Regulatory requirements
The integrity of reference standards must be proven for products that are used in registration applications, commercial releases,
stability studies, or pharmacokinetic studies. FDA requires reference standards to be of the "highest purity that can be obtained
through reasonable effort" and to be "thoroughly characterized to assure the identity, strength, and quality" (3). This requirement
is meant to ensure that the product being evaluated is accurately tested to determine the amount of API present and to classify
and identify related substances, process-related impurities, and degradation products.
To fully understand the development of a reference-standard material program, the required method validation needs to be discussed.
FDA requires noncompendial reference standards to be "of the highest purity" and asks that reference standards validate analytical
methods (1). This raises the question, Which requirement should be met first: the qualification of the reference standard
or its method validation? The answer is a compromise based on suitable parameters for the intended application.
Quantitative analytical procedures for impurities' content or limit tests for the control of impurities must be validated
and suitable for the detection and quantitation of impurities as directed by the International Conference on Harmonization
(ICH) (6). FDA cites "failure to submit well characterized reference standards" as a "common problem that can delay successful
validation" (3). An insufficiently characterized reference standard may delay or prevent FDA approval of a drug product to
market.
To ascertain the degree to which an analytical method is deemed suitable for its intended use, the validation parameters set
forth in ICH Q2(R1) Validation of Analytical Procedures (6) stipulates the following criteria:
- Specificity—evaluation of interference from extraneous components
- Linearity—linear range of the method
- Range—the interval between the lower and upper concentration amounts of analyte in the sample
- Accuracy—a measure of the closeness of agreement between the value obtained and the theoretical
- Precision—a measure of the closeness of agreement (degree of scatter) of the data values over a number of measurements (i.e.,
injection repeatability, analysis repeatability (multiple measurements, same analyst) and intermediate precision (multiple
measurements, different days, different analysts), reproducibility (precision between different labs)
- Detection limit—the lowest level the analyte can be detected
- Quantitation limit—the lowest level the analyte can be quantitated
- Robustness—effects of small changes in method parameters
- System suitability testing—evaluation of the suitability of the equipment.
Table I: Types of reference-standard material compared with recommended qualification.
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Not all parameters can be evaluated because a reference standard is required to perform quantitation. In this case, where
the reference standard is the sample, the parameters validated are restricted. However, the method can be assessed for parameters
applicable to evaluating the reference material. The analytical method is therefore qualified for use but not validated per
ICH guidelines. Table I presents recommended qualification parameters compared with reference-standard material type. ICH
also requires the reference material to be proven stable under the intended storage conditions for the intended use period
(7). The reference-standard material program, therefore, must be designed so that the material is assessed at its intended
storage condition over time.
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