Alexion’s response to the Form 483 from August 2012 preceded an FDA warning letter from late March, which the company responded to in April, Irving Adler, a spokesman for Alexion told In-Pharmatechnologist.com.
Adler also noted there has not been any interruption of supply at the company’s Rhode-Island facility where the warning letter was issued. One other CMO in New Hampshire has been approved to supply the company’s rare blood and kidney disorder drug Soliris (eculizumab), while another CMO is expected to be fully approved in the fourth quarter of this year, Adler said. If the product is approved, in addition to the second CMO, the amount Soliris the company will have on hand will almost double, Adler said.
Despite Alexion’s ability to keep the warning letter and violations under control, an opportunity to dig deeper into the original Form 483 and Alexion’s response is a rarity when the vast majority of FDA inspections, notifications of violations and company responses are kept under wraps.
In addition, the company noted in an 8-K filing with the SEC from March that the warning letter “may impact our ability to supply Soliris manufactured at our Rhode Island facility outside the United States.”
Details of the Violations
The Form 483 and warning letter said the FDA’s inspectors found the bacterium Bacillus thuringiensis and the microorganism Acinetobacter adioresislens in lots of APIs developed for the production of. The agency also found residues of the contaminants in the Smithfield, Rhode Island-based manufacturing facility.
However, in its response to the FDA, Alexion said that neither the bacterium nor the microorganism “are considered common human pathogens.”
The company added that “the risk assessments also demonstrated that the Iikelihood of foreign proteins or low molecular weight molecules reported to be produced by Bacillus thuringiensis or Acinetobacter radioresistens being co-purified with eculizumab is low.”
Due to the FDA’s expectations when in-process bioburden action limits are exceeded, Alexion noted that “the corresponding risk assessment should quantify the potential impurities generated,” and that it “will assess analytical methodologies and procedures to ensure expectations for risk assessments are met.”
In addition, the FDA’s Form 483 said that inspectors found contaminations in five of the company’s bioreactors at the site. And although Alexion believes three of the contaminations were due to “faulty high-high limit switches,” another root cause for the contamination events was not ruled out.
The two SOPs (standard operating procedures) related to Alexion’s control of contaminants in its bioreactors were investigated, according to the company’s response. “Removal of the limit switches prevented contamination reoccurrence as consecutive production bioreactor runs were successful after removal,” the company said.
But for the more recently discovered bioreactor contaminations, which do not seem to be related to the faulty switches, the company has contacted consulting firms to support its investigation. It also suspended production in the bioreactors “to support completion of investigational and corrective actions. Initial findings suggest ineffective routine [clean in place processes] of non-routine soils contributed to ineffective [sterilization-in-place].”
Alexion further evaluated its existing decontamination to assess how adequately it can mitigate “heavy bioreactor soiling as a result of the contamination events.”