USP <1225>

Validation of Compendial Methods is a procedure to prove through a series of studies that a particular method will meet the intended analytical application. Those studies being that of:

  • Accuracy
  • Precision
  • Specificity
  • Detection Limit
  • Quantitation Limit
  • Linearity
  • Range
  • Ruggedness

Data Elements Required For Assay Validation

Compendial assay procedures vary from highly exacting analytical determinations to subjective evaluation of attributes. Considering this variety of assays, it is only logical that different test methods require different validation schemes. This chapter covers only the most common categories of assays for which validation data should be required. These categories are as follows:

Category I: Analytical methods for quantitation of major components of bulk drug substances or active ingredients (including preservatives) in finished pharmaceutical products.

Category II: Analytical methods for determination of impurities in bulk drug substances or degradation compounds in finish pharmaceutical products. These methods include quantitative assays and limit tests.

Category III: Analytical methods for determination of performance characteristics (e.g., dissolution, drug release).

Category IV: Identification tests.

For each assay category, different analytical information is needed. Listed in Table 2 are data elements normally required for each of the categories of assays.

Analytical Performance Characteristics Assay Category I Assay Category II Assay Category III Assay Category IV
Quantitative Limit Test
Accuracy Yes Yes * * No
Precision Yes Yes No Yes No
Specificity Yes Yes Yes * Yes
Detection Limit No Yes * No
Quantitation Limit No Yes No * No
Linearity Yes Yes No * No
Range Yes Yes * * No
*May Be Required, Depending On The Nature Of The Specific Test.
The validity of an analytical method can be verified only by laboratory studies. Therefore, documentation of the successful completion of such studies is a basic requirement for determining whether a method is suitable for its intended applications. Appropriate documentation should accompany any proposal for new or revised compendial analytical procedures.

USP <1226>

The verification process for compendial test procedures is the assessment of whether the procedure can be used for its intended purpose, under the actual conditions of use for a specified drug substance and/or drug product matrix. If the verification of the compendial procedure is not successful, and assistance from USP staff has not resolved the problem,it may be concluded that the procedure may not be suitable for use with the article being tested in that laboratory. It may then be necessary to develop and validate an alternate procedure, as is outlined in USP <1225>.

Verification requirements should be based on assessment of the complexity of both the procedure and the material to which the procedure is applied. Although complete re-validation of a compendial method is not required to verify the suitability of a procedure under actual conditions of use, some of the analytical performance characteristics listed in chapter <1225> may be used for the verification process. Only those characteristics that are considered to be appropriate for the verification of the particular procedure need to be evaluated. The process of assessing the suitability of a compendial analytical test procedure under the conditions of actual use may or may not require actual laboratory performance of each analytical performance characteristic. The degree and extent of the verification process may depend on the level of training and expertise of the use, on the type of procedure and it’s associated equipment or instrumentation, on the specific procedural steps, and on which article(s) are being tested.

Verification should assess whether the compendial procedure is suitable for the drug substance and/or the drug  product matrix, taking into account the drug substance’s route, the method of manufacture for the drug  product, or both, if applicable. Verification should include  an assessment of elements such as the effect of the matrix  on the recovery of impurities and drug substances from the drug product matrix, as well as the suitability of chromatographic conditions and column, the appropriateness of detector signal response, etc.

Verification is not required for basic compendial test procedures that are routinely performed unless there is an indication that the compendial procedure is not appropriate forthe article under test. Examples of basic compendial procedures include, but are not limited to, loss on drying, residue on ignition, various wet chemical procedures such as acid value, and simple instrumental determinations such as pH measurements. However, for the application of already established routine procedures to compendial articles tested for the first time, it is recommended that consideration be given to any new or different sample handling or solution preparation requirements.

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