COMPANY CONTINUED TO FIND GRAM NEGATIVES IN PW WATER SYSTEM
ID Biomedical Corp, a subsidiary of GSK Biologicals, located in Quebec, Canada was audited by the FDA from March 31 through April 9, 2014. The FDA Investigators documented deviations from CGMP in the manufacture of their biological drug product, Flulaval and its intermediates. Significant objectionable conditions included:
- You failed to assure that appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile, are established and followed. Such procedures include validation of all aseptic and sterilization processes [21 CFR 211.113(b)]. Specifically, deviation #200217121 was initiated March 5, 2012 to investigate out of trend (OOT) results for endotoxin. The average endotoxin in the first 20 seasonal (b)(4) monovalent lots for 2012 was higher than the first 20 in 2010, and 2011. The investigation concluded that the endotoxin results have been atypical since May 2011.
COMMENT:
What is interesting within this particular citation is that the FDA indicated that the endotoxin results were OOT, not necessarily failing – but definitely atypical and should have been corrected, not an on-going issue. However when one views the next Observation, one recognizes that the Purified Water (PW) systems have had on-going issues for several years, and that the Client has not been able to satisfactorily cleanse the system and maintain it in an acceptable state. With the variety of Gram negative bacteria that were encountered, it may be somewhat surprising that the Client only had OOT and not OOS results.
- Controls for the purified water system at your facility are inadequate to prevent bioburden and endotoxin excursions.
- The 2012 Annual Product Quality Review report for water indicates that there were many bioburden excursions in purified water system (b)(4)(Loop (b)(4). Water from Loop (b)(4) is used in part to humidify air in (b)(4). Different types of bacteria were found, but in the majority of cases, the microorganisms found were Ralstonia picketti and Achromobacter spp.
- The 2013 Annual Product Quality Review report for water concludes that four alert limits and one action limit were reached for water system (b)(4) (Loop (b)(4). Water from Loop (b)(4) is used in part for equipment washing. Organisms isolated from these five excursions included Ralstonia picketti and Achromobacter xylosoxidans. Achromobacter xylosoxidans and other water borne gram negative bacteria have been implicated in product contamination issues at you facility as far back as 2011.
- There is not set schedule for disinfection of your water system. The system is only disinfected on (b)(4). The system was disinfected twice in 2011, five times in 2012, four times in 2013 and once in 2014 to date. In addition the water system is circulated (b)(4) temperature and is cleaned with (b)(4). No (b)(4) is used in the system.
COMMENT:
During 2012, 2013 and 2014 (to audit date), a number of bioburden and endotoxin excursions occurred. The bacteria found were those Gram negatives that are typically found in Purified Water (PW) Systems that are not maintained in a controlled state. Please note that while the specification for PW is 100 CFU/mL, when one finds a predominate number of a few species, and those species can be classified as “in-house” Gram negative isolates, it suggests that the PW system is not in control.
When PW is used for equipment washing, and the PW is contaminated, there is a high probability that the final product produced will have a high likelihood of being contaminated as well. Ideally, any equipment that will have contact with the final product should not be washed, and never rinsed, with anything other than Water for Injection (WFI).
Within the Warning Letter, it was also observed that the PW system was only disinfected twice (2011), five times (2012), four times (2013) and once (to date, 2014). It also appears that the FDA had an issue with the temperature maintained and what was used for cleaning. However, this information was redacted.
The FDA suggested that the SOPs governing disinfection of the water system was “weak” and that the SOPs should either suggest a schedule or provide guidance based upon testing. The author’s experience with both PW and WFI systems suggests that it is not difficult to control the bacterial count through the use of temperature control – either with continuous or intermittent heating.
Because the severity of these Observations, the Warning Letter requests that ID Biomedical and GSK arrange to have meetings with the FDA to discuss the issues cited as well as encourage frequent interaction between the Client and technical staff with FDA to move forward as rapidly as possible. ID Biomedical also has provided commitments of corrective and preventive actions. However, it appears that the FDA questions their abilities based upon their lackluster history.
Interestingly, the FDA has not placed any of their “boilerplate” verbiage re: Drug Shortages within the Warning Letter. Does this suggest that sufficient other manufacturing resources exist for this biological?
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