APP's Soon-Shiong: No Stranger to Suspect Chinese Suppliers

A big nod goes to the In Vivo Blog today for providing more background on APP and its CEO Patrick Soon-Shiong. Seems the company's top boss is not a stranger to less-than-stellar foreign drug suppliers, after all—despite his arguably opportunistic and hyperbolic assurance of the safety of APP's heparin in yesterday's WSJ.*

It all started way back in June 1998, when APP acquired Fujisawa's worldwide injectable pharmaceutical business. At approximately the same time (May 1-June 29), the FDA began receiving reports from a Los Angeles hospital of endotoxin-like adverse reactions (reactions not dissimilar to those recently described with Baxter's recalled heparin) after the administration of Fujisawa-produced IV gentamicin.

According to a 1998 MMWR report, the reactions were likely due to high endotoxin levels in the Fujisawa gentamicin, particularly with once-daily dosing of the drug (an unapproved regimen often used to reduce the risk of antibiotic-related ototoxicity and nephrotoxicity). Endotoxin levels in Fujisawa's product ranged from 25.6 to 32.0 endotoxin units (EU) per mL, while levels in gentamicin samples from another manufacturer were less than 2.0 EU/mL. The allowable limit for endotoxin in antibiotics, per USP standards, is 68 EU/mL. So, although the endotoxin levels in Fujisawa's antibiotic were within USP standards, the larger once-daily administration of the product likely delivered enough endotoxin to cause the pyrogenic reactions. The MMWR indicated that these kinds of reactions had not been observed previously with once-daily gentamicin.

APP voluntarily withdrew the Fujisawa antibiotic in November 1998, while still defending the product's safety and blaming the endotoxin-like reactions on the once-daily dosing, according to a 2002 NYT article. The company reintroduced the gentamicin in June 1999; but after additional adverse reactions were reported, the drug was again withdrawn. The NYT article also indicated that the high endotoxin levels in the gentamicin lots were traced to a Fujisawa plant and further implicated substandard conditions at a Chinese supplier; however, the article did not identify either facility by name or specific location.

Information from a 1998 article in the FDA Consumer and a 2000 article from Health-System Pharmacy News indicate that the suspect gentamicin from APP/Fujisawa had actually been provided by a New Jersey drug broker, Flavine International. According to these reports, Flavine had obtained gentamicin in 1995 from unapproved Chinese sources and had then repackaged the product to resemble antibiotic from Fujisawa's legitmate (and FDA approved) Chinese supplier, Long March Pharmaceutical Plant.** Flavine then sold the counterfeit gentamicin to Fujisawa (as well as to ESI Lederle).

According to HSPN, the FDA became aware of Flavine's counterfeit gentamicin sometime during the mid-90s, while investigating another counterfeit antibiotic (used for veterinary purposes) offered by Flavine. However, the FDA did not follow-up with any of Flavine's gentamicin purchasers (namely, Fujisawa) to ensure that the counterfeit drug was no longer on the market. These events predated the endotoxin-like reactions associated with APP's/Fujisawa's gentamicin in 1998.

*How anybody can ensure the ability to trace a heparin lot to a single pig defies all common sense, especially given the WSJ's images of intestinal slurries and gut-decorated wringing machines in China, even at the ostensibly modernized plant.

**In December 1999, Long March was cited by the FDA for deviating from good manufacturing processes, and the company's gentamicin was recalled at that time.