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Regulatory Focus™ > News Articles > FDA Warning Letter Hits GSK for Contaminated API, Reproducibility Challenges

FDA Warning Letter Hits GSK for Contaminated API, Reproducibility Challenges

Posted 01 April 2014 | By Alexander Gaffney, RAC

A new Warning Letter sent to GlaxoSmithKline CEO Andrew Witty chides the company for alleged manufacturing deficiencies found by US Food and Drug Administration (FDA) inspectors at the company's manufacturing subsidiary in Cork, Ireland.

That subsidiary, SmithKline Beecham (Cork) Ltd., is a manufacturer of active pharmaceutical ingredients (API) for GSK. During an October 2013 inspection, FDA said its inspectors found at least three major problems that caused the facility to run afoul of current good manufacturing practices.

For example, inspectors said they found that SmithKline had failed to "fully investigate" critical deviations within its manufacturing processes. In one noted instance, FDA said the company had discovered that one of its manufacturing processes had been contaminated with material from a pharmaceutical waste tank containing APIs, intermediates and solvents. While the company conducted a risk assessment, it ultimately distributed the products anyway.

In its letter, FDA said GSK should have conducted additional testing instead of relying solely on one approach, and that according to its own standard operating procedures, it should have notified the recipient of its APIs-an action that did not occur.

In another example cited by FDA, GSK was alleged to have improperly investigated out-of-specification results. Between September and October 2011, FDA said testing of a tank found contamination of one major component, as well as "small but detectable levels of at least ten other contaminants."

Said FDA: "These unexpected peaks should have indicated to your firm that the [redacted] tank had been contaminated with pharmaceutical waste ... Instead, your laboratory personnel ignored these unexpected peaks and conducted no investigation into what gave rise to them. As a result, your firm did not notice the [redacted] tank contamination until a third sample from the tank was tested in January 2012."

Reproducibility Challenges

A third problem also caught the eye of FDA inspectors: reproducibility.

GSK's protocols call for at least three consecutive pre-nominated batches to demonstrate initial process validation. However, initial testing failed to deliver reproducible results, according to records seen by FDA. As a result, GSK then brought in new manufacturing equipment, and ultimately three additional batches (for a total of six). However, the company's fifth batch also experienced problems. Based on the adequate results of the third, fourth and sixth tests, however, the company reportedly considered the parameters of its reproducibility protocol to have been met.

FDA, though, wasn't convinced. "The process performance qualification studies described above suggest that your equipment has not been sufficiently demonstrated to reliably perform its intended function," FDA wrote.

FDA also said that until all corrections have been made to SmithKline Beecham's facility, FDA may withhold approval from any new applications or supplements listing the company as an API supplier, and might also refuse entry for any articles manufactured at the facility.

FDA Warning Letter to GSK

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