Performance validation

Pharmaceutical scientists often raise concerns that indium is not representative of the type of sample that they would typically run on a day-to-day basis, hence the need for a performance standard. This is a sample where the thermal behavior is known, the sample can be obtained in high purity, and ideally has two or more peaks close together so resolution can be measured. If such a material exists as one of a company s own product, then this may be an acceptable performance validation material for that organization or laboratory. 

FIGURE 2.14 DSC data for 2.64 mg of the liquid crystal azodianisol heated at 10°C/min in an hermetic pan with lid inverted. Nitrogen purge gas at 25 ml/min. Data are shown full scale (left-hand axis) and 20 times expansion (right-hand axis). 

It is recommended to run these validation tests on a regular basis, perhaps weekly, and the results archived for future comparison and reference. These experiments do not take too much time (about an hour of instrument time) and the process can be run overnight if the DSC has an autosampler. When a new operator is assigned to running the DSC, ensure that they are competent in running these validation tests prior to analyzing other laboratory samples. 

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Software producers must fulfill the requirements for development, testing, and documentation. When the user is confident that these requirements have been met, and the system functions adequately to fulfill his or her needs, the user must perform validation prior to placing the software in service. An analytical laboratory is an example of an end-user that conducts testing prior to software/computer system installation. 

Sampling Interval To be able to perform valid toxicokinetic analysis, it is not only necessary to properly collect samples of appropriate biological fluids, but also to collect a sufficient number of samples at the current intervals. Both of these variables are determined by the nature of the answers sought. Useful parameters in toxico-kinetic studies are Cmax, which is the peak plasma test compound concentration Tmax, which is the time at which the peak plasma test compound concentration occurs, Cmin, which is the plasma test compound concentration immediately before the next dose is administered AUC, which is the area under the plasma test compound concentration-time curve during a dosage interval, and t which is the half-life for the decline of test compound concentrations in plasma. The samples required to obtain these parameters are shown in Table 18.12. Cmin requires one blood sample immediately before a dose is given and provides information on accumulation. If there is no accumulation in plasma, the test compound may not be detected in this sample. 

By using the combination of specific method accreditation and generic accreditation it will be possible for laboratories to be accredited for all the analyses of which they are capable and competent to undertake. Method performance validation data demonstrating that the method was fit-for-purpose shall be demonstrated before the test result is released and method performance shall be monitored by on-going quality-control techniques where applicable. It will be necessary for laboratories to be able to demonstrate quality-control procedures to ensure compliance with the EN 45001 Standard,3 an example of which would be compliance with the ISO/AOAC/IUPAC Guidelines on Internal Quality Control in Analytical Chemistry Laboratories.12... 

The process of method development and validation covers all aspects of the analytical procedure and the best way to minimize method problems is to perform validation experiments during development. To perform validation studies, the approach should be viewed with the understanding that validation requirements are continually changing and vary widely, depending on the type of product under test and compliance with any necessary regulatory group. 

Further discussion of method validation can be found in Chapter 7. However, it should be noted from Table 11 that it is frequently desirable to perform validation experiments beyond ICH requirements. While ICH addresses specificity, accuracy, precision, detection limit, quantitation limit, linearity, and range, we have found it useful to additionally examine stability of solutions, reporting threshold, robustness (as detailed above), filtration, relative response factors (RRF), system suitability tests, and where applicable method comparison tests. 

The quality assurance department is responsible for providing support to the parent company, affiliates, and contract manufacturers in the development, upgrading, and maintenance of GMP requirements. Validation SOPs is required to give step-by-step direction in performing validation. 

There should be an appropriate and sufficient structured system, including organizational structure and documentation infrastructure, sufficient sufficient personnel and financial resources to perform validation tasks in a timely manner. Management and the personnel responsible for quality assurance should be involved in this discussion. Validation performance must be under the responsibility of appropriate and experience personnel that should represent different departments depending on the validation work to be performed. 

Agilent Capillary Electrophoresis System Operational Qualification/Performance Validation, Agilent Technologies, Waldbronn, Germany, 2000. 

Perez R., Stewart R., Arbogast C., Seals R., Scott J., An anisotropic hourly diffuse radiation model for sloping surfaces description, performance validation, site dependency evaluation. Solar Energy 1986 36 481M97. 

Since every system under consideration is subject to different efficiency, it is of interest to have efficiency as the integral parameter of the system which comprises element characteristics of the system. The performance indicator in this assessment procedure is composed of number of sub-indicators efficiency, total energy cost, capital cost and lifetime. The efficiency of the system is considered as the integral parameter for the performance validation. The total energy cost is result of the system optimization with minimum energy cost constrain. The capital cost is a measure of the investment per unit energy produced in the lifetime of the system. Also, the important parameter in the assessment of performance of the energy system is the lifetime of system. 

In many cases method development chemists hold advanced degrees and possess years of laboratory experience. Their cGMP training is often limited, however, and thus inadequate for performing validation. The training program, therefore, must emphasize regulatory compliance, especially in notebook documentation skills. 

The ability to perform validation cost-effectively is dependent on an organization s understanding of requirements and its validation capability. This chapter applies the established Capability Maturity Model (CMM) to computer validation. Examples of validation metrics and measures are examined. The metrics cover prospective validation as well as operation and maintenance of computer systems. Lean Manufacturing and Six Sigma are promoted as tools that organizations can use to streamline and improve the performance of their validation processes. 

By monitoring the validation status of the applied analytical procedure, for example, with control charts, reliable information on the long-term behavior of the procedure can be obtained and trends can be detected very early. Transferring in this way data to information to knowledge, the analytical system (or the production process) can be adjusted before problems such as OOS results occur (action instead of reaction). In analogy to equipment qualification, a continuous system is proposed design, operational, and performance validation (three Vs). 

Schuster, J.A. Farr, S.J. Cipolla, D. Wilnbanks, T. Resell, J. Lloyd, P. Gonda, I. Design and performance validation of a highly efficient and reproducible compact aerosol delivery system AERx . In Respiratory Drug Delivery VI Dalby, R.N., Byron, P.R., Farr, S.J., Eds. Interpharm Press, 1998 83-90. 

In order to be able to perform validation of the model, not all 30 cases can be used to determine the model. Also care must be taken to which cases will be used for validation and which cases for determination of the model. Because it is easy with an experimental model to fit noise in the data, a Targe vahdation set has been chosen (5 cases in the validation set and 25 cases remaining in the set to determine the model (=training set)). To avoid coincidental results, the whole procedure is repeated 5 times with different training sets and vahdation sets, where the cases in the validation set have been selected randomly. 

Prospective applicants are advised that validation of the aneilytical methods is required in accordance with the latest USP and chromatograms must be submitted where relevant. If, however, compendial methods are used, system suitability according to the criteria of the latest USP can be performed. Validation data for titration methods need not be submitted if an adequate separate method to determine degradation products exists. Reference may be made to recognised pharmacopoeia although the actual Annexure 7B form reflects the contrary. 

An important part of any validation protocol for NIR or other instrumental methods is the process of instrument qualification. In any GMP/GLP facility, instrument performance must be validated. This instrument performance validation, also called instrument qualification, involves three phases [9] installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ). 

Diagenetic analysis has proved to be useful in order to constrain the depths at which faulting occurs, and may help to predict deformation mechanisms and the related fault characteristics. The diagenetic processes are also important after the faults have been generated, as modifications of fault structures may occur during deeper burial. Understanding the deformation mechanisms is important in order to perform valid evaluations of the sealing potential of faults in reservoirs. 

The technical specifications identified and described by most of the manufacturers of absorption photometers for medical use include wavelength accuracy, spectral half-width of spectral radiation flux at the detector, photometric accuracy, percentage of wavelength integrated, false radiation, and photometric short-time repeatability. As discussed previously [2], the Instrumental Performance Validation Procedures, issued by serious manufacturers of analytical instruments, indicate the methods and the reference materials required to test and to maintain optimum spectrometer performance in daily routine analysis. 

Analysts and end users of the measurement results should be aware of the new dimension of the procedure validation definition given in ISO/IEC 17025, which requires that a procedure s performance parameters are fit for a specific intended use. In other words this means that the work of an analyst is not finished when performance capabilities of a specific method (or preferably procedure ) are evaluated, but he/she has to go a step further and check whether these characteristics are in compliance with the client s needs. Of course, it is up to the client to specify his/her re-quirements/properties the result should have. Furthermore, ISO/IEC 17025 is introducing evaluation of measurement uncertainty as a mean of performing validation through systematic assessment of all quantities influencing the result. 

Validating and Refining the Model Once an initial set of simulations has been performed, validation against actual experimental data can be performed. During this phase, a priori simulations under a specific exposure scenario can be conducted and the simulation results compared with available experimental data. As an example, Figure 3.2 gives a comparison of experimental data and PBPK model simulations from Fisher and coworkers [17], who were interested in the disposition of TCE and its toxic metabolites. Parameters whose values were not available in the literature were adjusted to bring simulations in line with measured results over a series of different simulations. 

Personnel with appropriate qualifications and experience should be responsible for performing validation. They should represent different departments depending on the validation work to be performed. 

Worst case perform validation under different conditions (e.g. speed, data volume, frequency). 

The process of method development and validation covers all aspects of the analytical procedure, and the best way to minimize method problems is to perform validation experiments during development. 

One performance validation material that is often used is 4,4 -azoxydianisol, which undergoes a solid-to-liquid crystal (anisotropic) transformation at around 115°C, followed by an anisotropic to isotropic conversion at around 134°C. 4,4 -Azoxydianisol can be thermally cycled and used repeatedly. This sample enables resolution, sensitivity, and signal and noise to be established quickly on any DSC system. Figure 2.14 shows the data from a single 4,4-azoxydianisol sample, but displayed at two different sensitivities, so that small transitions at 135°C can easily be seen. This material has been suggested as a useful sample to compare the performance of various DSC systems (6). 

The development of a VMP requires several decisions. If the facility is new, due consideration is given to determine, on time, the target dates for routine production to ensure completion of validation for facility approval otherwise manufacturing at risk is the alternative choice. The deadline determination provides ample opportunity to perform validation of utilities, critical equipment installation, and qualification prior to construction work. In addition, it provides a sufficient time frame to identify the critical processes and steps involved. The parameters critical for each step shall be established. The critical equipment required shall be determined. Critical processes, steps involved, parameters, and equipment are identified. For existing facilities, establish the criteria for revalidation based on known vulnerabilities and engineering projects in progress. 

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