Sterile Manufacturing and Drug Shortages: Where Does the Industry Stand?

By Patricia Van Arnum - DCAT Editorial Director

July 27, 2016

Manufacturing issues and a limited number of suppliers contributed to drug shortages for generic sterile injectable drugs, a problem that peaked in 2010 and 2011, but has the industry made progress since then? A recent US government report shows that the number of new drug shortages has generally decreased since 2011 although the number of ongoing shortages remain high.

The report, issued by the US Government Accountability Office (GAO), also looked at the number of Warning Letters issued by the US Food and Drug Administration (FDA) to sterile drug manufacturing establishments during this time. So what did the report find? DCAT Value Chain Insights takes an inside look.

To compile its analysis, the GAO report used drug shortage data from the University of Utah Drug Information Service from 2010 through 2015 as well as data from the FDA, including data on Warning Letters related to inspections conducted through October 2006 through September 2013 and data on prioritized reviews from January 2010 through July 2014, which were generally the latest available data at the time the GAO began its analysis. The GAO also interviewed FDA officials and reviewed agency documents.

Drug shortages: a look at the numbers
To address the issue of drug shortages, the FDA prioritized the review of 383 drug applications and supplements during the time GAO examined the data. Most were for generic sterile injectable drugs. Although the GAO report found an increasing number of Warning Letters for sterile injectable drugs during the time of the GAO analysis, the percentage of inspections resulting in Warning Letters remained relatively small as the number of inspections increased. Moreover, seven establishments that were linked to widespread shortages and that received Warning Letters all had previous indications of difficulty complying with manufacturing standards.

So what did the report show? With respect to drug shortages, although the number of new shortages has generally decreased since 2011, new drug shortages continue to be reported each year. New shortages peaked in 2011 with 257 reported while 136 new shortages were reported in 2015, a decrease of 47% from 2011. Meanwhile, since 2012, the number of ongoing shortages (shortages that began in prior years) has remained high with over 250 ongoing shortages each year from 2012 through 2015 (see Table I). As a result, the majority of drug shortages each year since 2012 have been ongoing shortages rather than newly reported shortages. For example, in 2015, 68% of the shortages (291 out of 427) were ongoing shortages that began in a prior year. Since 2013, the majority of the ongoing shortages in a given year were first reported at least two years earlier (see Table II). For example, in 2015, 171 of the 291 ongoing shortages (59%) were first reported during 2013 or an earlier year while the remaining 120 ongoing shortages were first reported during 2014.

Table I: Number of Drug Shortages from 2010 Through 2015.
Calendar year Number of new drug shortages Number of ongoing shortages, which began in prior years
2010 201 127
2011 257 184
2012 193 262
2013 135 289
2014 179 277
2015 136 291

Source: GAO analysis of University of Utah Drug Information Service data; GAO Report: Drug Shortages: Certain Factors Are Associated Strongly With This Persistent Public Health Challenge, US Government Accountability Office, July 2016.


Table II: Duration of Ongoing Shortages From 2010 Through 2015
Calendar year Drug shortage first reported during previous year Drug shortage first reported at least 2 years earlier
2010 91 36
2011 121 63
2012 153 109
2013 119 170
2014 75 202
2015 120 171

Source: GAO analysis of University of Utah Drug Information Service data; GAO Report: Drug Shortagages: Certain Factors Are Associated Strongly With This Persistent Public Health Challenge, US Government Accountability Office, July 2016.


The duration of drug shortages reported from January 2010 through December 2015 varied, ranging from 1 day to almost six years. Of these shortages, 65% lasted one year or less while 12% lasted more than three years. The average duration of all shortages reported during this time period was 418 days. The GAO report said the fact that some shortages have lasted three years or more suggests that manufacturers and the FDA have had difficulty addressing the issues behind these persistent shortages, which may be either a decision by the manufacturer to not continue to manufacture a drug or not be able to address the issues behind the shortage.

Sterile manufacturing: trends in Warning Letters
The number of Warning Letters issued by the FDA annually to sterile injectable drug-manufacturing establishments found to be out of compliance with manufacturing standards generally increased from fiscal year 2007 through fiscal year 2013, according to the GAO report. The number of letters ranges from one Warning Letter resulting from an inspection conducted in fiscal year 2007 to 11 Warning Letters resulting from fiscal year 2010 inspections, and another 11 Warning Letters from fiscal year 2011 inspections. In addition, the FDA issued a growing number of such letters to non-injectable drug-manufacturing establishments, ranging from 16 letters from fiscal year 2007 inspections to 45 letters from fiscal year 2010 inspections and another 45 letters resulting from fiscal year 2011 inspections.

Although the number of Warning Letters increased, the percentage of inspections that resulted in Warning Letters in a given years remained relatively small. One percent of FDA's fiscal year 2007 inspections of sterile drug manufacturing establishments resulted in the issuance of Warning Letters, compared with 5% of such inspections in fiscal years 2010 and 2011, according to the GAO analysis. The percentage of inspections of non-injectable drug-manufacturing establishments that resulted in Warning Letters was similar, ranging from 1% of fiscal year 2007 inspections to 4% of fiscal year 2013 inspections.

As the number of Warning Letters issued to sterile injectable drug establishments for noncompliance with manufacturing standards generally increased from fiscal year 2007 through fiscal year 2013, so did the number of shortages of these drugs (see Table III). While a corresponding rise in Warning Letters and shortages could correspond to an increase in FDA inspection rigor, it could also indicate manufacturing problems, as noted in the GAO report.


Table III: Number of New Shortages of Sterile Injectable Drugs and FDA Warning Letters Issued to Sterile Injectable Drug Establishments for Noncompliance with Manufacturing Standards, Fiscal Years 2007 Through 2013
Fiscal year Number of new shortages Number of Warning Letters related to inspections conducted in this fiscal year
2007 54 1
2008 84 5
2009 61 6
2010 130 11
2011 147 11
2012 88 5
2013 74 8

Note: The number of FDA Warning Letters issues to non-injectable drug establishments from fiscal year 2007 through 2013 by fiscal year of inspections, were as follows: 16, 26, 28, 45, 45, 22, and 42.
Source: GAO analysis of University of Utah Drug Information Service and US Food and Drug Administration data; GAO Report: Drug Shortagages: Certain Factors Are Associated Strongly With This Persistent Public Health Challenge, US Government Accountability Office, July 2016.


The GAO report found that between fiscal years 2007 and 2013, the percentage of inspections with a for-cause component was consistently higher for sterile injectable drug-manufacturing establishments than it was for non-injectable establishments. Across this time period, the percentage of sterile injectable drug establishment inspections with a for-cause component varied. After declining from its fiscal year 2007 peak, the percentage of sterile injectable drug establishments inspections with a for-cause component grew to 17% of fiscal year 2011 inspections. Fiscal year 2011 was also both the peak in new sterile injectable drug shortages and Warning Letters issued to sterile injectable drug establishments.

From fiscal year 2010 through fiscal year 2012, seven sterile injectable drug manufacturing establishments that received FDA Warning Letters for noncompliance with manufacturing standards slowed or shut down production, which led to widespread drug shortages. For example, the fiscal year 2013 voluntary shutdown of one of the seven establishments reportedly led to the actual or potential shortage of more than 100 drugs. Another of the seven establishments manufactured more than 300 drugs, so its production shutdown also led to multiple shortages, according to the GAO analysis.