DPT Lakewood, LLC was inspected between February 15 through March 7, 2012. During this audit the FDA found that Santyl Ointment to be adulterated and that the methods used in, or the facilities or controls used for, the manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with, cGMP.
Specific violations observed during the inspection include the following:
Failure to thoroughly investigate a batch or any of its components to meet specifications (21 CFR 211.192).
Investigations into the failure of several lots was attributed to a contract laboratory. As part of the corrective action, DPT ceased using the contract laboratory and started conducting the sterility testing in house. Lots continued to fail sterility testing. The continued sterility failures of these products question the conclusion that the contract laboratory was at fault.
It is not unusual for a company to assume that sterility failures arise from contract testing laboratories. However, often companies commence sterility and other testing without performing any Suitability of the Method testing to assure that no inhibition or enhancement is occurring. Likewise, testing laboratories should be inspected to assure that the technicians are following sterility protocols and have performed “mock” sterility testing to assure that their technique is satisfactory. The environmental aspects of the lab should be reviewed as well as frequency of cleaning and disinfection. Technician gowning must also be reviewed. Again, all of this should be completed prior to, not after sterility testing of the company’s products commence.
“The investigation into the failure of the media fill conducted in June 2011 was inadequate. A Bacillus species was identified in the samples incubated for the media fill. The failure was attributed to inadequate aseptic technique by an operator based on the video recording of the media fill operation. However, the Bacillus species identified is a ubiquitous environmental organism that could have been introduced into the aseptic area via multiples sources. Nevertheless, you failed to consider other sources of contamination in your investigation. Subsequently, your quality unit released (b)(4) lots of Santyl Ointment manufactured between the last successful media fill in February 2011 and the failed media fill in June 2011 based on the review of the video recording of the manufacturing operations even though the review notes included deviations from procedures for many lots (e.g., (b)(4) were present in areas designated for (b)(b4) as the maximum allowable limit).”
Bacillus sp. is a very commonly found environmental isolate. As noted within the FDA’s comments, it could have entered through a number of other sources aside from an operator. Accugenix has kindly provided a list of the most commonly isolated bacteria (Search “Accugenix” within this Blog site) which includes many Bacillus sp. as well as Staphylococcus sp. I would expect a Staphylococcus issue from an operator, rather than a Bacillus.
“You stated in your response, that you will reevaluate the entire cleaning and disinfection program for the Santyl Ointment manufacturing areas and re-train operators. (b)(4) Re-training operators and conducting media fill runs have been your standard corrective actions following the sterility failures that were obtained from lots manufactured in December 2010 and May 2011. However, these actions have been insufficient to control the microbial contamination in your facility and to prevent recurrence. Following the May 2011 sterility failures and then the failed media fill conducted in June 2011, you committed to completing three successful media fills prior to resumption of manufacturing. However, these three simulations did not appear to provide adequate assurance that effective corrective actions were implemented, as evidenced by additional sterility failures in January 2012.”
Re-training of operators has often been the mantra when a sterility failure occurs within an aseptic operation. The FDA has seen so many re-training corrective actions subsequently fail that they have developed an “I’m from Missouri, Show me”. Also, based on a requirement for an incubation time of fourteen days, it is quite desirable if one is encountering aseptic filling difficulties, they should wait the full fourteen days prior to commencing another fill to assure that the fills are not contaminated.
Please visit the entire Warning Letter at: http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2012/ucm317364.htm