Qualification, Validation, and Verification - Pharmaceutical Technology

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Qualification, Validation, and Verification
This article considers the distinction among the terms qualification, validation, and verification in the context of pharmacopeial usage.A recommendation for a standardized usage of the terms validation and verification is provided,and general requirements for validation and verification activities are given.The article also emphasizes the importance of knowing when validation or verification is necessary relative to the use of a method to satisfy pharmacopeial article requirements (for which a monograph..


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Range is directly related to linearity, and ties in accuracy and precision as well. It represents the lowest and highest quantities of material of interest contained within the samples under analysis that provide data with acceptable accuracy, precision, and linearity.

Detection limit represents the least amount of material of interest contained within the sample under analysis that produces a signal exceeding the underlying noise. No assertions pertaining to accuracy, precision, and linearity are necessary at this level of material of interest. For example, if a method is validated to have a detection limit of 3 ng of total protein using Method 3 (1), then a sample containing 3 ng would elicit a signal discernible from underlying noise. It would not be possible to state from such data alone whether there was in fact an exact quantity ng of protein in the sample, only that there were at least 3 ng.

Quantitation-limit determination is more demanding in that currently it is necessary to establish the minimum quantity of material of interest contained within the sample that produces a signal that lies within the linear range of data. That is to say, the quantitation limit represents the lowest end of the range.

Intermediate precision (ruggedness in USP Chapter ‹1225› [1]) pertains to the establishment of "...the effects of random events on the precision of the analytical procedure" (4). Referring to the previous discussion under accuracy pertaining to error components, intermediate precision considers random error introduced by such factors as specific equipment, analysts, laboratories, days, and so forth. It is not meant to include systematic error (bias).

Robustness is probably most directly related to the consideration of conditions under which a validated method is shown to be suitable. This text is very useful in considering robustness:

"If measurements are susceptible to variations in analytical conditions, the analytical conditions should be suitably controlled or a precautionary statement should be included in the procedure. One consequence of the evaluation of robustness should be that a series of system suitability parameters (e.g., resolution test) is established to ensure that the validity of the analytical procedure is maintained whenever used (4)."

General requirements for verification

One question that may be asked of the compendia is whether a method provided as official (in the compendia or supplements) requires validation. USP Chapter ‹1225› states:

"...users of analytical methods described in the USP-NF are not required to validate accuracy and reliability of these methods, but merely verify their suitability under actual conditions of use (1)."

This text is consistent with the proposal in this article that the term validation be reserved for the process whereby one determines if a given method is suitable for its intended purpose (which must be clearly defined), and that the term verification be reserved for the demonstration that the conditions under which the method is to be performed will be appropriate for the method.

Another question may be given that verification involves demonstrating that the conditions to be evaluated are suitable for use with the validated method, how does one go about assessing that? It should be evident that a subset of the determinations performed during the validation would be appropriate. Important conditions to consider include equipment, possible matrix effects (components included in the article to be tested that were not evaluated during the validation), and other conditions for which there is no clear indication provided in the method as to their suitability. A proposed new General Chapter ‹1226› "Verification of Compendial Procedures" (see reference 9 for a discussion of this chapter) provides some guidance as to how the verification process may be executed, but ultimately the user is responsible for selecting which of the characteristics (data elements) evaluated during the validation should be examined as part of the verification. The user should establish which of those validation characteristics are critical to the successful use of the validated method.


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