Editorial: Should Industry Step Up Redundancy to Prevent Drug Shortages?

To address what is becoming a "significant public health problem," FDA this week released the report, "A Review of FDA's Approach to Medical Product Shortages." In particular, it details several agency concerns about sterile injectables, which have accounted for the majority of drugs in short supply. FDA's findings bring to mind the number of drug recalls the industry has seen over the last couple years because of quality concerns. While improving product quality could eliminate some shortages, industry should also consider establishing redundant drug manufacturing and packaging processes as part of contingency planning.

FDA reports that "of the 127 studied drug shortages in 2010-2011, sterile injectables accounted for the majority"---a whopping 80%. Serious manufacturing quality issues were behind many of these shortages, such as "findings of glass shards, metal filings, and fungal or other contamination," FDA reports. In fact, the "leading" cause of shortages overall were "problems at the manufacturing facility," reaching 43%, reports FDA.

FDA is urging drug manufacturers to step up their notifications to the agency regarding any manufacturing challenge. In a letter to industry issued on the same day as its report, FDA reminded manufacturers that for "certain sole source drugs, Section 506C of the Federal Food Drug and Cosmetic Act requires you to notify us of any manufacturing discontinuance at least 6 months prior to the date of the discontinuance." However, FDA is also urging manufacturers to voluntarily notify the agency of any other products that could be in short supply because of the following events:

1. Interruptions or other adjustments in manufacturing that may adversely affect market supply.
2. Delays in acquiring critical raw materials or components.
3. Production problems that occur during or after manufacturing that could result in supply disruptions.
4. Import delays.
5. Unexpected increases in demand.

Sterile injectables themselves may be particularly vulnerable. The "manufacturing of such products is complex," writes FDA in the report, "and can more easily lead to problems that affect safety." In addition, "dedicated manufacturing lines are often required," FDA added. The agency also noted in reviewing the reasons behind shortages that "the main differences between injectable and non-injectable drugs were that injectables were more likely to have had a quality issue and less likely to have had an API shortage issue."

Manufacturers of such products therefore must maintain tight control over manufacturing and packaging to ensure quality. Some argue that increasing product inspection efforts on processing and packaging lines could help manufacturers catch problems such as contaminant presence or dosing inconsistency, errors that in the last few years have led to several recalls. (Please see the story, "The State of Inspection.") Others argue that real strides can be made in adopting process analytical technologies (PAT) in which the processes themselves are continuously monitored and controlled rather than weeding out off-spec products through end-of-process inspection. (See "Uhlmann's Push for PAT.")

In addition to such technologies, manufacturers of injectable drugs should also consider redundant or parallel manufacturing processes that can support production should a quality issue occur. FDA noted in its report that in some shortage cases, "manufacturers responded to a serious problem at the manufacturing facility by discontinuing production." Of course, FDA can work to mitigate a shortage by "finding another manufacturer to begin production" or provide "expedited review of new manufacturing lines . . . to help firms increase production," it wrote in the report. But if contingency plans were in place before manufacturing problems occurred, drug supplies may see no (or very little) disruption. Given the fact that 28% of the drugs currently in short supply are oncology drugs, avoiding disruption could help ensure the continuity of life-saving therapy.

It certainly is expensive and laborious to establish, qualify, and validate redundant manufacturing lines or facilities. FDA is aware of this, stating in its report that "flexibility is limited because of the cost, expertise, and complexity associated with the maintenance of sterile injectable manufacturing facilities." And given the effects of the economy on the industry, such back up could be seen as too costly to execute. FDA documented in the report "a shift to just-in-time manufacturing and inventorying practices . . . [that] reduce expenses by eliminating surpluses."

But FDA is now under an executive order to take action, and given its finding that "supply disruptions of sterile injectable products not only are more likely to turn into drug shortages, but they also typically last months," the agency likely will be taking a closer look at manufacturers' contingency plans. FDA is planning to develop guidance and regulations regarding shortages, so manufacturers should prepare themselves for future scrutiny.

Published in the November 2011 ePackage Newsletter.

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