Validation process specifications

Construction and equipment meet the design specifications. Obtaining field verification or performing document review for the new or modified process can validate design specifications for construction and equipment. If a change is not physical (such as a setpoint for an interlock shutdown), the method for the change and its anticipated effects should be reviewed. 

Following development of the study direction, the evaluation describes the efforts of obtaining and validating process information, and then discusses equipment specifications and a cost estimate of the feasibility or budget type i.e., with plant costs factored from major material. Finally, project economics and financing complete the evaluation. 

Production and service provision - Operate production and service provision under controlled conditions, maintain batch records, validation processes that cannct be verified, maintain identification and traceability of materials, address specific requirements for sterile products, provide suitable conditions for storage and distribution... 

The positive results obtained at production scale give us confidence in the validity of our approach. Derivation of a simple scaling factor enabled us to conduct a series of experiments in a small pilot plant which would have been expensive and time-consuming on a production scale. Time series analysis not only provided us with estimates of the process gain, dead time and the process time constants, but also yielded an empirical transfer function which is process-specific, not one based on... 

The validation process is subject to the following design specifications, user and performance requirements, preparation of a master plan/validation protocol (installation qualification, operational qualification, and performance qualification), execution of the protocol, preparation of a summary report, and on-going validation (and revalidation if changes are made). 

Focusing on validation process of in vitro methods, it is possible to underline some differences between tools for research and ones for toxicological testing. A research model is validated when there are some specific evidences confirming that the information from the model is able to correctly describe the process in the intact animal. Tools for toxicity testing are often used to evaluate safety hypothesis so they can be used without requiring in vivo confirmation. They are validated using a subset of well-known materials and, once validated, systems will be applied to new unknown materials or mixtures in order to evaluate their toxicity and compare their potential with other chemicals. 

Selectivity and specificity are important performance characteristics of analytical procedures, especially in connection with validation processes. Nevertheless, both terms are used mostly verbal and a quantification is avoided, as a rule (IUPAC see Vessman et al. [2001]). Moreover, the concepts of selectivity and specificity are used interchangeably and synonymously. Occasionally, specificity is regarded as an intensification of selectivity, viz. the ultimate of selectivity (den Boef and Hulanicki [1983] Persson and Vessman [1998, 2001] Prichard et al. [2001]). 

Method validation is defined in the international standard, ISO/IEC 17025 as, the confirmation by examination and provision of objective evidence that the particular requirements for a specific intended use are fulfilled. This means that a validated method, if used correctly, will produce results that will be suitable for the person making decisions based on them. This requires a detailed understanding of why the results are required and the quality of the result needed, i.e. its uncertainty. This is what determines the values that have to be achieved for the performance parameters. Method validation is a planned set of experiments to determine these values. The method performance parameters that are typically studied during method validation are selectivity, precision, bias, linearity working range, limit of detection, limit of quantitation, calibration and ruggedness. The validation process is illustrated in Figure 4.2. 

Computer validation establishes documented evidence to show that the computerized system will consistently function and meet its predetermined specification and quality attributes with a high degree of assurance. Some of the parameters tested in the validation process include the following ... 

There are occasions where new analytical methods have to be developed specifically for testing raw materials, intermediates, and finished products that are not covered by compendial methods. In these situations, the analytical methods are required to undergo a validation process to ensure they are suitable. One or more of the following parameters as defined in Exhibit 9.10 must be validated for newly developed analytical methods ... 

HPLC methods can usually be transferred without many modifications, since most commercially available HPLC instruments behave similarly. This is certainly true when the columns applied have a similar selectivity. One adaptation, sometimes needed, concerns the gradient profiles, because of different instrumental or pump dead-volumes. However, larger differences exist between CE instruments, e.g., in hydrodynamic injection procedures, in minimum capillary lengths, in capillary distances to the detector, in cooling mechanisms, and in the injected sample volumes. This makes CE method transfers more difficult. Since robustness tests are performed to avoid transfer problems, these tests seem even more important for CE method validation, than for HPLC method validation. However, in the literature, a robustness test only rarely is included in the validation process of a CE method, and usually only linearity, precision, accuracy, specificity, range, and/or limits of detection and quantification are evaluated. Robustness tests are described in references 20 and 59-92. Given the instrumental transfer problems for CE methods, a robustness test guaranteeing to some extent a successful transfer should include besides the instrument on which the method was developed at least one alternative instrument. 

Process validation, including dose settings for meeting process specifications... 

Revalidation is the repetition of the validation process or a specific portion of it. 

When new equipment is purchased or there is a change in the manufacturing site, qualification exercises are performed as part of the validation process. Qualification (installation qualification, operation qualification, and performance qualification) for any equipment or facility is an extreme process which involves testing, verification, and documentation to assure that the particular equipment or facility is per the specification and meets the appropriate standards as defined by vendor and required by manufacturing and engineering personnel [14]. 

Traceability and MU both form parts of the purpose of an analytical method. Validation plays an important role here, in the sense that it confirms the fitness-for-purpose of a particular analytical method [4]. The ISO definition of validation is confirmation by examination and provision of objective evidence that the particular requirements of a specified intended use are fulfilled [7]. Validation is the tool used to demonstrate that a specific analytical method actually measures what it is intended to measure and thus is suitable for its intended purpose [2,11]. In Section 8.2.3, the classical method validation approach is described based on the evaluation of a number of method performance parameters. Summarized, the cri-teria-based validation process consists of precision and bias studies, a check for... 

A VMP should be divided into chapters covering different subjects. First, an introduction should state the manufacture s validation policy, general description of the scope of those validation activities covered by the VMP, and their objectives, derivation, location, and schedule. Then, it must declare all validation activities and their organizational structure in terms of personnel responsibility for the VMP, validation protocols, validation work, report and document preparation projects, approval of the same validation protocols, reports in all stages of validation processes, and the training needs in support of validation. Other requirements of the VMP are cross references to other documents and to specific characteristics of the processes that are critical for yielding a quality product. Next, all validation activities comprised in the VMP should be summarized and compiled in a matrix format. Such a matrix should provide an overview and contain all items covered by the VMP that... 

In this chapter we guide quality assurance (QA) managers, lab managers, IT personnel, and users of equipment hardware and software through the entire qualification and validation process, from writing specifications and vendor qualification to installation and initial and ongoing operation. The following points are covered ... 

As discussed, the manufacture of suspensions presents additional problems, particularly in the area of uniformity. The development data should address the key compounding and filling steps that ensure uniformity. The protocol should provide for the key in-process and finished product tests, along with their specifications. For oral solutions, bioequivalency studies may not always be needed. However, oral suspensions, with the possible exception of some of the over-the-counter antacids, usually require a bioequivalency or clinical study to demonstrate their effectiveness. Comparison of product batches with the biobatch is an important part of the validation process. Make sure there are properly written protocol and process validation reports and, if appropriate, data for comparing full-scale batches with biobatch available during FDA inspection. 

The validity of a specific method should be demonstrated in laboratory experiments using test samples or standards that are similar to the unknown samples analyzed in the routine. For example, control tissue samples from non-treated animals, control tissue samples spiked with the analyte at several known concentrations, and dosed or incurred tissue samples from animals that have been treated with the drug, should all be available to the analyst before starting a validation process. All these samples will enable the analyst to define the background noise, to identify the amounts of the analyte added to the control tissue, and demonstrate that the method can satisfactorily recover the biologically incurred residue. 

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