequently lead to additional investments in stockpiles' inventory, thus improving national preparedness for different mass casualty scenarios.

The Israeli Ciprofloxacin Stockpile

In view of the many threats posed to the State of Israel, the Israeli Ministries of Defense and Health have jointly decided on the establishment of a national medical stockpile for emergencies. This stockpile provides medical countermeasures for the entire population, covering different kinds of natural and manmade outbreaks and other kinds of mass casualty incidents. Different response plans and procedures exist for the rapid distribution of the stockpile components to the population upon a decision by policymakers, but these are beyond the scope of this article.

Ciprofloxacin is one component of the Israeli national strategic stockpile. The drug was initially purchased for stockpiling purposes during 2001-02 and again in 2004, with total costs of over 25 million New Israeli Shekels (NIS), or about US$5.5 million. At first, the Israeli stockpile was based on products of 3 different manufacturers; the products were made of different raw materials and subject to different regulations. In addition, unequal prescribed doses were obtained from the different manufacturers, adding to the logistical complexity. The only common denominator of all products was the manufacturers' assigned shelf life of 3 years.

As a result, the Israeli stockpile of ciprofloxacin expired during 2004–05 and again in 2008. Without other immediate options, the Israeli Ministry of Health (IMOH) conducted tests to estimate the remaining content of active ingredient in 15 ciprofloxacin batches and extended the validity of the stockpile based on the results. Nevertheless, a broad consensus for the need to establish a better managed stockpile and extension program led the Israeli Ministries of Defense and Health to suggest a reform in 2009. The reform included a plan for gradual purchase of new products over a period of 5 years (2009–2013) in order to avoid repeated expiration of the entire stockpile at the same time. Additionally, products were purchased from only 2 manufacturers, which met strict requirements outlined in the IMOH tender, including aspects of raw material quality, high standards of manufacturing practices, and a 5-year shelf-life commitment by the manufacturer for the end product—2 years longer than usual.

The gradual manner of purchasing conducted over several years has resulted in both cost reduction, due to long-term contracting with manufacturers, and stockpile stability, in the form of 4 years' notice for additional procurement following expiry of first batches. Nevertheless, to facilitate further savings in stockpile expenses, a more detailed program for shelf-life extension of the drug was needed.

Israeli Ciprofloxacin Shelf-Life Extension Program

Establishment of a national shelf-life extension program for ciprofloxacin required the setting of basic regulations for batch approval. To do this, the ministry of health first adopted regulations governing good manufacturing practices (GMP), good storage practices (GSP), and good distribution practices (GDP) as fundamental requirements for batch approval and handling.²⁸ Manufacturers who were awarded tenders were required to present GMP certificates for each batch produced and acquired by the government. However, meeting GSP and GDP standards—that is, assuring the quality of pharmaceutical product maintenance through storage and distribution processes—meant that the ministry of health had to invest in upgrading its storage and distribution systems.

For this purpose, the defense ministry invested in upgrades and improvements of warehouses currently used by the ministry of health for stockpiling, including rigorous cleanup and installation of air-monitoring systems and back-up generators to meet GSP and GDP criteria, as well as construction of new state-of-the-art storage facilities. In addition, the ministry of health invested in an innovative pager-based alert system that immediately indicates any deviation in storage conditions (ie, temperature and humidity) in any storage facility, allowing prompt restoration of adequate storage conditions.

The fulfillment of storage and distribution requirements by the government set the foundation for the establishment of a shelf-life extension program for ciprofloxacin. Based on consultations with leading experts in the Israeli health system, IMOH's Emergency and Disaster Management Division, which is responsible for maintaining the medical SNS, together with the ministry's Institute for Review and Standardization of Pharmaceutical Products, have determined a statistics-backed pharmaceutical and chemical evaluation plan for the drug, called the Israeli Ciprofloxacin Shelf-Life Extension Program (ICSLEP).

The ministry of health has decided that ICSLEP will focus on 5 compliance tests for batch extension approval, deemed by the ministry as critical for quality, effectiveness, and safety assurance of the product:

1. Active ingredient content: minimum of 90%, according to U.S. Pharmacopeia (2011);

2. Impurities and degradants content;

3. Dissolution and disintegration (as an indicator for active ingredient release rate);

4. Average tablet weight (to determine loss of water content); and

5. Package integrity (due to long-term storage conditions).

Acceptance range was determined according to pharmacopeia regulations for each criterion, with the decision that any deviation from this range could be deemed sufficient for batch rejection and exemption from the stockpile.

Periodic testing of each batch is carried out once every 12 months in addition to tests conducted by the manufacturer according to regulations of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)²⁹ at 3, 6, 9, 12, 18, 24, 36, 48, and 60 months postproduction at 25 degrees Celsius and 60% relative humidity conditions (see Figure 1).

Figure 1.

Gradual Stockpile Procurement. First 5 batches (2009–2013) are shown with black arrows. Circles indicate ICSLEP extension testing intervals (in months) up to 120 (10 years) according to IMOH estimates. Theoretically, following dismissal of first batch in 2019, stockpile managers will have 4 more years to renew drug production and procurement before all batches expire (purple arrow). Color images available online at www.liebertonline.com/bsp

By applying this process, the ministry of health estimates that the drug's shelf life may be extended an additional 5 years to a total of 10 years. Such an extension would contribute more than 60 million NIS (approximately US$15 million) in savings (including testing expenses) over a 10-year period. Further extension for up to 12 years may allow savings of an additional 6 million NIS per year. Budget figures are detailed in Table 1.

Table 1.

Budgetary Comparison for Previous (2001/2004) and Current (2009) Israeli Ciprofloxacin Strategic Stockpiles. Figures given in millions of New Israeli Shekels (NIS) (US$1 is approximately 3.7 NIS).

	Old Contract (2001/2004)	New Contract (2009)	One-Year Difference	Difference Over 10 Years
Overall stockpile purchase cost^a	−25.500	−17.850
Single year renewal costs^b (exchange expired batch for a new one)	−8.500	−3.570	+4.930	+49.300
Single year savings due to extension^c	NR	+1.785	+1.785	+17.850
Storage system upgrade (one-time expense in 2010)	NR	−2.900	−2.900	−2.900
Single year maintenance costs	NR	−0.055	−0.055	−0.550
Single year extension program costs	NR	−0.120	−0.120	−1.200
10 years' savings				62.500

High pricing of old contract stockpile was partly due to patent protection, which later expired.

Product's ascribed shelf life by manufacturer in old contract=3 years, new contract=5 years.

Estimated 5 years' extension for each batch in the new contract reduces its total cost by half.

Conclusion

The trends we are witnessing in global terrorism indicate that bioterrorism poses a real and serious threat to our populations. The 2001 anthrax incident in the U.S. is an example of how complicated this scenario can get in terms of pharmaceutical intervention, even if the death toll is “low.” And naturally occurring outbreaks can pose the same, or worse, implications, as we witnessed in the 2003 SARS outbreak. One of the key components of mitigating disease outbreaks, whether natural or intentional, is having proper medical countermeasures, which have to be procured and maintained in advance in a strategic national stockpile.

However, purchasing and acquiring medical supplies against an unknown offending agent can be difficult to justify to decision makers, especially when accompanied by a considerable price tag. To overcome this hurdle, policymakers should consider establishing a shelf-life extension program to extend expired pharmaceuticals beyond their prescribed expiration date as long as they comply with the program's approval criteria. Through a process of regulated shelf-life extension, major reductions in stockpile costs can be achieved, allowing either stockpile justification to politicians (in terms of cost-effectiveness) or expansion of the stockpile on the basis of annual savings.

This realization, as well as the outcomes of the U.S. Shelf-Life Extension Program (SLEP), led the Israeli Ministries of Health and Defense in 2009 to launch a reform in the national ciprofloxacin stockpile. The reform enabled the establishment of a new stockpile of the drug together with an Israeli SLEP, predicted to result in savings of more than 60 million NIS over a period of 10 years. As a result of this experience, other SLEPs might be implemented with other medications, extending savings of taxpayer money even further.

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