ABSTRACT
The proverb “those ignorant of the past are doomed to repeat it,” is not one that should apply to pharmaceutical manufacturing.
INTRODUCTION
Fortunately, or perhaps as a testament to the utility of the Limulus amebocyte lysate (LAL) test, there have been few significanta cases of pyrogenic responses to drugs manufactured in the United States after almost a century of parenteral therapy. When such adverse drug events (ADE) do occur they are usually complex and, should, rightfully, receive a great deal of attention. Such misadventures can be instructive from many perspectives. This chapter will describe three events and learning points from them. One event occurred at the beginning of the application of Limulus technology to pharmaceutical products. The two more recent events described appear to involve the presence of a nonendotoxin pyrogen that either contributed alone or in synergy with endotoxin. The proverb: those ignorant of the past are doomed to repeat is not one that should apply to pharmaceutical manufacturing. The events described include:
1. The demonstration in 1972 that aseptic meningitis (AM) is caused by endotoxin as administeredvia the intrathecal routeduring radionuclide cisternography (RC) (1).
2. A pyrogenic outbreak (2) resulted from an active pharmaceutical ingredient (API) supplied from a Chinese manufacturer (synergistic effect of lipopolysaccharide combined with nonendotoxin pyrogen at pyrogenic levels due partly to once-daily-dosing as allowed by the FDA’s Modernization Act). The bulk supplier in question was later cited for significant current good manufacturing practices (cGMP) violations.
