MECHANICS OF MEDICAL PRODUCT SUPPLY CHAIN FAILURES

As noted in Chapter 2, medical product supply chains facilitate the flow of medical products from raw material or component suppliers to producers to distributors to providers and finally to patients. See Figure 4-1 for a graphical representation of a typical supply chain under normal, nondisrupted conditions.

FIGURE 4-1

Simple schematic of a medical product supply chain under normal conditions. SOURCE: Adapted from NASEM, 2020.

The field of supply chain management views a network like the one shown in Figure 4-1 as an end-to-end system, with the overarching goal of managing the flow of goods from the supplier to the end consumer through cooperation of the supply chain as a unified entity (Mentzer et al., 2001). However, it is rare to find supply chains for almost any product type that are contained entirely within a single vertically integrated organization. For medical products, the levels in Figure 4-1 are usually operated by separate entities—often with multiple entities at some levels. This means that supply chains are not centrally controlled systems but are instead distributed networks with multiple decision makers that have different objectives. This can lead to mismatches in supply and demand, even under normal conditions. The challenges presented by decentralization during normal times become even greater when the supply chain is disrupted by a natural disaster, infectious disease outbreak, manufacturing process problem, or other event. At a high level, a disruptive event can cause a mismatch between supply and demand—a shortage—in medical product supply chains in three ways:

1.

Demand surge: An event drives demand for a medical product well above the normal level for an extended period of time. For example, a major natural disaster, such as a tornado or earthquake, can spike regional demand for certain medical products if these events result in a significant number of casualties requiring medical care. As seen during COVID-19, a pandemic can drive up global demand for many medical products.

2.

Capacity reduction: One or more production or transport processes are impeded by lack of assets, power, or people. For example, a natural disaster could cause a factory to lose power and halt production or regulatory barriers or manufacturing quality problems could restrict the output of a supplier or producer, and could even eliminate inventory stock if a product is recalled. As seen during the COVID-19 pandemic, production of some products may have decreased because of lockdown measures or the need for workers to quarantine or be on sick leave.

3.

Coordination failure: Events that prevent supply from being matched to demand can cause shortages of medical products even when total supply is sufficient to meet total demand. For example, geopolitical issues or communication system failures during a hurricane or other natural disaster can reduce or obstruct the delivery of emergency supplies to the people that need them.

A central concept for describing the capacity of flow in a supply chain is a bottleneck. In general, bottleneck is the stage in a supply chain with the highest utilization (demand as a percentage of capacity) (Hopp, 2008). Under normal conditions, the bottlenecks in medical product supply chains can be the supply of raw materials, a production process of a supplier, a final assembly plant, or a distribution process. Under normal conditions, all stages of a supply chain, including the bottleneck, remain safely below 100 percent of capacity. However, an event that causes a demand surge or capacity reduction can push the use of one or more production or transport resources above 100 percent. A resource with use above 100 percent capacity is said to be overloaded (NASEM, 2020). When this happens, supply will not be able to keep up with demand. At first, this will cause stock levels at various points in the supply chain to decline. When this eventually depletes stock at the health care provider level, patients experience shortages (NASEM, 2020).¹

Figure 4-2 illustrates a snapshot of a supply chain that is experiencing a shortage. In this scenario one of the raw material suppliers has become overloaded. This could be the result of a capacity reduction affecting that supplier, such as an earthquake damaging a facility or a manufacturing quality problem that has restricted shipments. It could also be the result of a demand surge that caused the supplier, which was already the bottleneck, to become overloaded. In either case, the bottleneck resource will define the overall capacity of the supply chain. If that capacity is insufficient to keep up with demand, patients will experience a shortage once any inventories in the supply chain are exhausted. Finally, note that Figure 4-2 indicates that some providers are experiencing shortages, while others are not. This could be the result of some nodes holding more buffer inventory or some receiving higher priority in the distribution of limited supplies.

FIGURE 4-2

Schematic of a typical shortage found in a medical product supply chain. SOURCE: Adapted from NASEM, 2020.

It is important to note that disruptions can overlap and interact—demand surges and capacity reductions may occur simultaneously, or capacity reductions may precipitate subsequent demand increases and vice versa. Additionally, disruptions do not cause medical product supply chains to shift instantly from the normal conditions of Figure 4-1 to the shortages of Figure 4-2. Because all supply chains contain at least some amount of inventory, and because decision makers will take steps to increase capacity, such as run overtime shifts, in response to an impending shortage, it will take time for a disruption to turn into a shortage experienced by patients. Figure 4-3 gives a graphic illustration of how a capacity overload of a raw material supplier might propagate through the supply chain to affect patients as a shortage.

FIGURE 4-3

How shortages propagate through a medical product supply chain. SOURCE: Adapted from NASEM, 2020.

The time-phased nature of failures in medical product supply chains has important implications for building supply chain resilience. First, steps that increase the time from a disruption to a product shortage may help avoid shortages altogether; for example, if the length of the disruption is shorter than the timeframe covered by the inventory held in the supply chain, then inventory provides a buffer against a shortage. Second, even if a shortage does occur, inventory buffers delay the shortage from reaching patients and thereby provide time to execute contingency plans and response measures to protect patients. Chapter 5 will build on these insights to create a medical product supply chains resilience framework. This chapter will first explore types of demand surges, capacity reductions, and coordination failures, along with examples of each (see Figure 4-4).

FIGURE 4-4

The three causes of shortages in medical product supply chains—demand surges, capacity reductions, and coordination failures—and examples of each.

DEMAND SURGES

When an event drives demand for a medical product well above the normal level for an extended period of time, a demand surge occurs. Whether a demand surge results in shortages or not depends on whether the various actors in the medical product supply chains have enacted mitigation and preparedness measures, such as hardening of the supply chain, building sufficient inventory or capacity buffers, and planning for contingencies (as will be discussed in detail in Chapter 5). Three types of events can cause demand surges: pandemics and other public health emergencies, natural and man-made disasters, and behavioral reactions to supply chain disruptions (FDA Drug Shortages Task Force, 2020; Socal et al., 2020).

Pandemics and Other Public Health Emergencies

As seen during the COVID-19 pandemic and previous infectious disease outbreaks, a pandemic or other public health emergency can severely strain medical resources at different levels—locally, regionally, nationally, and internationally—when the demand for health care services increases dramatically (IOM, 2009). The COVID-19 pandemic directly led to a demand surge for personal protection equipment (PPE), ventilators, and medications required for critical care (Ammar et al., 2021; Farrell et al., 2021; Ranney et al., 2020). Subsequent shortages led to intense competition for products in short supply, which in turn caused price increases and in some cases price gouging (Butler et al., 2020; Linskey et al., 2020). See Box 4-1 for a case study on the surge in demand for N95 masks. These shortages highlighted the effect of demand surges in the context of a major public health emergency (Schondelmeyer et al., 2020), the risks of having a single source for an item, the need to better manage supply risk, and the importance of end-to-end transparency across the supply chain (NASEM, 2021).

BOX 4-1

Case Study on N95 Masks.

Behavioral Reactions to Supply Disruption

Behaviors such as hoarding and panic buying can create demand surges and exacerbate existing supply disruptions. Hoarding can be both a result of a shortage and increase the likelihood that a disruption will become a shortage (Childs, 2019; Fox and McLaughlin, 2018). During a shortage, hoarding by institutions or individuals may be driven by concerns about maintaining or acquiring an adequate supply of products, particularly if there is a lack of awareness and transparency about the severity of the shortage, its expected duration, and any ongoing mitigation strategies. A national survey of more than 700 hospital pharmacy managers looked at rationing practices during shortages at U.S. hospitals. Eighty one percent of respondents reported using hoarding of the available supply of a drug in shortage as a mitigation strategy (Hantel et al., 2019). In turn, hoarding exacerbates a shortage by making the product unavailable for others, which can result in black and gray markets that can be counterproductive and potentially dangerous. Furthermore, frequent updates to clinical guidance and touting of potential treatments during a public health emergency can make demand difficult to predict (Callaway Kim et al., 2021). For example, the 2001 anthrax attacks led to a demand surge attributable to panic buying of ciprofloxacin (Weschsler, 2001). The ciprofloxacin shortage was not caused by widespread medical use of the drug to treat anthrax victims, it was the result of panic buying and limits on expanded production owing to intellectual property rights (Herper, 2001). See Box 4-2 for an additional example of health care providers hoarding saline solutions as a response to, and an exacerbation of, an existing shortage.

BOX 4-2

Case Study on Saline.

CAPACITY REDUCTIONS

A capacity reduction occurs when one or more production or transport processes are impeded by lack of assets, power, or people. Capacity reductions can arise at any part of the supply chain, including raw material production, component production, final assembly, and transportation (FDA Drug Shortages Task Force, 2020). Each of these steps can be disrupted by factors such as declines in manufacturing quality, inability to ramp up production, lean inventory management practices, regulatory barriers, and natural and man-made disasters.

Declines in Manufacturing Quality

The single biggest cause of drug product supply chain disruptions under routine conditions is a failure to maintain manufacturing quality, according to an analysis by FDA (FDA Drug Shortages Task Force, 2020). The 2020 update of the FDA Drug Shortages Report found that quality problems are responsible for 62 percent of the drugs that went into shortage between 2013 and 2017. Declines in quality are often attributable to factors such as the use of older facilities, the introduction of new products that require companies to share production facilities, contracting practices that lead to poor oversight, and increased price competition (Woodcock and Wosinska, 2013). In a market with a small number of manufacturers, a capacity reduction or market exit by a single manufacturer due to quality problems places pressure on the other manufacturers to fill the gap in supply, which they may not be able to do (Childs, 2019). Furthermore, the market currently does not recognize or incentivize robust quality management systems. The entry of low-cost competitors can cause a ripple effect that affects established manufacturers and ultimately forces some of them to exit the market because of price decreases (Childs, 2019).

Declines in manufacturing quality and consequent supply disruptions occur frequently among generic manufacturers—particularly disruptions at the finished dosage level. Generic drugs administered by injection are the most common products in shortages, largely because there are fewer manufacturers of these drugs and because the manufacturers that do produce them typically operate at full capacity, making it difficult to respond to and recover from disruptions (Fox and McLaughlin, 2018). Box 4-3 provides a case study of the anticoagulant heparin, which illustrates how quality issues led to both direct and indirect health effects owing to a supply shortage. This case also highlights difficulties in monitoring and regulating quality in global supply chains and some challenges and successes in both diversifying and on-shoring supplies.

BOX 4-3

Case Study on Heparin.

All manufacturers must adhere to FDA’s current good manufacturing practice regulations, which include “minimum requirements for methods, facilities, and controls used in manufacturing, processing, and packing of a drug product” (FDA, 2020a). Buyers, therefore, assume the product is safe for use and contains the ingredients at the strength it claims to have and do not distinguish between the quality of any given generic drug. As a result, the market does not reward for production quality. Without a price premium for quality, and with low margins that minimize the value of protecting continuity of supply, generic manufacturers typically do not invest enough in quality systems or equipment modernization to prevent quality failures.

The expansion of multiple foreign manufacturing sites presents new challenges in FDA’s work to ensure the quality and safety of imported products entering the domestic market (Woo et al., 2008). To address these challenges, FDA relies on a number of measures to ensure quality and safety of medical products in facilities around the world including preapproval inspections, surveillance inspections, and for-case inspections.² FDA also relies on automated systems to screen import shipments of drugs, biologics, and medical devices at the U.S. port of entry for compliance with regulatory requirements. These electronic systems review import entries and flag products that may require additional information, a physical exam, or sample analysis (FDA, 2017).

The lack of visibility into the quality of the manufacturing processes used for medical products, and therefore the quality of the products themselves, prevents the market from rewarding quality manufacturers, and causes supply disruptions and shortages (FDA Drug Shortages Task Force, 2020). The committee’s examination of quality-related shortages highlights important observations that must be included in thinking about how to make medical product supply chains safer and more resilient: For nearly a decade, analyses have found that quality problems are responsible for a majority of the drugs that go into shortage. As a result, there have been repeated calls for a robust and mature quality management system to ensure consistent and reliable drug manufacturing and quality performance. However, there is still no such system and the quality problems persist. Purchasers of medical products lack access to sourcing and quality information, which limits their ability to incorporate supply chain resilience when making contracting, purchasing, and inventory decisions.

Counterfeit Medical Products

Counterfeiting, or the proliferation of substandard or falsified medical products, is also a challenge with a globalized supply chain. The complex, and at times circuitious, distribution routes that medical products follow from manufacturer to patient can lead to unregistered/unlicensed, substandard, and falsified (SF) medicines entering the market (The PEW Health Group, 2011). Diverted, stolen, or counterfeited medical products may make their way to American consumers from both domestic and foreign sources (The PEW Health Group, 2011). The American market is particularly vulnerable to the entrance of SF medical products during shortages, when wholesalers and distrubtors may exchange products multiple times, complicating the tracability of the products and raising concerns about the authenticity and quality of the medical products being sold (Rockefeller et al., 2012).

Counterfeiting in the global supply chain is more than a safety issue; it can become a national security issue if individuals introduce counterfeit drugs into the supply chain with the intention to cause harm (Marucheck et al., 2011). For instance, if a counterfeit drug contains contaminated components, it can cause serious harm beyond the lack of therapeutic effect (Bos, 2009). While the World Health Organization’s (WHO’s) Global Surveillance and Monitoring System³ for SF medical products maintains a database of suspected and validated SF reports, the data cannot be extrapolated to country-specific prevalence because regulatory authorities are not always willing, able, or incentivized to report the incidents (NASEM, 2021). One option to address counterfeiting used for pharmaceuticals is serialization, whereby individual drug units are assigned unique identification numbers. This allows for tracking the product, authenticating the product within the distribution chain, as well as identifying counterfeits (Pascu et al., 2020). However, in order for such a system to be successful for globalized supply chains, coordination between international health authorities, such as the World Health Organization, and regional or national authorities is crucial to maintaining the integrity and transparency of supply chains (Pascu et al., 2020).

Inability to Ramp Up Production

Manufacturers’ inability to quickly ramp up production is a factor that compounds capacity disruptions. Manufacturers may face multiple barriers to ramping up production in response to intermittent supply disruptions (NASEM, 2021). For most companies, maintaining standing capacity to ramp up production rapidly is neither logistically nor financially feasible. Generic drug manufacturing, in particular, is a low-margin business that does not allow for idle capacity. If a competitor experiences a supply disruption or demand surge, there will likely be insufficient excess capacity available for other manufacturers to increase production to fill the gap, as was the case during a 2010 propofol shortage (FiercePharma, 2010; Jensen and Rappaport, 2010; Woodcock and Wosinska, 2013).

Additional factors that limit the ability of manufacturers to ramp up production can include operational and regulatory risks as well as packaging and labeling capacity (Jung, 2020). Operational delays may include limits on production, constraints on plant or shipping capacity, and problems with transportation and distribution. Particularly if the disruption is caused by a disaster or public health emergency, operational risks could include human resource deficits (e.g., absenteeism), restrictions of work shift capacity that limit output, or constraints in certain parts of supply chains (e.g., cold-chain storage), especially if multiple manufacturers are attempting to ramp up production to meet demand signal fluctuations (Jung, 2020). Among the potential regulatory risks that manufacturers may face when increasing production are facility inspection delays for new products, generics, and biosimilars, which can lead to longer approval times, as well as inspection requirements following importation (Jung, 2020). The packaging and labeling needed to contain, transport, distribute, and administer products often relies on foreign sources for components, such as resin-based bottles and films, paper cartons and labels, and stainless steel needles. If those components are not consistently available, it can contribute to disruptions in the supply of the finished product (Jung, 2020). Furthermore, decisions to manufacture a new product or ramp up production of an existing product can force companies to make production trade-offs if they are already operating at full capacity, as many generic manufacturers do.

Manufacturers may also have other reasons not to increase their manufacturing capacity during a shortage. For example, after the 2009 H1N1 influenza pandemic, when the mask manufacturer Prestige Ameritech ramped up production during the emergency, they were left with excess product and financial problems when demand suddenly disappeared. Consequently, the company was initially reluctant to ramp up N95 production during the early weeks of the COVID-19 pandemic. The company did eventually install several new mask-making machines and secured investments and multiyear contracts from facilities to make additional masks, which enabled them to ramp up production significantly (Noguchi, 2021).

The above observations lead the committee to conclude that manufacturers often lack incentives to maintain surge capacity in their supply chains, as it is neither financially nor logistically feasible. This limits the ability of supply chain managers to react to disruptions and leads to shortages.

Lack of Investment in Modern Technology

The use of outdated technology is common in medical product manufacturing, and it contributes to manufacturers’ ability to ramp up production. It also introduces product errors that can subsequently lead to shortages. While other industries typically function at an error rate below 3.4 defects per million opportunities, the pharmaceutical manufacturing industry operates at a rate of around 66,000 defects per million opportunities—owing in part to out-of-date manufacturing processes (Woodcock and Kopcha, 2020). Public and private investment in advanced manufacturing is needed to improve the reliability of medical products and reduce the opportunity for quality defects.

Advanced manufacturing techniques, such as continuous manufacturing, and additive manufacturing, such as 3D printing, can improve product quality and address shortages (FDA, 2021a). However, a survey of medical product manufacturers, conducted by Manufacturing x Digital (MxD) and the International Academy of Automation Engineering (IAAE), found that surveyed manufacturers largely still relied on manual, paper-based processes and were only just beginning to advance to more automated and integrated process stages (MxD and IAAE, 2021).

The committee concludes that advanced manufacturing techniques can improve product quality and reliability, thereby addressing frequent causes of shortages. However, medical product manufacturers have little incentive to harden supply chains through updated techniques, processes, and controls that promote reliability and quality in medical products. The medical product industry will likely require additional incentives to spur investment in updated manufacturing technologies that promote reliability. Namely, health systems will need information regarding products’ manufacturing processes to provide manufacturers the incentive to invest in quality.

Lean Inventory Management

Lean inventory management practices can lead to capacity reductions and increase the risk of medical product shortages. It is common practice among manufacturers, distribution centers, and health care organizations to use a just-in-time (JIT) inventory management system (Fox and McLaughlin, 2018). In many cases, JIT leads to smaller inventory levels across the supply chain, which, as illustrated in Figure 4-3, reduces the time it takes for a shortage to reach patients and thereby makes shortages more likely to occur. Lean practices are an example of policies that optimize profits under normal conditions but can also make supply chains less able to respond to disruptions and emergencies. A lack of transparency of inventory practices across supply chain actors and regulators further compounds these challenges (NASEM, 2018). Lean systems are especially vulnerable during major disruptions caused by a natural disaster or public health emergency (NASEM, 2020). The committee therefore concludes that market forces incentivize lean inventory management in medical product manufacturing and ordering, which limits the ability of the health care system to withstand shortages and increases the likelihood that shortages will affect patients.

Regulatory Barriers

In 2020, the FDA Drug Shortages Task Force found that logistical and regulatory challenges can make market recovery difficult following a supply disruption (FDA Drug Shortages Task Force, 2020). Furthermore, as drug supply chains have become more complex, it has become increasingly difficult for manufacturers to respond to shortages because of additional regulations involved, gaps in API procurement, and FDA application requirements for new market entry (FDA Drug Shortages Task Force, 2020). If U.S. medical product supply chains depend heavily upon a few manufacturers, and one manufacturer exits the market, there can be a significant time lag before a new manufacturer can enter the market and increase the available supply. FDA is taking steps to bring greater efficiency to the generic drug review process and respond to shortages. For example, when a shortage is reported, FDA can expedite review of new production lines or new raw material sources. The agency can also consider extending the expiration date for a product experiencing shortage if expired stock is available (FDA, 2013) and thereby increase the available supply. FDA has also taken steps to expedite the development and marketing of generic drug products. For example, in 2019 the agency announced a process to expedite U.S. Pharmacopeial Convention small molecule monograph updates (FDA, 2019b). However, the approval of a new manufacturer can still take 1 to 2 years (FDA, 2021a; Sullivan, 2018).

Other forms of regulation can also lead to unintended capacity reductions in medical product supply chains. In 2019, the firm Sterigenics closed a sterilization plant after the Illinois Environmental Protection Agency prohibited the firm from using the carcinogen ethylene oxide in its sterilization process because of the resulting chemical emissions from the plant (Goldberg, 2019). Closure of the plant severely reduced the total medical device sterilization capacity in the United States. The closure caused several devices to go into shortage (Crotti, 2019) and FDA warned that widespread shortages were possible (Maxwell, 2019). At the time of the closure, about 50 percent of devices requiring sterilization used ethylene oxide (Maxwell, 2019), and only 2 percent of those had an alternate validated sterilization method available for use (Lim, 2019). FDA is now working to advance innovation in ways to sterilize medical devices using lower levels of ethylene oxide and other currently available agents, and it is funding research into alternative sterilization techniques (FDA, 2020b).

Natural and Man-Made Disasters

In addition to causing demand surges, natural and manmade disasters can also cause capacity reductions. The past three decades have seen drug shortages result from natural disasters, either by affecting product availability, damaging production facilities, and/or creating unexpected demands for drugs needed to treat the injured (Fox et al., 2009). In 2017, for example, Hurricane Maria severely disrupted the production of medical use saline (NASEM, 2020). At the time, the majority of saline produced for the U.S. market was manufactured by a single firm, Baxter International, at three facilities in Puerto Rico. Hurricane Maria disrupted power at these facilities in September 2017, and power was not completely restored until January 2018. The 4-month supply disruption resulted in widespread saline shortages at hospitals in the United States throughout 2018 (NASEM, 2020). See Box 4-2 for a case study on saline, which illustrates the vulnerabilities created by concentrated production (even when that production is located on U.S. territory), how hoarding exacerbated the shortage, and the importance of being able to tap the global supply chain for backup supplies in an emergency.

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