The US Food and Drug Administration (FDA) has revealed evidence linking the heparin contaminant with the series of reported adverse reactions, and has also now issued a warning letter to the Chinese facility at the centre of the safety scare after completing its inspection.
In a media briefing, director of the FDA's CDER Janet Woodcock said that the agency has both in vitro and animal data displaying a "solid mechanistic link" between the contaminant found in various lots of heparin that originated in China, and the series of serious adverse events and deaths that have been reported after patients were administered the contaminated product.
This data confirms that the contaminant, which was earlier identified as over-sulfated chondroitin sulfate, can cause events that would lead to adverse reactions in patients given the drug.
However, Woodcock did point out that although identifying the mechanism by which the contaminant could cause the reactions strengthens the association considerably, not every patient who received the contaminated product was adversely affected.
"The adverse reactions appear to be related to the method of administration and the dose size," Woodcock explained.
France, Italy, and Denmark, the US, Germany, Switzerland and Japan are among the countries to recall heparin products after a heparin contamination scare over product materials linked to China.
Baxter's heparin was the first to be found to contain the contaminant in February after the FDA received hundreds of reports of serious injuries and/or deaths in patients who had been administered heparin made by the company. Baxter subsequently pulled its product from the market while an investigation ensued.
Meanwhile, this week the agency issued a warning letter to the Chinese firm that supplied the heparin active pharmaceutical ingredient (API) to Baxter along with some other companies - Changzhou SPL, a subsidiary of US firm Scientific Protein Laboratories (SPL) - after an inspection of its facility revealed "significant deviations" from current good manufacturing practice (GMP).
"The inspectional observations and the concerns identified indicate significant deficiencies in your overall quality system… These deviations caused the API to be adulterated," wrote the FDA, who went on to highlight four specific areas of major concern.
Firstly, the agency inspection concluded that there is "no assurance" that processing steps Changzhou used to manufacture heparin sodium, USP are capable of effectively removing impurities.
Secondly, the FDA said that the firm "fails to have adequate systems" for evaluating the suppliers of heparin crude materials, and the crude materials themselves, to ensure that these materials are acceptable for use.
In addition, the test methods performed by Changzhou for heparin sodium USP "have not been verified to ensure suitability" under actual conditions of use, the FDA wrote.
Moreover, the equipment used to manufacture heparin sodium USP "is unsuitable for its intended use", the agency said.
Changzhou was told by the FDA to respond to the agency in writing with a corrective action plan.
In response to the warning letter, Changzhou has stated that it "does not reflect its actual state of compliance with GMP" and insisted that it is cooperating with the FDA on the matter and will soon provide a comprehensive response to the letter as instructed.
In the meantime, shipments to the US of products manufactured by Changzhou are currently being refused admission into the country because "the methods and controls used in their manufacture do not appear to conform to cGMP," the FDA said.
"If you wish to ship your products to the US, it is the responsibility of your firm to
assure compliance with all US standards for cGMP," the agency told Changzhou.
"Until all corrections have been completed and the FDA can confirm compliance
with CGMP, this office will continue to recommend disapproval of any new applications or supplements listing your firm as the manufacturer of APIs."