Pharmaceutical validation

Similar to the production of a finished pharmaceutical, validation of analytical methods must be performed in a suitable facility. Any organization responsible for developing and validating analytical methods must have the quality elements shown in Table 1 to demonstrate suitability and control. 

Levels of precision and accuracy should be determined in conjunction with other testing laboratories providing the same services and with the legal systems operating in the region. Pharmaceutical validation offers the highest level of accuracy and precision. Therefore, setting this as a benchmark from which to work would be considered reasonable. 

The principle of insignificancy , enabling use of the given principle for any level of probability is substantiated. The systematic application of the given principle results in developing metrological criteria for pharmaceutical reference substance, analytical validation, evaluation of results of interlaboratory testing and suitability of the analytical equipment for the phamiaceutical analysis. 

A simple, rapid, precise and economical High Performance Thin Layer Chromatographic (HPTLC) method has been developed and validated for determination of Alprazolam and Melatonine in its pharmaceutical preparation. It was performed on silica gel 60 Thin Layer... 

The synthetic process proceeding under physiological conditions can be imitated in vitro with the object of establishing the validity of biogenetic hypotheses (293) as well as finding new potential routes for the synthesis of pharmaceuticals (294). 

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.

Process validation is the procedure that allows one to establish the critical operating parameters of a manufacturing process. Hence, the constraints imposed by the FDA as part of process control and validation of an SMB process. The total industrial SMB system, as described, is a continuous closed-loop chromatographic process, from the chromatographic to recycling unit and, with the use of numerical simulation software allows the pharmaceutical manufacturer rapidly to design and develop worst-case studies. 

Pharmaceutical sites will usually create a dedicated team of validation specialists to coordinate all validation activities. They should operate according to a validation master plan that has been developed using risk analysis to identify the most critical systems requiring validation/re-validation. Before validating a system or process, a written protocol should be prepared that describes the system, the critical aspects, the objectives, the test methods and the acceptance criteria that will be applied. A validation report should be prepared on completion of each protocol. 

Pharmaceuticals for injection must be presented in a sterile form. Sterility may be achieved by filtration through 0.22 pm filters under aseptic conditions, or by steam, dry heat, radiation or gas sterilisation methods, which may be applied to packaged products. Irrespective of the method, the process must be validated and monitored to assure its effectiveness. As discussed in Chapter 2, this is an example of a process that cannot be assured by verification testing because of its destructive nature. 

Comprehensive physicochemical characterization of any raw material is a crucial and multi-phased requirement for the selection and validation of that matter as a constituent of a product or part of the product development process (Morris et al., 1998). Such demand is especially important in the pharmaceutical industry because of the presence of several compounds assembled in a formulation, such as active substances and excipients, which highlights the importance of compatibility among them. Besides, variations in raw materials due to different sources, periods of extraction and various environmental factors may lead to failures in production and/or in the dosage form performance (Morris et al., 1998). Additionally, economic issues are also related to the need for investigating the physicochemical characteristics of raw materials since those features may determine the most adequate and low-cost material for specific procedures and dosage forms. 

Raffin, R. P., Jornada, D. S., Re, M. L, Pohimann, A. R. Guterres, S. S. (2006). Sodium pantoprazole-loaded enteric microparticles prepared by spray drying Effect of the scale of production and process validation. International Journal of Pharmaceutics, Vol. 324,1, (October 2006), pp. (10-18), ISSN 0378-5173... 

A pharmaceutical specialty is produced in three dosage strengths (major component A) A and a second component B are controlled by HPLC for batch release purposes. It is decided to replace the manual injection of the sample solution by an automatic one. It is expected the means will remain the same but the standard deviations will be smaller for the automatic injection. Cross-validation of the methods is effected by running both methods on each of 10 samples. The mean and the standard deviation for each series of 10 measurements is given in Table 4.19. 

Since the U.S. vs. Barr decision in 1993 (relevant to pharmaceuticals and related fields, rules applied by the Federal Food Drug Administration, FDA), outlier tests may no longer be applied to physicochemical tests, under the assumption that such test methods, having been optimized and validated for the particular set of circumstances, rarely produce outliers. These tests may not be applied to CU results at all. Good manufacturing practices mandate that operators work according to pre-set procedures and write down any observed irregularities as they... 

Research reports—Research reports such as stability reports, method validation and transfer reports, and pharmaceutical development reports are key documents used for NDA/MAA filings. These documents are strictly version controlled. 

Friedli D, Kappeler W, Zimmermann, S. Validation of computer system practical testing of a standard LIMS. Pharmaceut Acta Helv 1998 72 343-8. 

The FDA [51] has used the MDL QSAR software [19] to develop QSARs for the carcinogenic potential of pharmaceuticals and organic chemicals. These were validated using a test set of 108 compounds, with 72% correct prediction of carcinogens and 72% correct prediction of noncarcinogens. 

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