PDA82文件翻译召集令

shanerain

关于low endotoxin recovery 的技术报告。

4.0 Proposed Mechanisms of LER
The likely molecular mechanisms causing LER in biopharmaceutical drug products are of interest in
that they suggest mitigation strategies, which are discussed further in Section 4.2.
As described in Section 6.3, detectable LAL activity can be variable, depending on the primary and
supramolecular structure of (lipopolysaccharide)LPS. In addition, measured biological activities can
vary depending on the detection method. Analysis of LER-affected samples comparing different test
methods(e.g, LAL VS MAT vs. RPT)can sometimes lead to different results. Due to the general
molecular structure of endotoxin, including poly- or oligo-saccharide regions(core region and O-antigen), LPS possesses an amphiphilic nature. In an aqueous environment, and above a specific concentration, amphiphilic molecules such as LPS form supramolecular structures. The type of aggregation has been shown to depend, in part, on the chemical structure of the aggregate-forming molecules (22). The aggregation state of LPS has also been shown to have an effect on biological activity (22-24).
LER mechanisms are proposed based on the hypothesis that the supramolecular state of the endotoxin
is altered in a way that makes it less detectable (i. e, masked). Endotoxins found during contamination
are known to exist in a vast array of chemical forms. One of the most potent forms of endotoxin is a
molecule containing two D-gluco-configurated hexosamine residues, two phosphoryl groups, and six
fatty acids, including 3-acyloxyacyl groups with a defined chain length and in a distinct location. LPS
with these structures, such as CSE and RSE, are obtained from Gram-negative bacteria(e.g, E coli)
(25). Reportedly, the organism and a host of environmental factors infuence the chemical structure
of LPS and its supramolecular state, resulting in various masking susceptibilities ofLPS. For LPS
susceptible to LER, a two-step mechanism has been proposed (chelation of divalent cations ＋change of aggregation state)(26, 27). CSE and RSE Preparations are standardized LPS that have been shown to
be susceptible to LER and, thus, are commonly used as the source of LPS for LER hold-time studies.
Although the two-step mechanism is believed to cause LER due to destabilization of salt bridges; other
endotoxins with different substituent groups (e.g. aminoarabinose) are not destabilized in the same
manner(28).
Section 4.5 describes a potential mechanism by which some LPS exhibit LER in certain formulations
and other types are less likely to do so. Different results are reported in hold-time studies depending

novacyl277

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亦心

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ahwuci

如果手上有文件 ，方便分享下吗，谢谢
PDA82 Low Endotoxin Recovery

二街五号

楼主，请问能分享下这份资料吗？谢谢