Vahdation

An observation of the results of cross-validation revealed that all but one of the compounds in the dataset had been modeled pretty well. The last (31st) compound behaved weirdly. When we looked at its chemical structure, we saw that it was the only compound in the dataset which contained a fluorine atom. What would happen if we removed the compound from the dataset The quahty ofleaming became essentially improved. It is sufficient to say that the cross-vahdation coefficient in-CTeased from 0.82 to 0.92, while the error decreased from 0.65 to 0.44. Another learning method, the Kohonen s Self-Organizing Map, also failed to classify this 31st compound correctly. Hence, we had to conclude that the compound containing a fluorine atom was an obvious outlier of the dataset. 

Strictly, the mean observed values, (y), which appear in Equation (12.39) should corresponc to the mean of the values for each cross-vahdation group as appropriate rather than the overall mean value of the dependent variables, though often the mean of the entire date set will be used instead. 

Reversed-phase high performance Hquid chromatography has come into use for estimating the purity of proteins and peptides as weU. However, before employed, a high performance Hquid chromatographic (hplc) profile of a given protein must be completely vaHdated (43). 

Although Brevundimonas (Pseudomonas) diminuta (ATCC 19146) is most commonly used for steriliziug-grade filter vaUdation, iu certain appHcations other bacteria are used. For example, when it is necessary to demonstrate removal of mycoplasma in appHcations involving sera and tissue culture media, membranes having a smaller pore size rating, eg, 0.1 p.m, are frequentiy used. For these membranes,laidlawii may be employed for vaHdation purposes (9). 

Improvements ia membrane technology, vahdation of membrane iategrity, and methods to extend filter usage should further improve the performance of membrane filters ia removal of viral particles. Methods to improve or extead filter life and iacrease flow rates by creating more complex flow patterns could possibly be the focus of the next generation of membrane filters designed to remove viral particles. 

In the laboratory or process research section a laboratory procedure for a fine chemical is worked out. The resulting process description provides the necessary data for the determination of preliminary product specifications, the manufacture of semicommercial quantities in the pilot plant, the assessment of the ecological impact, an estimation of the manufacturing cost in an industrial-scale plant, and the vaHdation of the process and determination of raw material specifications. 

In these cases most customers expect the producer to comply with a quaHty standard such as ISO 9001 /9002, ie, only released raw materials can be used, the process must be vaHdated, and documentation of each produced batch is kept. 

Another quaHty control problem of multipurpose plants is the clean out for a product change. A test for residual cleaning solvents in the ppm level is a necessity. The best vaHdation of the cleaning process is to develop an analytical method that is able to find the previous product in the new product at a level of not more than 1 ppm. Tests should be mn on at least the first three batches. 

The primary thmst of GMP is that it is not enough merely to make chemicals to meet USP or other apphcable specifications. The chemicals must be made under clean and sanitary conditions, procedures and processes must be vahdated and documented, and processing and packaging must be carried out under conditions that preclude mixup and mislabeling. Records must be kept of complaints, and the manufacturer must know enough about the storage properties of the products to specify storage conditions and, if necessary, expiration dates on the label. 

The early immunoglobulin products prepared by cold-ethanol fractionation were found to be free from transmitting hepatitis infection (106,108) this was not the case with products prepared by alternative methods (109). Subsequentiy, some batches of intravenous immunoglobulin transmitted hepatitis infection (110), emphasizing the importance of estabHshing vaHdated procedures for dealing with potential viral contaminants (111). 

The business activity of the organi2ation dictates quaUty requirements for the LIMS. Security and regulatory requirements for LIMS data define the level of effort expended to vahdate a LIMS and the data being stored. In addition, the quahty of the hardware and software used to implement the LIMS both play a role in determining overall system quahty. 

The hardware and software used to implement LIMS systems must be vahdated. Computers and networks need to be examined for potential impact of component failure on LIMS data. Security concerns regarding control of access to LIMS information must be addressed. Software, operating systems, and database management systems used in the implementation of LIMS systems must be vahdated to protect against data cormption and loss. Mechanisms for fault-tolerant operation and LIMS data backup and restoration should be documented and tested. One approach to vahdation of LIMS hardware and software is to choose vendors whose products are precertified however, the ultimate responsibihty for vahdation remains with the user. Vahdating the LIMS system s operation involves a substantial amount of work, and an adequate vahdation infrastmcture is a prerequisite for the constmction of a dependable and flexible LIMS system. 

The responsibihties of the quahty assurance unit generally fall into two categories support for or improvement of the existing quahty system (31). The support activities of QA often include employee training, quahty system documentation, method vahdation and method transfer, audit, and customer complaints. 

The second aspect of quahty documentation is to detail how the work processes referred to in the manual are performed. The QA unit is often the organization responsible for issuing a set of procedures designed to assure conformance to the appropriate standards or to company poHcy. The procedures, often called standard operation procedures (SOP) or quahty operating procedures (QOP), should include such topics as customer complaints, audit protocols, stabihty testing, preparation of COAs, test method vahdation, etc. 

Test Methods. In addition to that provided by proper sampling and rephcation of analysis, a test method also has a significant impact on the accuracy and precision of the results. Preferred methods are those which are accepted in the chemical industry such as those from the American Society of Testing Materials (ASTM), Association of Official Analytical Chemists (AO AC), or from compendia such as the United States Pharmacopoeia (USP) or the Pood Chemical Codex (FCC) (36). The use of such methods eliminates the need for method vahdation. 

Method vahdation is the demonstration, accompanied by a high degree of assurance, that the test method consistently performs as expected. Vahdation of test methods is especially important when the intended method differs from a compendial or other referenced method and yet is expected to provide equivalent or perhaps better test results. When the reference method is to be used unchanged, no vahdation is necessary. Thus a primary benefit of using compendial methods as written is not needing to do a method vahdation. 

An analytical method vahdation study should include demonstration of the accuracy, precision, specificity, limits of detection and quantitation, linearity, range, and interferences. Additionally, peak resolution, peak tailing, and analyte recovery are important, especially in the case of chromatographic methods (37,38). 

The analytical research and development (R D) unit is often responsible for the preparation and vahdation of test methods. The R D lab is not faced with the same pressures for rapid analysis as the QC unit, where pending results often hold up production. In addition, R D often assigns personnel to specific instmments or techniques, whereas QC generally requires technicians to perform varied analyses. This leads to an expertise on the part of analytical chemists and technicians which is difficult to duphcate in QC. Therefore the R D test method should be mgged enough to withstand the different environment of the QC lab and stiU provide vahd results. 

Dimensional Analysis. Dimensional analysis can be helpful in analyzing reactor performance and developing scale-up criteria. Seven dimensionless groups used in generalized rate equations for continuous flow reaction systems are Hsted in Table 4. Other dimensionless groups apply in specific situations (58—61). Compromising assumptions are often necessary, and their vaHdation must be estabHshed experimentally or by analogy to previously studied systems. 

A method should be vaUdated for its iatended use with an acceptable protocol. AH experiments conducted to make claims or draw conclusions about the vahdation of the method should be documented in a method vaUdation report. 

Semm is expensive, the 1992 price was 400/L, and supply depends on cattie supply. Use of this semm also poses significant difficulties in vahdating processes for absence of viral contamination. Hence, a goal in cell culture technology is to develop semm-free media for cell culture. Much work has gone into developing semm-free media and a sizable portion of cell culture research is devoted to this project. A detailed discussion of semm-free media development is available (5). 

A spreadsheet program is intuitive in its operation and can immediately show the effect of any one change throughout the whole spreadsheet. It is thus a subtie form of data vaHdation an error may be spotted immediately. Furthermore, when a material balance is set up, the total effect caused by a change in one variable may be seen at once. 

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