Revalidation

The revalidation process is essential to maintain the validated status of the plant, equipment, manufacturing processes, and computer systems. It should be as important as calibration and maintenance. 

Possible reasons for starting the revalidation process include  

Changes to the product, the plant, the manufacturing process, the cleaning process, or other changes that could affect product quality 

Note to point 1 For the transfer of a product from one plant to another qualified production plant, it is essential to revalidate the entire manufacturing process in the new plant. It is possible that several new critical or noncritical parameters must be determined. 

Note to point 2 In the case of the following changes, revalidation might be necessary  

According to the validation life cycle,test methods may reqnire additional validation or revalidation when regnlatory agencies issne new reqnirements or when changes are made to the methodology. Method changes and additional validation activities may be required when there are 

Revalidation may be necessary after changes in (a) drug substance synthesis, (b) drug product composition, and (c) the analytical procedure. The degree of revalidation required depends on the nature of the changes made. 

Any discussion of the method development/validation process should consider obtaining a sufficient quantity of a qualified reference standard and appropriate samples to support the development and validation campaign. In most cases, the limit of the accuracy of the analytical test will be related to the correctness of the standard s assay. There is little consensus on the common requirements of reference standards as outlined by the regulatory authority typical practice favors an approach of thorough analytical characterization of the standard supported by adequate documentation. 

Primary reference standard of the active compound. The standard of an active compound is typically comprehensively characterized. Table 3 lists the detail required. 

Secondary standard (working standard). A material of high purity that has been characterized against a primary or compendial standard. A secondary standard is often used to conserve the amount of primary standard. 

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. 

The extent of revalidation required for formulation changes should be determined on a case-by-case basis. Slight adjustments to the formulation may not require further validation work. This would include an adjustment of the excipient ratios, a change in tablet shape, etc. Specificity and accuracy should be re-evaluated for the inclusion of a new excipient into the formulation (e.g., antioxidants, dyes, preservatives). A change in the formulation such as going from a tablet to a capsule or from a liquid to a solid would mean a significant change to the formulation and complete validation should be performed. 

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 

Eventually, even well-validated methods become dated and obsolete due to improvements in technology. When this occurs, development of a new method using the new technology should occur and start a new round of method-validation activities. Any change to the method should take into account the effect on the long-term data for the product. Comparison of the validation for the old and new procedures should verify that the change will provide some benefits before it is accepted. 

It is the responsibility of the validation team members to follow the procedures. The quality assurance manager is responsible for SOP compliance. 

Revalidation provides a guarantee of consistent system, process, or equipment usage. It assures that monitoring controls are sensitive enough to identify major problems or drifts in quality and that process or equipment variations have no adverse effect on quality. 

Hardware and software Cleaning agents Material changes Supplier change 

Note Prior to starting the revalidation, it should be evaluated whether the whole or only a part of the system, process, or equipment has to be revalidated. 

In the event that no major changes are brought into the systems, process, and facilities, retrospective validation shall be conducted every 3 years. 

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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. 

Some of the pre-startup activities may need to be revisited when physical increases in volume and changes to equipment are planned. A PHA may need to be revalidated prior to implementing such a change to evaluate any secondary issues it could cause. 

The employer establishes a system to promptly address the team s results, timely resolve recommendations, schedule completion, and communicate the activities to affected personnel, livery five years after the completion of the initial process hazard analysis, it is equivalently updated and revalidated. Employers retain the required process hazards analyses for the life of the nmei-v -.. 

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. 

Second, the efficiency of exonucleases and endonucleases in hydrolysing DNA is greatly affected by modification of the bases (Dizdaroglu et /., 1978 Breimer, 1991). For example, Maccubbin et al. (1991) reported that the presence of 8-OH-Gua severely inhibits digestion of dinucleotides by phosphodiesterase. Thus it is not always certain that modified bases are completely hydrolysed from DNA, especially when published hydrolysis techniques are transplanted from one laboratory to another and not revalidated. 

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). 

Frank, W. I. and Whittle, D. K. (2001) I Revalidating Process Hazard Analysis (AIChE). 

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. 

I think it is important not to always presume vendors of components are infallible— neither the IC manufacturers nor the discrete suppliers. We must look at any data with our own judgment and experience. I personally think Murata needs to revalidate their ESR data, or at least the design tool that generated the curves shown in Figure 4-9. 

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. 

Each PrHA must be updated and revalidated at least every 5 years after its initial completion to assure that it is consistent with the current process. 

In each case where there is no unequivocal answer to a question in the flowcharts either further investigations or modifications to the process or equipment are required. The next step in the overall evaluation of the process is the determination of the consequences of possible deviations (also known as failures or upsets). If the evaluation of upsets results in process or equipment changes then the normal operation evaluation needs to be revalidated. 

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. 

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... 

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