Method revalidation

If uneontrolled, temperature ean have a signifieant effeet on reprodueibility and the robustness of separations. This ean eause major problems in metlrod transferability between laboratories and at its worst ean require a method to be reoptimised or revalidated. Most separations therefore require a tlrermostated environment. However, the important faetor is tire temperature witlrin the eolumn bed, not just the sunounding enelosure. Cireulating ah ovens, statie air ovens, metal bloek heaters and eireulating water baths ean all generate different effeetive temperatures even if set to the same nominal values. 

If the analytical method survives all of the above criteria (suitably modified to match the situation), it is considered to be under control. Changing major factors (instrument components, operators, location, etc.) means revalidation, generally along the same lines. 

The underlying calibration procedure of a newly developed analytical method has to be examined by basic validation studies to determine the reliability of the method and its efficiency in comparison with traditional methods. In order to ensure long-term stability, it is necessary to perform revalidations, which can be combined with the use of quality control charts, over meaningful time periods. 

When no validation data are available, then all of the relevant parameters will have to be studied. The degree of rigour with which the study is carried out will depend on issues such as criticality of the measurement and the availability of validation data on similar methods. There will be cases in the laboratory where a method has been used, satisfactorily, for a long period of time but there is no documentation to demonstrate the performance of the method. It seems unreasonable to require full revalidation when a method has been used successfully for some years. However, the need for objective evidence prevents the validity of such a method being taken for granted. A possible approach is to follow the plan below ... 

Method validation is carried out to provide objective evidence that a method is suitable for a given application. A formal assessment of the validation information against the measurement requirements specification and other important method performance parameters is therefore required. Although validation is described as a sequential process, in reality it can involve more than one iteration to optimize some performance parameters, e.g. if a performance parameter is outside the required limits, method improvement followed by revalidation is needed. 

In the early stages of new product development, it may not be necessary to perform all of the various validation studies. However, the process of validating a method cannot be separated from the actual development of the method conditions, because the developer will not know whether the method conditions are acceptable until validation studies are performed. The development and validation of a new analytical method may therefore be an iterative process. Results of validation studies may indicate that a change in the procedure is necessary, which may then require revalidation. During each validation study, key method parameters are determined and then used for all subsequent validation steps. 

In the pharmaceutical industry, chromatographic QC methods are often used with no changes over long time frames. The basic reason for this is the amount of effort necessary for a complete revalidation of a method on a new column brand. Because of these constraints, chromatographic columns should be chosen from reliable and reputable manufacturers that can sustain a reproducible production of the columns over such extended time periods. Until recently, the capability of column manufacturers to reproduce the packing materials was not known, and users needed to rely on their intuition and trust the column manufacturers. 

Upon identification of a new source for API, or in the event that the current API supplier makes any significant change to the approved synthetic process, revalidation should be considered. At a minimum, specificity of the method should be re-evaluated to ensure that any new process impurities and/or synthetic intermediates, precursors, etc. do not interfere with the analyte of interest. Revalidation is complete if the specificity study demonstrates that the change to the API has no adverse affect on the performance of the method. If the method is affected and changes are required, revalidation should proceed according to an original plan. 

In many cases the purchase of new equipment for use with validated methods is not considered as a means for revalidation. Instruments that are reportedly equivalent to models used during validation have repeatedly caused problems due to unknown or minor changes. For... 

A. Case Studies Requiring Revalidation and New Method Development... 

During the life of a drug substance or drug product, changes in raw materials or processing may result in the current method becoming inadequate for its original purpose. This may require a revalidation of the current method or the development of a completely new method which will need to be validated. In other cases, while the method provides appropriate... 

Initially, robustness testing was performed to identify potentially important factors, which could affect the results of an interlaboratory study.Therefore, the robustness test was executed at the end of the method validation procedure, just before the interlaboratory study. Flowever, a method found to be non-robust should be redeveloped and revalidated, leading to a waste of time and money. For these economical reasons, nowadays, method robusmess is verified at an earlier stage in the lifetime of the method, i.e., at the end of method development or at the beginning of the validation procedure. ... 

This chapter deals with the validation of capillary electrophoresis (CE) methods. It describes the various validation characteristics, namely accuracy, precision, specificity, detection limit, quantitation limit, linearity, and range in accordance with the official guidelines. Practical aspects related to the calculation of these parameters and factors affecting them in CE analysis have also been described. Validation requirements have been described according to the goal of the method. The chapter contains numerous tables and diagrams to illustrate these ideas. It also covers other related aspects such as instrument qualification, revalidation, and method transfer. 

According to the ICH guideline, revalidation of a CE method is necessary in case of a major change, e.g., in the synthesis of the drug substances, in the composition of the finished product, or in the analytical procedure [ICH Q2 (Rl)]. ... 

Methods have successfully been transferred to various laboratories in inter-company cross-validation exercises for a chiral separation, for an assay of the main component in a formulation and for drug stoichiometry. Revalidation is an alternative to method transfer in case of changes in product composition or analytical procedure (cf. Section I.L). Although a method transfer in CE is not a major difficulty, some aspects have to be considered, especially if a method is transferred to an instrument of another manufacturer. 

A revalidation of linearity should not be required. Deviations from linearity are rare when PAs are used for calibration. If they occur, they are certainly dependent on the method (e.g., overload effects). 

There are various circumstances under which a method needs to be revalidated. Some of the common situations are described below ... 

During the optimization of the drug substance synthetic process, significant changes were introduced into the process. To ensure that the analytical method will still be able to analyze the potentially different profile of the API, revalidation may be necessary. 

If a new impurity is found that makes the method deficient in its specificity, this method will need to be modified or redeveloped and revalidated to ensure that it will be able to perform its intended function. 

A change in the excipient composition may change the product impurity profile. This change may make the method deficient in its specificity for the assay or impurity tests and may require redevelopment and revalidation. 

Changes in equipment or suppliers of critical supplies of the API or final drug product will have the potential to change their degradation profile and may require the method to be redeveloped and revalidated. 

Validation is required in the first place for any new method. As the definition says, validation always concerns a particular analytical system. This means that for a particular type of material and a particular operating range of concentrations, the method must be able to solve a particular analytical problem [4]. As a consequence, revalidation is needed whenever any component of the analytical system is changed or if there are indications that the established method does not perform adequately anymore [15,56, 57]. 

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