FDA Issues Warning Letter to Boehringer Ingelheim for cGMP Violations

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Company receives notice from FDA for not fully investigating foreign particles in APIs and finished products made from its facility in Ingelheim am Rhein, Germany.

FDA issued a Warning Letter to Boehringer Ingelheim for cGMP violations for the manufacture of APIs and finished pharmaceuticals at its facility in Ingelheim am Rhein, Germany. The letter, issued on May 6, 2013, was based on an inspection of the facility Nov. 5–12, 2012 and subsequent response by the company based on that inspection in which FDA cited insufficient corrective actions.

Specifically, FDA said that the company’s quality unit failed to investigate critical deviations in the manufacturing of APIs by not thoroughly investigating the source of foreign particles in an API and by not implementing timely and appropriate corrective and preventive actions (CAPA). FDA said that lots contaminated with foreign particles were manufactured in 2008 and 2009, but that Boehringer Ingelheim did not begin a formal project to implement comprehensive corrections to mitigate the presence of foreign particles until July 2012. FDA also said contaminated lots of the API were used to produce capsules and that the company failed to conduct thorough complaint investigations regarding the presence of foreign particles found in its APIs.

FDA has requested that the company provide a list of API batches produced after the implementation of the July 2012 CAPA and to indicate whether foreign particles have been observed. FDA also requested that the company inform the agency of appropriate corrective actions taken by its quality unit to prevent foreign-particle contamination in its APIs.

On the finished product side, FDA said the company failed to reject drug products that did not meet established standards or specifications by not rejecting multiple batches of capsules that were contaminated with foreign particles. The letter said that during 2010 and 2012, several lots containing a given API were contaminated with extrinsic foreign particles that were found during weighing or by visual inspection and were used for finished-drug manufacturing. The size and weight of the particles ranged from approximately 200 microns to approximately 5 mm, from 0.4 micrograms to approximately 9 mg, respectively. The agency said that it disagreed with the company’s decision to use the API because the contaminated batches met the final specifications and noted that use of appropriate manufacturing, controls, quality standards, and systems for investigations of atypical events (e.g., contamination) are all essential parts of a robust quality system.


Lastly, FDA cited the firm for failing to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet specifications, whether or not the batch had already been distributed. FDA said that the company failed to determine the cause of out-of-specification (OOS) results for a lot of Spiriva HandiHaler, which failed the uniformity of a delivered-dose test specification for a nine-month stability test and 12-month stability interval. “It was only after the 12-month OOS result that your firm decided to initiate a product recall for this Spiriva lot,” said FDA in its letter. “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 has requested that the company inform the agency of its action to prevent recurrence as well as provide a retrospective evaluation of all lots currently in the stability program and assess whether an OOS was obtained at any testing interval.

In a statement, Gerhard Koeller, head of corporate division quality at Boehringer Ingelheim, said: “Boehringer Ingelheim is taking this issue very seriously and is fully committed to working with the FDA on a comprehensive action plan that addresses the FDA’s concerns, ensuring that it implements corrective and preventive actions to optimize its quality systems.”