cGMP Judgment Day

A look at recent FDA enforcement activities and lessons to be learned.

By Agnes Shanley, Editor in Chief

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The last few years have seen an increase in drug manufacturers’ failures to follow current good manufacturing practices (cGMP) consistently. This year’s numbers have not yet been released by FDA. But last year, the number of cGMP-related drug recalls increased substantially, exceeding a record set in 2009 (see below).

Contamination Drives Spike in Recalls, Warning Letters in 2011

By Bowman Cox, managing editor of "The Gold Sheet"

Contamination issues drove drug recalls to record levels in 2011 and contributed to yet another increase in FDA warning letters that year, according to analysis by “The Gold Sheet,” a publication from Elsevier Business Intelligence that focuses on drug manufacturing quality.

Analysis of this year’s recalls and warning letters will appear in “The Gold Sheet” early next year.

U.S. drug recalls last year soared past the record set in 2009 due to a spike in contamination-related recalls.

As in 2009, most of the spike was from a single repackaging incident. Much of the rest was from potentially contaminated antiseptic swabs, pads and wipes sold by H&P Industries Inc., Hartland, Wis., and distributed through its Triad Group Inc. unit.

Of last year’s 2,329 drug recalls, 1,024 resulted from a single incident, in which Aidapak Services LLC, Vancouver, Wash., realized that penicillin could have cross-contaminated numerous products repackaged in its facility. The incident mirrors previous repackaging failures that inflated recall numbers in 2000, 2006 and 2008.

Aside from the Aidapak and Triad recalls, there were another 248 contamination-related drug recalls in 2011, still four times the prior decade’s annual average.

Of those 248 contamination recalls, 33 involved issues related to glass containers such as cracked syringes or the presence of glass flakes. Another 10 involved malodorous plastic bottles tainted with 2,4,6-tribromoanisole (TBA), a degradant of the chemical wood preservative 2,4,6-tribromophenol (TBP).

There were also a number of cases involving foreign tablets, a few involving precipitation or crystallization, and a variety of cases of particulate contamination of injectables involving stainless steel, polyvinyl chloride, rubber and food grade gasket materials or unspecified materials.

Injectables recalls were three times the prior 10-year annual average due to the same combination of factors that drove them to record levels in 2010 and that have contributed to shortages of critical drug products.

The number of drug GMP warning letters increased 6 percent from 49 in fiscal year 2010 to 52 in FY 2011, just six letters short of the 58 letters in FY 2002, the last Clinton year.

There was a huge increase in warning letters to injectable drug manufacturers in FY 2011, which corresponded to the increase in recalls for injectable drugs.

FDA inspections also found more problems with sterility assurance for injectables. The number of warning letters going to injectables manufacturers shot up from four in FY 2010 to 13 in FY 2011.

Also, FDA inspections last year identified more problems in the global supply chain. Of the 52 warning letters issued in FY 2011, 17 went to active pharmaceutical ingredient manufacturers, up from eight in FY 2010.

An analysis of the 52 warning letters by “The Gold Sheet” found that production record review, which includes batch failure investigations, was the most common deficiency cited during the last fiscal year. This deficiency was noted in 28 of the 52 warning letters issued, or about 54 percent.

The increase in warning letters going to sterile drug manufacturers is reflected in the higher number of deficiencies noted in the microbiological controls area.

The full analysis of FY 2011 FDA recalls and warning letters is available at the website.


Both Warning Letters and recalls of injectables were notably higher, with injectable recalls three times the 10-year annual average reported two years ago, according to Bowman Cox, managing editor of “The Gold Sheet,” which analyzes and reports regularly on FDA data.

“We’re seeing the same types of failures we saw in the early 1980s, when nearly 70 percent of ethical pharma was under Warning Letter or Consent Decree,” says one consultant, who asked to remain nameless. cgmps

These compliance failures have far-reaching effects, not only on corporate reputations and bottom lines, but also on patients. In discussions earlier this summer between FDA and members of U.S. Congress, manufacturing noncompliance was noted as a key reason for chronic shortages of important drugs, including injectable anesthetics and cancer treatments.

According to Jeanne Ireland, FDA’s Assistant Commissioner for Litigation, who detailed facts in a July letter to Elijah Cummings on the House Committee on Oversight and Government Reform, this year, quality control issues at drug manufacturing facilities continue to account for shortages of drugs, particularly injectables. Last year, manufacturing issues, including QC problems, resulted in nearly 70% of shortages.

Consider the critical anesthetic injectable Propofol. Serious contamination issues at its manufacturer’s, Teva Pharmaceutical’s facility in Irvine, Calif., led to a shutdown of the facility, resulting in chronic shortages. The plant was reopened this spring.

Problems involved endotoxin contamination of Propofol emulsion. The company had failed to test for endotoxin in its lot samples, had been unable to find the reason for out of trend results in endotoxin level, and failed to maintain cleaning and sterilization equipment effectively, FDA said.

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