Sterile Injectables Shortages: Can Innovation End A Crisis?

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In 2011 and 2012, when the number of drug shortages in the United States skyrocketed, media focus intensified on the issue. Sterile injectables, particularly generics, accounted for 80% of the materials in short supply (1). As workhorse drugs became impossible for hospitals and clinics to get, there were reports of desperate attempts to buy drugs on the grey market from unlicensed distributors, drug substitutions, dosing mistakes that resulted in adverse reactions, as noted in a survey by the Institute for Safe Medication Practices (2), and patient deaths.

In 2014, the Associated Press reported that drug shortages were costing US hospitals more than $230 million per year, and that 90% of hospitals surveyed noted that they had experienced at least one drug shortage that year that might have caused a dosing or other error. Results suggested that the situation had not improved much since 2010 (3).

The full impact of drug shortages has yet to be assessed, but the crisis is far from over. As seen in 2009-2011, when Teva stopped producing the anesthetic, propofol, and a number of contract manufacturers, notably Ben Venue Labs, left the market, the industry is still seeing product recalls and plant closures. In August 2016, Pfizer, which had acquired contract manufacturer Hospira in 2015, closed its facility in Chennai, India due to ongoing manufacturing and quality issues. The plant had received a warning letter from FDA in 2013 (4). A number of manufacturers issued voluntary injectable product recalls due to particulate and other contamination in 2016.

Measuring the effect of drug shortages is proving as difficult as coming up with a solution to a multi-pronged problem that involves artificially depressed product prices, complex manufacturing and quality-control processes and outdated facilities, industry’s resistance to change, and lack of financial incentives to invest in modern filling and manufacturing technology.

But the situation is clearly taking its toll. “When you fill out a family member’s death certificate, you only have to include the name of the disease that he or she suffered from, not what drug they were taking [or unable to get],” says Dr. Jacalyn Duffin, a hematologist and chair at Queens University in Ontario and founder of canadadrugshortage.com, which tracks drug shortages in Canada. She believes that an Essential Medicines List (5), such as the one used by the World Health Organization (WHO), and concerted global efforts, would help the situation in Canada and the US. 

Reports in the Associated Press in 2011 found that at least 15 patient deaths that year could all be traced to drug shortages (6). The following are some of what has been reported:

• Sixty-four patients died and more than 800 became ill due to contaminated steroid injections (then in short supply from conventional sources) manufactured by the New England Compounding Center (7).

• Two patients died from accidental overdoses of morphine substitutes, while nine patients died and 19 became ill when they received infusions of contaminated solution that the hospital had bought from an unlicensed source (8).

• Single-use 50-mL vials of the anesthetic, propofol, were used to treat more than one patient, resulting in an outbreak of hepatitis C (9).

The FDA Safety and Innovation Act of 2012 established processes for preventing shortages by requiring manufacturers to notify FDA, prioritizing FDA review of drug applications and supplements that might alleviate existing shortages, and requiring FDA to consider supply issues carefully when issuing warning letters (10). These efforts have had some impact, particularly in helping prevent new shortages.

Existing shortages remain high

Existing drug shortages, particularly for emergency response staples, remain serious. The US Government Accountability Office (GAO) has analyzed shortages and their underlying causes. Its latest study (11), released in July 2016, shows that, despite a reduction in new shortages, existing drug shortages have remained consistently high for the past five years (Figure 1).

Figure 1: Number of drug shortages from 2010–2015. Adapted from Reference 11.

The drugs in shortest supply are still the generic injectables most widely used in emergency and acute care. According to research (12), roughly half of the drugs in short supply are used in emergency care, and shortages of these drugs have been more frequent and prolonged than shortages of non-acute-care drugs, lasting 242 compared with 173 days.

Another study (13) found that, between 2001 and 2014, of 1798 shortages, nearly 34% were for drugs used in emergency medicine. Of those, more than half were for treatments used in lifesaving interventions, and 10% were for drugs with no available substitutes.

Researchers found that each shortage lasted an average of nine months. In shortest supply between 2001 and 2014 were the antibiotic acyclovir (which experienced six shortages), the pain treatment hydromorphone (with eight shortages), the antidote antivenin (which experienced five shortages), and epinephrine (which had seven shortages). Of the reasons given for the shortages, which were not reported by more than half of the manufacturers involved, more than 25% were caused by manufacturing problems, 15% by supply issues, 4% by raw material sourcing issues, another 4% by discontinued manufacturing, and roughly 2% each by regulatory actions and business decisions (13).

Novel approaches to manufacturing will also be needed to improve flexibility and reduce the risk and cost of entering a market with small margins. Currently, the costs for building a sterile injectables manufacturing plant are extremely high, and the timelines long, with two years for approval time suggesting breakneck speed, notes Chris Procyshyn, CEO of Vanrx Pharmasystems, a Vancouver-based company. 

Vanrx has developed automated filling technology using robotics, integrated inside an isolator. Its technology is based on the standard “workcells” used in semiconductor manufacturing--a model that, he says, helps reduce capital project lead time, investment and operating costs.

Costs for building a traditional cleanroom facility can run up to $37 million, compared to $42 million for constructing a restricted access barrier system (RABS ) facility and $46 million for a facility using isolators, according to industry sources (14).

Technology focuses on flexibility

Technology vendors are stepping up their efforts to develop technology that can address the need for flexibility, and automation, to minimize operator interaction with product.  Blow-fill-seal (BFS) technology, which packages products in single-dose plastic, provides a number of benefits, says Tim Kram, general manager for Rommelag Engineering in North America.  It eliminates operator intervention, because the process is automated, and obviates the need to buy high-quality glass, which is becoming increasingly expensive and in short supply.

Unit-dose packaging also reduces the waste often found with vaccines, which are typically packaged in multidose form, especially for distribution to developing nations, Kram says. He notes that critical product can be wasted with multidose packaging, when the numbers of patients to be treated does not match the number of available doses.

Rommelag recently introduced the Bottelpack 430 L, which is designed to bring increased flexibility to higher-speed filling and to allow manufacturers to be able to switch quickly and more easily between different products.  The company has also introduced a vision system for inspecting product for visible particles, eliminating the need for operators to do this. The system vibrates the container lightly, and if there are any, moving particles can be found by the camera system. Traditional systems, Kram explains, spin the container, stop, and then take pictures of the moving water column, and can result in inaccuracies.

More products, lower volumes

Vanrx was established in 2007 by Procyshyn, a microbiologist by training, and Ross Gold, a chemical engineer.  They had worked together at the ophthalmic drug manufacturer QLT and were frustrated by conventional fill/finish equipment. “Existing technology was not keeping up with the industry’s move to manufacture a higher number of more specific products,” says Procyshyn, who notes the need for manufacturers to adapt quickly to changing market needs.

In response to those needs, Vanrx developed the SA25 Aseptic Filling Workcell, a gloveless isolator that eliminates operator intervention. It allows filling of vials, syringes, and cartridges within the same machine using nested containers and closures. The work cell features faster changeover times, a smaller footprint, and automation using robotics and machine vision, Procyshyn says. Employing a limited number of change parts, it relies on software for product changeover, which can take three days in a conventional facility.

The future, Procyshyn says, will involve facilities with many small lines, not a single large filling line. This picture doesn’t yet exist in the pharma industry, but is now common in semiconductors where workcells dominate. In July 2016, Bloomington, Indiana-based Singota Solutions acquired Vanrx’s technology, and a number of other lines are already in place in Asia, Procyshyn says.

Vanrx is also a founding member of the Matrix Alliance, a group of packaging manufacturers collaborating to optimize and standardize nested container and closure products. Alliance members believe that working together on testing and compatibility should support drug manufactures in bringing products to market more quickly. Alliance members include ARaymond Life, Daikyo Seiko, Datwyler Group, Ompi, SCHOTT, and SCHOTT Kaisha.

The group’s efforts are currently focusing on testing pre-sterilized container and nested closure systems, and ensuring compatibility of components from different member companies. Container-closure integrity testing results are now becoming available from member companies. Greater performance certainty and component availability will contribute to solving the shortage issue by solidifying drug manufacturers’ supply chains and reducing risks in bringing products to market, Procyshyn says.

Currently, facilities using isolators cost more to build than traditional cleanrooms or RABS, but reduce operating costs dramatically. After 10 years, operating costs for a traditional cleanroom run to $79 million, $83 million for a RABS, but $67 million for isolators (14). Automation will be crucial to preventing the quality and compliance problems that often lead to sterile injectables shortages. Says Kram, “We’re getting very close to ‘lights out’ operation.”

References

1. M. Aitken et al., “Drug Shortages: A Closer Look at Producers, Suppliers, and Volume Volatility,” IMS Institute for Healthcare Informatics, IMShealth.com, November 2011, 
2. ISMP, “Drug Shortages National Survey Reveals Higher Frustration, Lower Level of Safety,” ismp.org, September 23, 2010. 
3. L. Johnson, “Hospitals Coping Better as Drug Shortages Persist,” Associated Press, Feb. 27, 2014, AP.com.
4. E. Silverman, “Pfizer Closes Plant in India After Several Regulators Find Problems,” StatNews.com, August 8, 2016.
5. G. Eom et al., “The Case for an Essential Medicines List,” Canadian Medical Association Journal, June 13, 2016, CMAJ.com.
6. L. Johnson, “Hospital Drug Shortages: Deadly, Costly,” Associated Press, September 22, 2011, posted on Cancer Survivors Network.
7. “Multistate Outbreak of Fungal Meningitis and Other Infections Case Count,” October 30, 2015, Centers for Disease Control, CDC.gov.
8. R. Stein, “Shortages of Key Drugs Endanger Patients,” The Washington Post, washingtonpost.com, May 1, 2011.
9. V. Jensen, The New England Journal of Medicine, 363 (9), 2010, pp 806-807.
10. Hyman, Phelps and McNamara, P.C.,“Food and Drug Administration Safety and Innovation Act, Summary and Analysis,”  July 11, 2012, hpm.com.
11. GAO, “Drug Shortages: Certain Factors are Strongly Associated with This Persistent Public Health Challenge,” U.S. Government Accounting Office, gao.gov, July 7, 2016.
12. S. Chen et al., Health Affairs, Vol. 35 No. 5, ppp. 798-804 (May 2016).
13. K. Hawley et al., Academic Emergency Medicine, 23 (1), pp. 63-69 (January 2016). 
14. J. Ferreira et al., “A Comparison of Capital and Operating Costs for Aseptic Manufacturing Facilities,” Chapter 12, Advanced Aseptic Processing Technology, edited by James Akers and Jim Agalloco, pp 118-143 (CRC Press, New York, NY, 2010).

Article Details

Pharmaceutical Technology
Vol. 40, No. 9
Pages: 20–24

Citation

When referring to this article, please cite it as A. Shanley, “Sterile Injectables Shortages: Can Innovation End A Crisis?," Pharmaceutical Technology 40 (9) 2016.