TOTAL MANAGEMENT COLLAPSE OF TERMINAL STERILIZATION OCCURS AT THE MARION, NC FACILITY BASED UPON FDA FINDINGS
The FDA recently audited two Baxter Healthcare facilities to include Marion, NC (November 7 to 16,2012) , and Jayuya, Puerto Rico (March 13, 2013 to April 19, 2013). Their Investigators identified significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals.
Observations at the North Carolina facility included the following:
1. Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements (21 CFR 211.67(a)).
For example, FDA inspection of Fill Line (b)(4) on November 14,2012, revealed that numerous HEPAÂ filters, HEPAÂ filter supporting grid work, HEPAÂ filter screens, and HEPA filter screen tracks contained varying amounts of discolored areas, chipping paint, multicolored coalescing droplets, and clumps of dark material that FDA testing later revealed was mold.
In your response, you state that you ceased production on large volume parenteral (LVP) Fill Line (b)(4) on November 14, 2012, and LVP Fill Line (b)(4), on November 17, 2012. You state further that you suspended release of product “prior to those dates,” and did not resume production until remediation and qualification activities were completed. However, your response is inadequate because you have not yet indicated how long the objectionable conditions described above persisted prior to intervention, nor have you identified the root causes that allowed these conditions to go uncorrected. We are especially concerned that you have not identified the root cause that allowed the mold to proliferate to a level of TNTC (Too Numerous to Count) in several environmental samples directly over your filling line. Without identifying, correcting, and preventing the root cause of the mold growth at your sterile fill lines, the contamination hazard to the products manufactured on those lines could continue and potentially pose risk to patients.
This is a repeat observation from the August 2012 inspection at the Marion, North Carolina facility.
COMMENT:
If the above Observation is correct, and it appears that it is because the FDA indicate this is a repeat Observation from August 2012, it’s amazing that Plant Management did not recognize their problem and didn’t take any action until the Investigators were on site. As the Warning Letter stated ” FDA inspection of Fill Line (b)(4) on November 14,2012, revealed that numerous HEPAÂ filters, HEPAÂ filter supporting grid work, HEPAÂ filter screens, and HEPA filter screen tracks contained varying amounts of discolored areas, chipping paint, multicolored coalescing droplets, and clumps of dark material that FDA testing later revealed was mold” (Underlines represent author’s emphasis).
Even though the facility indicated that they had suspended release “prior to the dates”, the FDA was still quite concerned because “you have not identified the root cause that allowed the mold to proliferate to a level of TNTC (Too Numerous to Count) in several environmental samples directly over your filling line. Without identifying, correcting, and preventing the root cause of the mold growth at your sterile fill lines, the contamination hazard to the products manufactured on those lines could continue and potentially pose risk to patients.”
2. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).
For example, the inspection revealed that your maintenance personnel had documented evidence of visible discoloration and stains and “possible mold” on the “clean” side of the HEPAÂ filters supplying air to LVP Lines (b)(4) at least as far back as July 6, 2010. You did not properly investigate and remediate this condition. No samples of the discoloration or stains were tested at the time to determine if mold was in fact present.
In your response, you state you will establish acceptance criteria for critical attributes, such as discoloration, stains, and particulates associated with the visual inspection of the HEPA filters. Your “acceptance criteria will include the requirement that any evidence of contamination (product, water or cleaning agents) or microbial growth will be investigated, the investigation documented, and the filter at issue will be replaced.” The procedure regarding (b)(4) inspections of ceilings, walls, and floors (on all fill lines) will be updated to include the newly established acceptance criteria. These acceptance criteria will also be included in (b)(4) inspections of the HEPA filters (on all fill lines). These inspections will include representation from the Quality organization and any potential quality-related issue identified will be escalated into the environmental deviations process. However, your response is inadequate because you did not perform a risk assessment of all the products that were manufactured since July 6, 2010 and that are within expiration in the market.
This is a repeat observation from the August 2012 inspection at the Marion, North Carolina facility.
COMMENT:
Observation 2 is also a repeat Observation from the August 2012 inspection. It appears that the Maintenance personnel were operating in a “silo” and not telling anyone else about the problems they had noticed. It is difficult to believe that neither the production nor the Quality Control personnel that were involved in these ISO Class 5 rooms on a day to day basis did not speak to the Maintenance personnel nor observe what was occurring within the HEPA filter units since they must be periodically evaluated. Perhaps it was because the products were subsequently terminally sterilized? It appears that they was a total breakdown of Management communication.
Further, the FDA noted that the facilities’ response was “inadequate because you did not perform a risk assessment of all the products that were manufactured since July 6, 2010 and that are within expiration in the market.” Any time one encounters potentially contaminated product that may have entered distribution channels, it is essential to determine the possibility of compromised product being used by the patient.
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