The import of heparin API from China is a prime example of the challenges pharmaceutical globalization creates. Baxter's supplier
of heparin, Scientific Protein Laboratories (SPL, Waunakee, WI), is an established API producer and contract manufacturer
of drugs and biologics. Until four years ago, SPL's Changzhou SPL facility near Shanghai supplied its parent company with
crude heparin. This activity did not require FDA inspection. In 2004, SPL expanded Changzhou's operations to produce heparin
sodium, which required Baxter to file a manufacturing supplement with FDA to add the Chinese plant as an alternate API supplier.
FDA should have inspected the Changzhou facility in 2004, but did not because of an error in identifying the facility. When
a new drug application (NDA), abbreviated application for a generic drug or manufacturing supplement adds a new production
site, FDA reviews the inspection records and history for the manufacturing sites listed, explained Joseph Famulare, deputy
director of CDER's Office of Compliance (OC). If a site has been inspected recently and is in compliance with GMPs, a PAI
may not be necessary.
It was not until Jan. 2008, when FDA and Baxter started receiving hundreds of adverse event reports, that the agency looked
more closely at the facilities producing this product and discovered the inspection omission. FDA found that it had approved
Baxter's supplement in 2004 without inspecting the Changzhou facility. "We evaluated another firm with a similar name for
its inspection history," Famulare explained. This other firm, which had been inspected, was entered into the record, so the
Changzhou plant was not followed up for inspection. Famulare termed this error an "isolated situation" that OC was moving
quickly to correct.
In addition, China's State Food and Drug Administration (SFDA) did not inspect the facility because it classified Changzhou
SPL as a chemicals manufacturer and not a pharmaceutical company. In addition, SFDA does not inspect plants that produce drugs
for foreign use.
As these discoveries unfolded, all parties scrambled to uncover the root cause of the adverse events. FDA inspectors swarmed
over SPL, its Chinese facility, and Baxter's New Jersey plant. "We go back to the original raw material and to every production
step," explained Michael Rogers, director of the Division of Field Investigation in FDA's Office of Regulatory Affairs (ORA),
at a Feb. 2008 press briefing. "We identify the manufacturing process and the raw materials used to make the product."
SPL describes its Chinese plant a "state-of-the art, fully validated CGMP compliant heparin API manufacturing facility" that
was "approved by FDA in 2004 under a US NDA for import and use in the United States."
A Feb. 2008 inspection of Changzhou SPL by FDA experts, however, uncovered several "potential deficiencies" in procedures
for removing impurities, ensuring proper cleaning of equipment, and process validation. Experts observed signs of improper
waste handling, inadequate product testing, and the use of crude heparin from an unacceptable vendor. Baxter says it found
similar problems at Changzhou during its own audit in Sept. 2007; evidently, the deficiencies were not addressed expeditiously.
FDA officials emphasized that they could not link the adverse events to these preliminary findings cited in a 483 inspection
report and that Baxter had been using this product since 2004 without any problems. To uncover the cause of the adverse reactions,
FDA inspectors expanded their investigation to upstream raw-material suppliers, including Chinese consolidators that purchase
heparin extract from village pig processors. One possibility was that widespread pig disease in China prompted consolidators
to accept products from small, untested operators, and that material from sick pigs were entering the supply chain.
At the same time, Baxter re-examined testing and inspection records from its Cherry Hill, NJ, facility that produces a broad
spectrum of generic injectible products, including Baxter's heparin line. This line generates some $30 million in annual revenue,
or about 1% of the company's total sales. An FDA inspection in Feb. 2008 found no problems in Baxter's product components