The US FDA reported that 251 drugs went into shortage during 2011, of which 73% were sterile injectables. The shortages followed a common pattern: one or more manufacturers temporarily stopped production to address a manufacturing quality problem, most often caused by microbial or particulate contamination. Sterility assurance, especially in facilities that are not fully automated, can be difficult to accomplish, but at the heart of the drug shortage problem is the inability of the market to observe, and therefore, to reward quality
Companies have been halting production of a growing number of generic sterile injectables in the past decade. Janet Woodcock and Marta Wosinska, from the FDA’s Center for Drug Evaluation and Research, argue that current economic incentives are driving the drug shortages and ask whether anything can be done.
The US Food & Drug Administration (FDA) reported that 251 drugs went into shortage during 2011. Some 73% of the drugs in shortage were sterile injectables. The sterile injectable shortages included drugs to treat cancer, anesthetic drugs such as propofol, crash cart (trolley) drugs such as epinephrine, and parenteral nutrition drugs used to sustain patients who cannot rely on their gastrointestinal (GI) tract.
The shortages of sterile injectables have followed a common pattern: one or more manufacturers temporarily stop production to address a manufacturing quality problem, most often caused by microbial or particulate contamination. The sterile injectable industry is highly concentrated, and generally just a handful of lines produce a given product. This means that a temporary shutdown of just a single line can cut market-wide production significantly. Because the shortfall is usually quite large and there is limited or no capacity to expand production on short notice, this shortfall cannot be made up by the remaining manufacturers of the product.
Shortages have fallen dramatically since the 2011 peak due to increased diligence by manufacturers in providing the FDA with early notification of potential shortages. Early notification has given the FDA’s Drug Shortage Program more time to work with manufacturers to mitigate the production shortfall by lining up alternative producers, finding temporary risk mitigation measures (such as validating that particulates could be safely filtered out of the product), or helping the firm resolve the underlying quality problem.
Early notification is a mitigating measure rather than a preventive one. To prevent shortages, we need to prevent supply disruptions
However, early notification is unlikely to eliminate the shortage problem entirely. One important reason is that early notification is a mitigating measure rather than a preventive one. To prevent shortages, we need to prevent supply disruptions. And given the extent to which such disruptions have been driven by quality system problems, preventing shortages in sterile injectables means addressing quality system failures that are at the heart of the problem.
While assuring quality is the responsibility of the manufacturer, sterility assurance, especially in facilities that are not fully automated, can be difficult to accomplish. Predictable and safe product results from a plethora of management decisions regarding staffing and training, equipment design, maintenance and upgrades, materials, process control and proper follow-through to resolve any problems. But complexity around assuring sterility is no excuse for an unreliable manufacturing process – there are many firms that have sustained dependable sterile injectable operations for many years. So why are we seeing so many quality systems problems?
At the heart of the drug shortage problem is the inability of the market to observe, and therefore, to reward quality
In a recently published paper,1 the authors argue that at the heart of the drug shortage problem is the inability of the market to observe, and therefore, to reward quality. Hospitals, clinics and individual providers cannot observe differences in quality of sterile injectables. In their minds, if the product is not being recalled, the company’s manufacturing operations must be yielding defect-free products. They see no reason to look for anything else other than the best deal.
Yet, when quality is not observable, manufacturers cannot differentiate one product from another on quality. Economic theory suggests that such an environment can encourage dampened investment and attention to quality systems. Economic theory also suggests that if customers don’t demand it, management is less likely to pay great attention to it. A reactive rather than proactive approach to manufacturing quality is then likely to result – a firm might wait until problems are identified before taking action, in contrast to taking a proactive and vigilant approach that is necessary to sustain a dependable operation.
Some people might question why the FDA cannot hold the line on these companies. Is it not just a matter of improving enforcement? The problem for the FDA is that when a product is medically necessary, it has to weigh the costs and benefits of taking swift action even when a firm’s operation is on the edge of failure. When no major product defects have been shipped to the consumer yet, but the facility is not in a state of control, the FDA will weigh loss of access due to supply disruption against the possibility that emerging manufacturing problems will escalate and result in defective, unsafe product.
The FDA may decide that current loss of access to the drug outweighs future risk of harmful defects. If defective product is identified, the FDA may also use regulatory discretion to import an unapproved product, release product with a filter to remove potentially harmful foreign particles, or use some other regulatory power to avert a shortage.
Economic theory predicts that regulatory flexibility provides improper incentives to manufacturers by reinforcing a reactive approach to quality systems management
Unfortunately, economic theory predicts that such regulatory flexibility provides improper incentives to manufacturers by reinforcing a reactive approach to quality systems management. This is similar to the too-big-to-fail problem for banks – the regulator wants to be tough but cannot. In the meantime, the regulated entity well knows that it is too important to let it fail.
There are a number of other factors that exacerbate the economic disincentive to address quality proactively and may have contributed to the recent prevalence of quality system failures. Many key facilities are ageing and require upgrades. If equipment is not well designed or is poorly maintained, repeated or extensive manual interventions often occur due to mechanical problems. These interventions in turn create opportunities for microbial contamination. Magnifying the problem of ageing facilities, firms have been adding many new products to their portfolios. All this has been taking place in an environment of increasing price competition, which some argue was fuelled by the 2005 change in reimbursement rules. And the recent economic downturn probably has not helped to stem those cost-cutting inclinations – according to the US Bureau of Labor Statistics, pharmaceutical manufacturing jobs shrank by a disconcerting 15% from December 2007 to June 2009.
There has to be another way that does not put the FDA in a position of choosing between loss of access today and potential safety issues down the road
So can the FDA do anything about this problem? First, it is worth noting what the FDA should not do – namely be less flexible. Regulatory flexibility is critical so that the FDA can address public health needs. Instead, there has to be another way that does not put the FDA in a position of choosing between loss of access today and potential safety issues (and loss of access) down the road.
We believe that the FDA has now reached a point where it needs to engage with the marketplace to help address the manufacturing problems, which manufacturers have not been able to prevent unilaterally. The FDA could develop a set of metrics that purchasers could use to assess the quality. This general approach is commonly used in other industries, with Six Sigma providing a good blueprint. This is a major, long-term effort to redefine how the FDA thinks about and deals with manufacturing quality. As a first step, the FDA is actively reaching out to manufacturers and other relevant stake-holders to seek input on which metrics are useful and how they might be used.
Public comments can be submitted by visiting http://www.gpo.gov/fdsys/pkg/FR-2013-02-12/html/2013-03198.htm.
The opinions expressed in this article are those of the authors and not necessarily of the FDA.
1. Woodcock and Wosinska (February 2013), “Economic and Technological Drivers of Generic Sterile Injectable Drug Shortages,” Clinical Pharmacology & Therapeutics 93, 170–176.