Validation studies and applications

Flynn LR, Bass SW, Meierer RE. 1991. Headspace screening/capillary column GC/MS analysis for volatile organics validation studies and applications. Waste Testing and Quality Assurance 106-114. 

Section 3). The discussion of validation studies and applications (Section 4) will start with chemical shifts of ligand atoms, continue with metal shifts, and close with a few examples on spin-spin coupling constants. A summary and a perspective for future work are given in Section 5. 

An applicant can submit one or more protocols (i.e., comparability protocols) describing tests, validation studies, and acceptable limits to be achieved to demonstrate the absence of an adverse effect from specified types of changes. A comparability protocol can be used to reduce the reporting category for specified changes. A proposed comparability protocol should be submitted as a prior approval supplement, if not approved as part of the original application. FDA intends to issue separate guidance on comparability protocols. 

The logical and necessary successors to the Human Genome Project, which delivers primary seqnence data, are comparable efforts in bioinformatics (to understand the meaning of the seqnences), in structural studies (to understand the structures and interactions of molecules derived from gene sequences) and the molecular design of interacting (small) molecules as well as (finally ) the overall biological systems for validation, verification and application (e.g., mouse, zebra fish. Drosophila and hnman). ... 

Validation and Application. VaUdated CFD examples are emerging (30) as are examples of limitations and misappHcations (31). ReaUsm depends on the adequacy of the physical and chemical representations, the scale of resolution for the appHcation, numerical accuracy of the solution algorithms, and skills appHed in execution. Data are available on performance characteristics of industrial furnaces and gas turbines systems operating with turbulent diffusion flames have been studied for simple two-dimensional geometries and selected conditions (32). Turbulent diffusion flames are produced when fuel and air are injected separately into the reactor. Second-order and infinitely fast reactions coupled with mixing have been analyzed with the k—Z model to describe the macromixing process. 

Lee N, Beasley HE, Silbum M, et al. 1997b. Validation and application of immunoassays to studies of the environmental fate of endosulfan. 213th National Meeting Of The American Chemical Society, San Francisco, California, USA, April 13-17, 1997. Abstracts of Papers American Chemical Society. Abstract 117. 

Liu, A. et al.. Validated LC/MS/MS assay for curcumin and tetrahydrocurcumin in rat plasma and application to pharmacokinetic study of phospholipid complex of curcumin, J. Pharm. Biomed. Anal, 40, 720, 2006. 

If analytical methods are validated in inter-laboratory validation studies, documentation should follow the requirements of the harmonized protocol of lUPAC. " However, multi-matrix/multi-residue methods are applicable to hundreds of pesticides in dozens of commodities and have to be validated at several concentration levels. Any complete documentation of validation results is impossible in that case. Some performance characteristics, e.g., the specificity of analyte detection, an appropriate calibration range and sufficient detection sensitivity, are prerequisites for the determination of acceptable trueness and precision and their publication is less important. The LOD and LOQ depend on special instmmentation, analysts involved, time, batches of chemicals, etc., and cannot easily be reproduced. Therefore, these characteristics are less important. A practical, frequently applied alternative is the publication only of trueness (most often in terms of recovery) and precision for each analyte at each level. No consensus seems to exist as to whether these analyte-parameter sets should be documented, e.g., separately for each commodity or accumulated for all experiments done with the same analyte. In the latter case, the applicability of methods with regard to commodities can be documented in separate tables without performance characteristics. 

Multi-residue Method S19 of the DFG Manual,including Cieanup Procedure Xll-6 (gel-chromatographic cleanup), has been used successfully in many laboratories because of its broad applicability for the gas-chromatographic determination of pesticide residues in foodstuffs. DFG method S19 is also included in the respective European Standards. Subsequently, a modification of the extraction and partition step has been implemented. The modified method requires less experimental effort and eliminates the use of dichloromethane, which is an undesirable solvent for toxicological and ecological reasons. As the results from validation studies demonstrate,... 

Table 4.1 summarizes the energies corresponding to breaking of bonds for different molecules and compares the results obtained by the method of semiconductor sensors with reference data flO]. Obviously, these results agree with each other, which indicates their validity and applicability of the SS technique for these studies. 

Traditional electrophoresis and capillary electrophoresis are competitive techniques as both can be used for the analysis of similar types of samples. On the other hand, whereas HPLC and GC are complementary techniques since they are generally applicable to different sample types, HPLC and CE are more competitive with each other since they are applicable to many of the same types of samples. Yet, they exhibit different selec-tivities and thus are very suitable for cross-validation studies. CE is well suited for analysis of both polar and nonpolar compounds, i.e. water-soluble and water-insoluble compounds. CE may separate compounds that have been traditionally difficult to handle by HPLC (e.g. polar substances, large molecules, limited size samples). 

Before undertaking a discussion of the mathematics involved in the determination of reaction rates is undertaken, it is necessary to point out the importance of proper data acquisition in stability testing. Applications of rate equations and predictions are meaningful only if the data utilized in such processes are collected using valid statistical and analytical procedures. It is beyond the scope of this chapter to discuss the proper statistical treatments and analytical techniques that should be used in a stability study. Some perspectives in these areas can be obtained by reading the comprehensive review by Meites [84], the paper by P. Wessels et al. [85], and the section on statistical considerations in the stability guidelines published by FDA in 1987 [86] and in the more recent Guidance for Industry published in June 1998 [87],... 

The sterilization processes described in the Ph Eur are preferred, especially terminal sterilization in the final container alternative processes have to be justified. All sterilization processes will need to be described and appropriate in-process controls and limits included. Where Ph Eur prescriptions are followed, there should be a statement to this effect in the application. Most of this information should be discussed in the development pharmaceutics section. Reference is made to the specific guidelines on ethylene oxide sterilization and irradiation sterilization, which are discussed further below. The possibility of parametric release for terminal processes such as saturated steam and irradiation is mentioned (see below). For all sterile products there should be a sterility requirement included in the finished product specification regardless of the outcome of validation studies. 

In this section, we will discuss some examples from the literature, in which the approximation methods derived in this chapter have been used. In several cases, the approximations have been compared with more-accurate path integral simulations to assess their validity. This is not meant as a full review rather, several case studies have been chosen to illustrate the tools we have developed. We will first look at simpler examples and then discuss water models and applications in enzyme kinetics. 

Y data. The data set used for this example is from Miller and Miller ([1], p. 106) as shown in Table 58-1. This dataset is used so that the reader may compare the statistics calculated and displayed using the formulas and figures described in this reference with respect to those shown in this series of chapters. The correlation coefficient and other goodness of fit parameters can be properly evaluated using standard statistical tests. The Worksheets provided in this chapter series can be customized for specific applications providing the optimum information for particular method comparisons and validation studies. 

The validation is therefore not complete until there is a detailed description of the method and records of the validation study. A responsible person needs to sign that the method meets the requirements, i.e. it is fit for purpose . The documentation facilitates the consistent application of the method, within its scope and defined performance parameters. This, in turn, helps ensure that when the method is applied in different laboratories or at different times, the measurand is the same and that the measurement results are comparable. Documentation is also required for quality assurance, regulatory and contractual purposes. 

The two major determinants of oral bioavailability are intestinal absorption and hepatic first-pass elimination. Caco-2 cells are useful to predict intestinal absorption. The validity of this application has been demonstrated in a number of studies in which percent drug absorption in humans was correlated with Caco-2 permeability coefficients.35-39113114... 

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