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12879652 Parenteral Quality Control

12879652 Parenteral Quality Control

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INTRODUCTION

When injected into humans in sufficient amounts, pyrogens
will cause a variety of adverse physiological responses (Table
2.1).Themostcommonor recognizableresponseisanincrease
in body temperature, from which the name “pyrogen” is de-
rived (Greek pyro fire, gen beginning). Pyrogenic re-
sponses rarely are fatal unless the patient is very sick and the
dose is verylarge. Nevertheless, pyrogens areconsidered toxic
substances and should never be injected knowingly. Pyrogen
contamination of large-volume parenteral (LVP) solutions is
especiallyserious becauseofthe largeamountsof fluidadmin-
istered to people whose illnesses must be severe enough to
warrant the use of such large volumes.
Pyrogens come from microorganisms. All microbial forms
producepyrogen; however,the mostpotent pyrogenoriginates
from gram-negative bacteria. The entity primarily involved in
pyrogenic reactions in mammals is the lipopolysaccharide
(LPS) from the outer cell membranes of gram-negative bacte-

119

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Chapter 2

Table 2.1 Adverse Physiological Effects of Pyrogens in Humans

Primary

Increase in body temperature
Chilly sensation
Cutaneous vasoconstriction
Pupillary dilation
Piloerection
Decrease in respiration
Rise in arterial blood pressure
Nausea and malaise
Severe diarrhea
Pain in the back and legs
Headache
Secondary
Cutaneous vasodilation
Hyperglycemia
Sweating
Fall in arterial blood pressure
Involuntary urination and defecation
Decreased gastric secretion and motility
Penile erection
Leucocytopenia, leucocytosis
Hemorrhage and necrosis in tumors
Altered resistance to bacterial infections
Depletion of liver glycogen
Rise in blood ascorbic acid
Rise in blood nonprotein nitrogen and uric acid
Decrease in plasma amino acids

ria (1). Another name for LPS is endotoxin. Although not en-
tirely correct,the namespyrogen, LPS,and endotoxin arerou-
tinely used interchangeably. Figure 2.1 is a schematic
representation of the three cell wall layers of a gram-negative
microorganism (1). The outer membrane shown in the figure
is not found in gram-positive bacteria. This structure contains
the LPS moiety that interacts with the coagulable protein of

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Pyrogen Testing

121

Fig. 2.1 Schematic representation of the three cell wall layers of
a gram-negative bacterium. (From Ref. 1).

the amebocytes of the horseshoe crab, a phenomenon from
which evolved the Limulus Amebocyte Lysate (LAL) test.
LPS, extracted and recovered as a colloidal suspension,
may be split by mild acid hydrolysis into lipid A and degraded
polysaccharides (2). Lipid A is composed of B-1, 6-glucosamine
disaccharide units with aˆ-hydroxymyristic acid replacing one
of the amino hydrogens and fatty acids replacing hydrogen in
some of theEOH groups (see Fig. 2.2). Each two glucosamine
units are separated by two phosphate moieties, forming a lin-
ear polymer (1). Lipid A alone lacks biologic activity, yet LPS
is toxic, probably because polysaccharide increases the aque-
ous solubility of lipid A. Kennedi et al. (3) showed that when
lipid A is separated from the polysaccharide component of en-
dotoxin, it loses more than 99.9% of its pyrogenic activity in
rabbits.

Freedom from pyrogenic contamination characterizes
parenteral products in the same manner as sterility and free-
dom from particulate matter. Preventing the presence of pyro-
gens is much preferred over removing pyrogens in parenteral
products. Preventing pyrogenic contamination primarily in-
volves the use of ingredients, solvents, packaging materials,

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122

Chapter 2

Fig. 2.2 Structure of unit of lipid A from Salmonella lipopolysac-
charide. KDO: 3-deoxy-D-mannooctulosonic acid; HM: aˆ-hydroxy-
myristic acid; FA: other long-chain fatty acids. (Adapted from Ref.
2 and Reitschel et al., Eur. J. Biochem., 28, 166, 1972).

and processing equipment that have been depyrogenated ini-
tially, then employing correct and proper procedures during
the entire manufacturing process to minimize the possibility
of pyrogen development.

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