FIRM FAILS TO SUFFICIENTLY INVESTIGATE PHARMACEUTICAL WASTE CONTAMINATION EVENT
During an FDA investigation of SKB in Cork, Ireland, the FDA encountered an unusual situation where the pharmaceutical waste tank was found to have contaminated various other tankage used to manufacture APIs. Part of the rationale provided by SKB was that no reason existed to suspect contamination and, therefore, the analyst did not look for any. Please read through the entire Blog to learn more about this unusual Warning Letter. It certainly should be shared with your Quality Control personnel.
During an October 18-23, 2013 inspection of a SKB pharmaceutical manufacturing facility, SmithKline Beecham (Cork) Ltd., located at Currabinny, Carrigaline, Cork, Ireland, investigator(s) from the U.S. Food and Drug Administration (FDA) identified deviations from current good manufacturing practice (CGMP) for the manufacture of active pharmaceutical ingredients (APIs).
The firm discovered that the (b)(4) used to manufacture (b)(4) batches of (b)(4) and (b)(4) batches of (b)(4) was contaminated with material from their pharmaceutical waste tank, which contained APIs, intermediates, and solvents…..Your firm became aware of this contamination in January 2012 and completed risk assessments to determine the impact on the quality of (b)(4) manufactured using the contaminated solvents on April 19, 2013. Your firm distributed (b)(4) shipments of (b)(4) potentially contaminated (b)(4) batches after becoming aware of this significant deviation. In contrast, (b)(4) batches made with the contaminated (b)(4) were rejected.
Quality impact assessments were made for both (b)(4) and (b)(4), but was noted that the approach taken in the two assessments was different. For instance, the (b)(4) assessment noted that the standard release testing did not detect significant quantities of contaminants in the potentially impacted (b)(4) batches, but that additional testing on (b)(4) from (b)(4) showed the impacted batches were exposed to significant amounts of (b)(4). The assessment states that the sample preparation used in the (b)(4) sample release testing appears to be incapable of complete extraction of the potential contaminants, and it therefore relied on results obtained from the additional testing from the (b)(4) of (b)(4) product to demonstrate that the (b)(4) batches were impacted by the pharmaceutical waste contamination event.
Your firm’s SOP regarding communication of significant deviations states that your firm must communicate to the receiving site information concerning deviations having a potential quality impact on the product. During the inspection, your personnel informed the investigator that your firm determined that there was no potential to impact the quality of the affected products manufactured with (b)(4) and chose not to “escalate” the deviation by notifying your customers.
In your response to this letter, please address the concerns outlined above. Please also describe why the quality assessments appear to assume uniform distribution of contaminants following addition of (b)(4) to the waste stream and before the backflow of contaminants into the (b)(4) tank. Provide a revised quality assessment for (b)(4) that clearly describes all calculations used to support the conclusions, and clearly describe any altered conclusions after addressing the issues described in this letter. For each analytical method used to support your conclusions, provide method qualification information, including the limit of detection for each potential contaminant. Also, provide a quality impact assessment for your (b)(4) product, which was also manufactured using (b)(4) around the time of the initial contamination in the (b)(4) tank. Describe any contact you have had with the customers of the potentially affected products and your plans with respect to the disposition of any potentially affected batches that remain within expiry.
In addition, your firm tested solvent from the (b)(4) tank in September 2011 and October 2011 to look for potential (b)(4) contamination via a gas chromatographic method. The chromatograms from both samples show large peaks for (b)(4) as well as small but detectable levels of at least ten other contaminants. These unexpected peaks should have indicated to your firm that the (b)(4) tank had been contaminated with pharmaceutical waste, as described above. 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 (b)(4) tank contamination until a third sample from the tank was tested in January 2012.
In your response to the Form FDA-483, you stated that there was no reason to expect (b)(4) contamination and therefore the analyst did not notice the (b)(4) peak. Your response does not address why the analyst did not notice the numerous other detected contaminants in the chromatogram, nor did it address why a second reviewer did not notice the unexpected peaks in the chromatograms.