FDA issued a Warning Letter to Baxter Healthcare on May 31, 2013 for cGMP violations for finished pharmaceuticals based on inspections that occurred Nov. 7 to Nov. 16, 2012, and Mar. 13, to Apr. 19, 2013 at the company’s manufacturing facilities in Marion, North Carolina and Jayuya, Puerto Rico.
At the Marion facility, FDA noted that in a fill line, numerous high-efficiency particulate air (HEPA) filters, HEPA filters supporting grid work, HEPA 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. Although the company ceased production on large-volume parenteral lines, suspended release of product, and did not resume production until remediation and qualification activities were completed, FDA said the response was “inadequate” because the company did not indicate how long the objectionable conditions persisted prior to intervention or the root causes. FDA also noted that the problem was a repeat observation dating back to August 2012 and that stains and possible mold on HEPA filters also dated back to July 2010. Although the company established acceptance criteria for critical attributes, such as discoloration, stains, and particulates associated with the visual inspection of HEPA filters, FDA indicated that response was not adequate because it did not contain a risk assessment of the products manufactured.
FDA also cited the firm for its sampling plans used for environmental monitoring in areas that manufacture terminally sterilized injectables. “Your environmental monitoring program was insufficient to detect contamination of concern, including mold observed on the clean side of the air filters supplying air to the sterile filling areas,” said FDA in the letter. In its response, Baxter noted that it uses formal risk assessment to justify the type, extent, frequency, and location of sampling and test procedures and created a procedure for periodic reassessment of that risk assessment to incorporate any relevant new or emerging information and continues to conduct bioburden testing.
Although FDA acknowledged the company's use of formal risk assessments in implementing revised environmental monitoring procedures and bioburden testing, FDA said the company “downplayed the product quality and safety impacts posed by the mold observed on the clean side of HEPA filters supplying air to sterile filling areas on the grounds that products made in these areas are terminally sterilized.” The products covered during the inspection of the Marion facility were made using a parametric release approach instead of sterility testing, which is permissible under FDA regulations. FDA acknowledged that the firm has been performing sterility testing on its terminally sterilized products since December 2012 as part of a corrective action plan. The agency is asking Baxter to evaluate all its terminal sterilization operations to verify that the overall operation of its sterility assurance program meets cGMP and drug application requirements, including, but not limited to, application commitments pertaining to the use of parametric release. FDA asked the company to update all of its drug applications containing parametric release provisions to incorporate the company’s newly enhanced environmental monitoring program as application commitments. FDA said it will evaluate the adequacy of the environmental control and monitoring program in a future inspection.
At the company’s Jayuya facility, FDA noted a nonconformance investigation report addressing a bag leak detected during routine microbiology testing. The root cause for bag leaking was weak membrane defects within the port component of the bag. FDA acknowledged that the company, upon identification of the defect, placed portions of the impacted lots on hold, developed sampling/inspection protocols to evaluate the impact of the bag-closure system defect on the referenced lots, and discarded portions of stock. FDA disagreed, however, with the company’s medical risk assessment that product sterility was not compromised by the defective closure on the grounds that the closure assembly was sealed off from the environment by a blue cap. FDA said that the evaluation of the membrane defect should have considered all common failure modes associated with container and closure integrity, including the loss of the blue cap. FDA is asking the company to describe how it will be correcting the root causes of these defects, including describing any remediation plans to improve manufacturing robustness. FDA also noted that although the company submitted a NDA Field Alert Report (FAR) report on the membrane-leak defect investigation initially, it did not submit additional FARs when additional lots were identified.
Lastly, FDA noted that at a recent FDA inspection at another undisclosed Baxter facility “a pattern of inadequate corrections and interventions concerning sterile facility sanitization” was observed. “While the response to that location's deficiencies appears adequate, we expect appropriate correction at all Baxter facilities in this critical area,” said FDA.