Revalidation of methods

Revalidation of methods is the approach by which methods are be transferred based on a complete revalidation of already existing fully vahdated methods. With this mode of transfer no prior agreement is required in deciding what analytical figures of merit require revalidation. Because use of preselected 

TABLE 16-6. Validation of Analytical Fignres of Meril Example of Acceptance Criteria 

The other aspect of this mode of transfer is that it does not normally require comparison of data generated at the receiving lab with data previously reported by the originator lab. The receiving labs are certified to perform the tests once they complete revalidation of the methods. 

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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. 

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)]. ... 

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 situations during the life cycle of a dissolution test that will require revalidation of the method. These are similar to those described for the potency assay in Chapter 2. 

In practice, the sheer nature of the dynamic validation process results in a substantiation of the original validation throughout the useful life of the method. As previously mentioned, a well-developed and-written method includes system suitability that must be met each time the method is performed. Additionally, the pharmaceutical industry has standardized on the need of formal method transfer exercises whenever an analytical method is to be performed by a different laboratory or in another facility. Also, change control procedures may require the revalidation of part or all of the method in the event of changes to the method, the process, or the formula of a drug product. The QAU should therefore have a system to formally monitor the... 

In order to have confidence that the chain of supply is not only operating properly, but to confirm that water quality is being maintained and achieved, verification is required. Verification is the use of methods, procedures or tests, in addition to those used in operational monitoring, to determine whether the water safety plan complies with the stated objectives outlined in the water quality targets, or whether it needs to be modified and revalidated. 

Unlike transfer from AR D to QC, methods available at this time may not have been fully vahdated and may either be Tier 1 or Tier 2 methods (Table 16-1). Depending on the status of the project at the time of the transfer, the receiving lab may have to redevelop and revalidate the methods. Transfer under this mode can be prompted by legally mandated timeline, especially in a merger situation, to ensure the timely and complete transfer of technology to the receiving lab. Assessment of success or failure of transfer may not be... 

Once the method is vahdated, any modification requires revalidation to demonstrate that it still works as defined. If the new parameter is within the tolerance range of the method as specified during the ruggedness test of method validation, the method does not need to be revalidated. In other cases, it should go through revalidation. With the system suitability software frequently offered by analytical equipment vendors, methods can be automatically revalidated with little operator interaction. The validation can be performed overnight. 

Finally, McGonigle discusses the types of method modifications that require revalidation. Any modification that could potentially affect the accuracy, precision, linearity, and range of a method require revalidation of these parameters. 

As a compound proceeds into first-in-human clinical trials, the assay method reaches an apex in terms of performance. These methods require maximal sensitivity to be able to support dose escalation studies. The selectivity of the method is well established versus matrix components, concomitant medications, and metabolites. The assay is revalidated in the human matrices (plasma, serum, and urine) and will again meet well-established guidelines for inter- and intraday precision and accuracy. If significant changes are made to the method, a comparison of methods study will be conducted to understand the relative accuracy of the methods. After this benchmark, assay requirements, especially limit of quantitation, are usually less demanding and use of the assay becomes more routine, as it is applied again and again to additional clinical studies for pharmacokinetic support. 

Method transfer is loosely defined as a process that qualifies a laboratory to use a test procedure or analytical method. According to this definition, any and all means of having a laboratory qualified would meet the criteria for transfer. The most common variations of method transfer are comparative testing, covalidation between two laboratories or sites, complete or partial method validation or revalidation, and the omission of formal transfer processes, sometimes termed the transfer waiver. ... 

In many cases and circumstances of the daily quality control of analytical work RMs and CRMs are helpful tools. Very often RMs are sufficient, in particular for statistical control actions. Where a rough estimate of accuracy or even precision is sufficient, a simple RM or calibration material is also largely adequate. However, for the establishment of the accuracy in the procedure of method development and validation, for revalidation of modified methods or whenever the analyst needs to demonstrate accuracy, e.g. measurements for court cases, CRMs should be employed as they have the advantage of being certified. It will be up to the operator and the laboratory s quality management to determine when, where, and how RM or preferably CRMs shall be used. 

One should verify that the method of recordkeeping in the development laboratory follows what is stipulated in the FDA s Laboratory Inspection Guide, from June 1992. The system should also be evaluated for the transfer of validated analytical methods. On-site validation of the method is required for analytical methods validated at another laboratory. A written procedure should be available covering both the transfer of methods and onsite validation and revalidation. When contract laboratories are being used, verification that the laboratory is using the correct analytical methods and specifications should be performed. 

If a method is being established at more than one location, it is essential that it is adequately demonstrated that the method is performing the same at all locations. In addition, should a method need to be changed from one kit to another (maybe different manufacturers) or where major changes in kit components have been made (e.g., antibodies), then it is essential that besides revalidating the method, it is also demonstrated that it is producing the same analytical results as the previous method for continuity of the study. 

The features of a particular biopharmaceutical are the result of the basic characteristics of the molecule such as amino acid sequence and three-dimensional structure as well as the specihc production, purihcation, formulation, and storage conditions (Box 12.4-2). To produce a biopharmaceutical of constant required quality, a company also needs the experience and the in-house standards to apply the methods used to analyze the structure of a given product. There are various guidelines of the European Medicine Evaluation Agency, the Food and Drug Administration, the Japanese Ministry of Health and Welfare, and the ICH, which require manufacturers to show that they control the production process and are capable of reproducibly manufacturing batches that not only meet product specih-cations, but also conform to the dehnition of the product as established through full characterization. Modihcations of the established process are only accepted if the manufacturer can show that the product of the new process is comparable with the initially manufactured product. Comparability studies include revalidation of... 

Miniaturization of the column is now slowly appearing on the agenda, and at many places is at least a discussion subject. An important hurdle to be overcome when promoting a shift towards lower diameter and length of the columns is certainly the immense effort necessary in strongly regulated laboratories to admit and revalidate new methods. 

Precision and recovery data. Validation data can be gathered for toxin analogues calibrated by RRFs. " Blank seafood matrices can be fortified with aliquots of semi-purified extracts of contaminated shellfish or algae containing the toxins of interest. Comparison to an aliquot spiked into solvent enables calculation of recovery and replication enables determination of precision. Thus, several key elements of method validation can be accomplished without a CRM and only minimal revalidation is required when one comes available. 

Validation of analytical methods used in the finished product specification is required in the same way as for drug substance. Revalidation of these methods may also be necessary if the composition of the product has been changed during development, e.g. to reassess specificity. 

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