Regulatory Focus™ > News Articles > Warning Letter to Boehringer-Ingelheim Alleges Particle Contamination, Deficient Investigations

Warning Letter to Boehringer-Ingelheim Alleges Particle Contamination, Deficient Investigations

Posted 21 May 2013 | By Alexander Gaffney, RAC

The US Food and Drug Administration (FDA) has released a copy of a warning letter sent last week to German pharmaceutical manufacturer Boehringer-Ingelheim, citing alleged manufacturing deficiencies found at the company's Rhein, Germany plant.

The letter, sent 6 May 2013, references a November 2012 inspection at the facility, which manufactures both active pharmaceutical ingredients and finished pharmaceuticals. FDA said its inspectors observed a number of violations of US current good manufacturing practice (CGMP) regulations for both types of products, raising concerns and causing those products to be identified as "adulterated."

API Deficiencies

The Warning Letter observes that the company allegedly failed to "thoroughly investigate critical deviations in the manufacturing of [its] active pharmaceutical ingredient."

Those failures included "foreign particles" in at least one product manufactured in 2008 and 2009. The company later used that contaminated API to produce an unidentified capsule drug. While the letter seemed to alleviate concerns about the type of contamination, avoiding any mention of potential harm, FDA said it was "concerned" that it took several years for the company to begin a "formal project to implement comprehensive corrections to mitigate the presence of foreign particles" in the drug.

The problem of uninvestigated particulate contamination extended to at least two complaints received in 2010 and 2011 as well, FDA charged. In one instance, the company identified particles in a product, but after failing to discover the root cause of the contamination classified the report as "not confirmed" and closed the investigation.

In a second incident, FDA said reports indicated that particles-some as large as 3 mm in size-were observed in a drum-sized API container. Regulators said Boehringer found one aspect of this contamination to be "confirmed" as being sourced from its manufacturing, but another related batch to be "not confirmed."

That discrepancy between findings led FDA to say that the company's investigational findings were "inconsistent, as both complaints were related to the presence of foreign particles found in your API, but your final conclusions were different."

"We are concerned about your inability to prevent the presence of foreign particles in your APIs and the adequacy of actions taken to address the situation," FDA added.

Finished Pharmaceuticals

FDA also highlighted problems related to the company's manufacture of finished pharmaceuticals, saying it failed to reject "multiple batches" of capsules that were observed to be contaminated with foreign particles.

Some of that particulate contamination was reportedly large-as big as 5 mm in size and weighing as much at 9 mg. That contamination, found in lots of source API, should not have been used by the company because of its failure to meet final specifications, FDA added.

"Quality cannot be added into a product after it has been manufactured," it noted.

The letter also notes that one lot of the company's Spiriva HandiHaler failed to meet specifications for its 9-month stability interval, but the company did not initiate a recall until the product failed a subsequent 12-month stability test as well.

"We are concerned about the management decision to allow adulterated product to remain in the market between the 9 and 12 month stability stations," FDA explained.

FDA said the inspection findings are grounds for the agency to withhold approval of new drug applications or supplemental filings and to deny the import of products manufactured at the Rhein facility.

Read the letter here.

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