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Weekly UpdatesApril 14--CDER
Appropriate systems and procedures were not in place at Qingdao Jiulong Biopharmaceuticals, according to FDA investigator Carl Lee and Compliance Officer Zi-Qiang Gu, Ph.D., who inspected the facility July 28-Aug. 1.
Significant deviations from drug GMPs were cited and the firm's quality unit failed to provide confidence that the drugs manufactured at the facility met the intended specifications for identity, strength, quality and purity.
In April 2008, FDA learned that 19 lots of heparin sodium were contaminated with Over-Sulfated Chondroitin Sulfate (OSCS), and these lots were later determined to have been manufactured at the Qingdao facility.
"Although this heparin sodium did not ultimately reach U.S. patients, your firm has not demonstrated that it has conducted an investigation of these contaminated lots, identified the source of this contamination, and taken appropriate corrective actions to ensure the quality of heparin sodium produced at this site," FDA's warning letter stated.
"There is no assurance that your quality unit has systems in place to prevent manufacture and distribution of heparin sodium that has been contaminated with OSCS or other hazardous contaminants. We are concerned that your firm lacked adequate systems to ensure the safety of raw materials used in your manufacturing, particularly to prevent the substitution of an unsafe substance (OSCS) in place of heparin sodium. It is essential that strict controls over your suppliers be established to prevent any such supply chain breach."
FDA also said the firm also failed to ensure that manufacturing and testing procedures apparently transferred to its facility provided for acceptable drug identity, strength, quality, and purity. During the inspection, FDA's investigators learned that the company's current manufacturing process for Heparin Sodium USP was apparently transferred in 2005 from Qingdao Kangyuan, "which you assert is a related business entity, to your site," the letter continued. "However, no information regarding the procedures, protocols and reports related to this technology transfer were available for review."
FDA also cited Qingdao for its failure to conduct and document regular product quality reviews for the drugs produced that would include, at a minimum, a review of critical in-process controls and test results; review of all batches that failed to meet the established specifications; and investigation of process deviations and complaints to ensure product remains within specifications and that corrective actions have been implemented.
In a letter to FDA sent in response, the company acknowledged the agency's concerns and committed to performing annual product reviews. "However," FDA said, "during the inspection, the investigators noted that your annual internal reviews involved only completing a check box document. This product quality review is inadequate in that it lacks adequate content or information, such as explanation of all deviations from established procedures and outcome of investigations of critical deviations."
Although in its response of Nov. 7, 2008, the company included a new SOP specifying that QA would perform annual quality reviews on all products manufactured, distributed and marketed, FDA deemed the corrective action inadequate. "We are concerned that you have only committed to conduct an 'annual product review for product lots produced during 2008.' As you are aware, 19 lots of heparin sodium manufactured at your facility during 2007 and shipped to the U.S. were found contaminated with OSCS."
FDA requested a copy of complete product quality review reports covering the manufacturing of heparin sodium for all lots that remain within expiration.
The firm failed to investigate specific discrepancies related to the lots of impure drugs supplied to its customers, the agency wrote. "We learned that heparin sodium lots manufactured at your facility were determined to be contaminated with OSCS. From our investigation, it appears that your customer requested that your firm investigate the OSCS contamination. Although the contamination of these lots was discussed during the inspection, you apparently had not initiated an investigation to determine the root cause of the contamination, identified whether other lots were implicated, or taken appropriate corrective actions to prevent recurrence of this contamination."
The firm's failure to investigate these significant customer complaints "is a serious deviation from GMP," FDA asserted.
Further, "No information was provided to assure that any of your firm's internal practices or upstream sources (e.g., suppliers) that may have been involved in the contamination of the 19 lots produced has been identified and removed from your supply chain," the letter continued. "Please include in your written response to this letter a copy of all investigations regarding OSCS that may have been conducted after the inspection, the root cause of the contamination, and the corrective actions implemented to prevent recurrence. Also include the list of the crude and other upstream suppliers for all of the contaminated lots."
The investigators were informed during the inspection that all lots of heparin sodium produced at the Qingdao facility would be tested using the CE and NMR methods beginning in September 2008. FDA asked the firm to provide notification that it had begun to test the heparin sodium using these methods or if these analyses were being outsourced, and when this testing commenced.
During the inspection, the investigators were informed that the firm did not distribute heparin sodium directly to the U.S. and that the product manufactured was shipped to Shanghai. During an inspection conducted at a U.S. facility, FDA found purchase orders and information indicating that since 2005, heparin sodium manufactured at Qingdao was being shipped into the U.S.
FDA added: "Please clarify whether you shipped drugs directly to the U.S. and provide a list of all lots of heparin sodium (intended for experimental or commercial use) shipped to the U.S. since your firm started to manufacture heparin sodium. Please also identify whether you shipped drugs that you understood were ordered by or ultimately destined for the U.S., even if you did not ship them directly to the U.S. yourself."
In light of the deficiencies found during the inspection and the fact that the company's predecessor, Qingdao Kangyuan, was never inspected by FDA, "we expect you to address the reliability of any information generated regarding the manufacture, processing, testing, packaging, and labeling of heparin sodium shipped to the U.S. and used to support your DMF 22222," FDA added. The agency suggested that the company employ a "third party auditor to conduct a validity assessment of the information you have provided or intend to provide to support your DMF regarding the production of heparin sodium. Conducting such an audit could expedite the process of re-qualifying your facility." QC/QS
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