After Heparin: - The Pew Charitable Trusts

PHARMACEUTICAL MANUFACTURING: GLOBALIZATION AND QUALITY MANAGEMENT
Case study 3
Gentamicin and Flavine International:
false labeling conceals unapproved
manufacturing plants
In the late 1980s and early 1990s, Flavine International Inc., a broker selling API to U.S. manufacturers,
bought low-cost materials from plants in China that were not approved by the FDA and
relabeled them as if they were active ingredients from the Long March Pharmaceutical Plant, an
FDA-approved facility. 202 Flavine sold the falsely labeled APIs, which included bulk shipments of
the antibiotic gentamicin to U.S. manufacturers. 203 A few years later, these manufacturers recalled
gentamicin products from the market. 204
Flavine’s labeling deception came to light because the broker was importing more product than
Long March’s facilities were physically able to produce, leading the FDA to suspect that some of the
API came from other unspecified sources. 205 In 1994, Long March officials confirmed that materials
sold by Flavine had not been made at Long March, even though they were labeled as such. 206
In 1997, Flavine International, Inc., was fined, and its owner sentenced to two years in prison. 207 A
Congressional review of the FDA’s Flavine investigation showed that, although the FDA received
reports of 1,974 adverse reactions (including 49 deaths) in patients taking gentamicin between 1989
and 1994, the agency’s final report did not document any steps taken to alert the two companies
that purchased the falsified product from Flavine or to track down suspect material that might
remain on the market. 208
In 1998, a year after Flavine was fined, the CDC identified 20 adverse patient reactions in California
related to gentamicin made by Fujisawa USA (one of the manufacturers purchasing gentamicin from
Flavine), including chills, shaking and drops in blood pressure. Thirty-seven similar events were identified
in seven other states. 209 The CDC report stated that the reactions were probably due to the
method of administration, combined with high levels of endotoxin (a toxin produced by bacteria) in
Fujisawa’s product. 210
Although the FDA had suspicions about gentamicin packaged under the Long March Pharmaceutical
label since the early 1990s, the agency did not recommend detaining gentamicin shipments
from the plant until 1999, after an inspection found good manufacturing practice violations at
the site. 211
This case and more recent investigations 212,* underscore the importance of purchasing companies
scrutinizing their suppliers to verify that all production is actually occurring at the declared sites, and
that sufficient quality systems are in place.
*
A recent examination of the impurity profiles of 39 samples of bulk gentamicin from the German and U.S. markets found drug substances listed from
individual producers with different impurity profiles, suggesting that these producers may have brought in material from other undisclosed sources.
After Heparin: PRotecting Consumers from the Risks of Substandard and Counterfeit Drugs 31