Bacterial endotoxin control

The opposite of harmony is disharmony. An example of disharmony is the need to repeat tests using rabbits for pyrogen where testing for bacterial endotoxin is otherwise prescribed. This represents the most extreme disharmony of methods. But there is even a greater disharmony, and that would be to reach different eonelusions as to pass/fail the speeimen. In this ease, the quality control professionals must make a judgment as to whether or not this material can be sold in one or more regions. Functionally equivalent to harmonization is the absence of disharmony. Because of a difference in policy, pharmacopoeias may not differ on adoption of a test at all. If certain tests are eonsidered neeessary by one pharmacopeia in order to protect the consumer, it is appropriate for that pharmacopeia to adopt the test without reference to any other region. 

Qualification of the laboratory. Qualification of the laboratory includes qualifying analysts initially by demonstrating their proficiency at preparing the necessary reagents, standards, and controls. Analyst qualification is necessary for each type of bacterial endotoxin analysis test prior to performance of any testing on actual samples. 

Mammalian MTs are known to accumulate after administration of various metal salts. This control is not exclusive, however, as a variety of other stimuli also trigger MT synthesis, including several hormones, tissue injury, bacterial endotoxin and interferon (see Karin, 1985 Hamer, 1986). Each of these factors relates directly or indirectly to various acute stresses. This could indicate that MT is a general stress protein. Such a definition is incomplete because MT levels also change during embryo-genesis and tissue differentiation. This has prompted the suggestion that the primary role of MT is as a modulator of cellular activity (Karin, 1985). 

Although bacterial endotoxins are of microbiological origin, they are not lost with loss of viability. Of the sterilization processes commonly used in the manufacture of sterile parenteral dosage forms (see above), only dry heat is capable of destroying bacterial endotoxins in a reasonable time frame. There is therefore no practical way of removing bacterial endotoxins from finished drug products thus, they must be controlled at source. 

The pharmacopoeias deal with ingredient water of two types. Purified Water and Water for Injection. The principal difference in biological quality between the two types of water is that Water for Injection is specified to be pyrogen-free (less than 0.25 Eu of bacterial endotoxin per mL). Only water of Water for Injection quality may be used to dissolve, dilute, or compound parenteral products, because endotoxins may pass through 0.22 pm sterilizing filters. Control of bacterial endotoxins is achieved in the first instance through control of microbiological contamination. 

Mesothelial cells, when stimulated with bacteria or bacterial products, release significant quantities of multiple chemokines, including IL-8, MIP-la and monocyte chemoattractant protein-1 (MCP-1, CCL2) (21-23). When activated by bacterial endotoxin, lipopolysaccharide, IL-lp, or TNF-a, both C-X-C and C-C chemokines are released. The temporal recruitment of specific subpopulations of leukocytes from the vascular compartment to the pleural space depends on a complex balance of soluble cytokines that control the release of chemokines... 

Components of parenteral solutions (active substances, excipients, intermediates and packaging material) should be routinely tested for bioburden and bacterial endotoxin level to ensure they are not adding an excessive microbial load. Bioburden is usually determined on the unfiltered bulk solution. Testing of filtered bulk parenteral solution either before or after filling into the final container may be done by comparison to the previously tested unfiltered bulk solution. Initial bioburden and endotoxin monitoring should be conducted to establish appropriately designed and sized terminal sterilisation methods such as filtration/aseptic filling or terminal heat treatment (see Sects. 30.5 and 30.6). Bioburden is also used as a parameter to evaluate process control. 

Because irrigations are used in or on body areas that are usually sterile or have a low degree of contaminatiOTi, there are strict requirements for their production and quality control. In this chapter the use, the design of formulation and preparation method as well as the on site preparation of irrigations will be discussed. With regard to solutions for various types of dialysis, the use of concentrates, the water quality and the requirements for bacterial endotoxins are fully discussed. 

A test of adrenocortical function based on the observation that bacterial endotoxins stimulate corticosteriod secretion. It is possible that this involves the stress control mechanism of cortisol secretion (see corticotrophin releasing factor). The test consists of injecting purified bacterial endotoxins and measur-... 

Endotoxins are found in some bacterial sources, such as E. coli. For other products they are considered a contaminant that should not be present and can be controlled by adherence to good manufacturing practices (GMPs). Nucleic acids, once considered a significant risk, are now thought of as cellular impurities, and their removal should be validated [2,3]. Proteins that pose a potential risk (e.g., immunogenicity) include host cell proteins, aberrant protein product, proteins used in cell culture, and those associated with the process (e.g., protein A affinity ligands or nucleases employed to reduce viscosity). 

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