GlaxoSmithKline Receives a Warning Letter from FDA for cGMP Violations

GlaxoSmithKline was issued a Warning Letter, dated March 18, 2014, from FDA based on an inspection made October 18-23, 2013, at the company’s pharmaceutical manufacturing facility in Currabinny, Carrigaline, Cork, Ireland, for deviations from current good manufacturing practice (cGMP) for the manufacture of active pharmaceutical ingredients (APIs). The agency noted that its review of the company’s response to these deviations lacked sufficient corrective actions.

The firm was cited for failure to investigate critical deviations. FDA said batches were contaminated with material from the company’s pharmaceutical waste tank, which contained APIs, intermediates, and solvents. FDA said the company became aware of this contamination in January 2012 and completed risk assessments to determine the impact on the quality of material manufactured using the contaminated solvents on April 19, 2013. According to FDA, the firm distributed shipments of potentially contaminated  batches after becoming aware of the deviation. FDA noted that quality impact assessments were made, but the approach taken in those quality assessments were different.

FDA raised concerns that the company chose not to “escalate” the deviation by notifying its customers. “We are concerned that your firm does not consider the entry of pharmaceutical waste streams into your manufacturing process a significant deviation with a potential quality impact,” said FDA. “In your response to the Form FDA-483, you acknowledged that you should have informed your customers of this incident; however, you did not describe any recent or future communication with your customers regarding the incident to rectify the prior lapse.”

FDA has asked the company  to describe why the quality assessments appear to assume uniform distribution of contaminants to the waste stream and before the backflow of contaminants into the tank. It has asked for a revised quality assessment that describes all calculations used to support conclusions and to describe any altered conclusions. For each analytical method used to support  conclusions, the agency has asked the company to provide method qualification information, including the limit of detection for each potential contaminant. The agency is also asking for a quality impact assessment for around the time of the initial contamination in the tank. The agency also asked for any contact the firm had with customers of the potentially affected products and its plans with respect to the disposition of any potentially affected batches that remain within expiry. 


FDA also cited the company for failure to investigate and document out-of-specification results, noting that testing revealed small but detectable levels of at least ten other contaminants and that these unexpected chromatographic peaks should have indicated that the 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,” said FDA.  “As a result, your firm did not notice the tank contamination until a third sample from the tank was tested in January 2012.” 

The firm also was cited for failure to demonstrate that its manufacturing process could reproducibly manufacture an API that met its predetermined quality attributes based on concerns that process performance qualification (PPQ) studies and related process validation protocol involved equipment suitability deficiencies. The agency has asked the company to provide justification for the selection of non-consecutive batches during the execution of its validation protocol, to describe any revisions to the company’s validation standard operating procedures to clarify under what specific circumstances “re-nomination” of PPQ batches would be considered acceptable, and to provide any additional evidence of the company’s ability to reproducibly manufacture  said product  while meeting all critical quality attributes. 

The company has 15 working days of receipt of the Warning to Letter to notify the agency in writing of the specific steps that it has taken to correct and prevent the recurrence of deviations and to provide copies of supporting documentation. 

Source: FDA
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