Human validation

The observed CEPH population mean IC50 for both docetaxel and 5-fluorouracil was similar to IC50 values observed across the NCI60 panel of human tumor cell lines (http //dtp.nci.nih.gov) (17). In addition, docetaxel- and 5-fluorouracil-induced cell death is mediated by caspase-3 cleavage, similar to that observed in tumor cells (17). These data are encouraging for the use of CEPH pedigrees as a discovery tool. However, the ultimate proof of the value of the cell-based models will be the human validation of markers derived from this process. These studies he ahead and will help position cell-based models in their correct place in the drug development process. 

Method validation was carried out in six (monkey) or seven (human) validation batches. Each batch included eight levels of standard calibrators, four levels of VS at concentrations at the LLOQ, low, mid, and high concentrations within the calibrator range, and two additional concentrations higher than the ULOQ. The >ULOQ VS were run at dilution factors of 20 and 400 to mimic the expected high concentration samples. The accuracy and precision data of the VS in human plasma are listed in Table 6.3. 

Heymsfield SB, Arteaga C, McManus C, Smith J, Moffitt S. Measurement of muscle mass in humans Validity of the 24-hour urinary creatinine method. Am) Clin Nutr 1983 37 478-94. 

Human validation requires the collaboration of experts from various disciplines (e.g. a multidisciplinary team, comprising quality assurance, engineering, manufacturing and other disciplines, depending on the product and process to be validated). 

In the next stage, human validation and modification is done. 

Mock DM, Henrich CL, Camell N, Mock Nf. Indicators of marginal biotin deficiency and repletion in humans validation of 3-hydroxyisovaleric acid excretion and a leucine challenge. Am J Clin Nutr 2002 76 1061—1068. 

This relation is only valid for small Ad and small lateral extensions. The influence of the inherent unsharpness is not taken into consideration and besides this the ability of the human eye to integrate over an area for noise reduction is not considered, which would have positive effects on the perception oflarge or longish flaws (or wires). 

The fact that ceU culture-derived products are often injected into humans as therapeutic agents makes it imperative that there be no component in the final product that can pose a potential health risk to the patient. Health risks can be introduced into a product from many sources including the ceUs themselves raw materials, such as semm, media components, etc materials used in purification, eg, antibodies and external contamination. Eor a therapeutic product such risk factors are identified at the outset and ways of reducing them to acceptable levels are designed into the process. Before a product is released by the EDA the manufacturer has to demonstrate this risk reduction by rigorous validation of the process. 

Test runs also allow the primary steps of operating procedures to be validated and checked for logic or human factors aspects. 

Many sophisticated models and correlations have been developed for consequence analysis. Millions of dollars have been spent researching the effects of exposure to toxic materials on the health of animals the effects are extrapolated to predict effects on human health. A considerable empirical database exists on the effects of fires and explosions on structures and equipment. And large, sophisticated experiments are sometimes performed to validate computer algorithms for predicting the atmospheric dispersion of toxic materials. All of these resources can be used to help predict the consequences of accidents. But, you should only perform those consequence analysis steps needed to provide the information required for decision making. 

An attempt to forecast the further shrinkage of integrated circuits has been made by Gleason (2000). He starts out with some up-to-date statistics during the past 25 years, the number of transistors per unit area of silicon has increased by a factor of 250, and the density of circuits is now such that 20,000 cells (each with a transistor and capacitor) would fit within the cross-section of a human hair. This kind of relentless shrinkage of circuits, following an exponential time law, is known as Moore s law (Moore was one of the early captains of this industry). The question is whether the operation of Moore s Law will continue for some years yet Gleason says that attempts to forecast an end to the validity of Moore s Law have failed dismally it has continued to hold well beyond expectations . The problems at... 

In the course of assessing your company s current PSM status, you and your team have almost certainly gained a clear sense of which facilities pose the greatest risk, whether by virtue of inherent process hazards, human factors, management systems, or a combination. As you set priorities for implementation you should closely review information gleaned from the assessment tasks. In addition, you should try to validate or flesh out your impressions through some more quantitative analysis that can help to identify priority facilities. 

The questionable validity if animal studies and short-term tests with respect to the prediction of long-term, adverse liealUi impacts in a human population... 

Figure 11.5 Chromatograms of plasma samples obtained with fully automated on-line SPE-LC (a) dmg-ffee human plasma (b) human plasma spiked with omeprazole (100 ng/ml) and phenacetin (internal standard 1000 ng/ml). Reprinted from Journal of Pharmaceutical and Biomedical Analysis, 21, G. Garcia-Encina et al., Validation of an automated liquid chromatograpliic method for omeprazole in human plasma using on-line solid-phase exti action, pp. 371 - 382, copyright 1999, with permission from Elsevier Science.

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