Compendial analytical procedures

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. 

The USP methods contained in the monographs are considered validated. The USP states ... users of analytical methods described in USP-NF are not required to validate the accuracy and reliability of these methods but merely verify their suitability for use. Recognizing the legal status of the USP and NF standards, it is essential, therefore, that proposals of new or revised compendial analytical procedures are supported by sufficient laboratory data to document their validity. The Code of Federal Regulations also recognizes that USP methods are validated. The section on laboratory records [8] states Laboratory records shall include completed data derived from all tests necessary to assure compliance with established specifications and standards,... and further states if the method employed is in the current revision of the United States Pharmacopeia [or] National Formulary... and the referenced method is not modified, a statement indicating the method and reference will suffice [8]. 

Analytical procedures are classified as being compendial or non-compendial in character. Compendial methods are considered to be valid, but their suitability should be verified under actual conditions of use. To do so, one verifies several analytical performance parameters, such as the selectivity/specificity of the method, the stability of the sample solutions, and evaluations of intermediate precision. 

III The analytical procedures being transferred are compendial in nature, unchanged and fully described in the most recent USP-NF. In those cases, method verification is applicable, and is described in general... 

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. Only the most common categories of assays for which validation data should be required are covered. These categories are as follows (see also Table 1) ... 

The corresponding secretariats may have to add information essential to the understanding of the implementation of the texts (e.g., the description of an analytical procedure or of reagents that do not exist in the pharmacopeia) and a translation is added by the European and Japanese Pharmacopoeias. The style may be adapted to that of the pharmacopeia concerned or global style may be used. A pharmacopeia can add text, either to amplify some of the requirements with additional information or because national requirements and compendial policy dictate that the addition is necessary. However, there must be a clear indication that this additional information is not part of the harmonized document. This will avoid additional text being included after the harmonization process is completed, but will allow interested parties to review a complete text. The three pharmacopeias endeavor to publish the drafts simultaneously or as close together as possible. 

A regulatory analytical procedure is the analytical procedure used to evaluate a defined characteristic of the drug substance or drug product. The analytical procedures in the U.S. Pharmacopeia/National Formulary (USP/NF) are those legally recognized under section 501(b) of the Act as the regulatory analytical procedures for compendial items. 

Validation of analytical procedures is intrinsic to both new drug approval and compendial revision.The USP had already established an informational chapter, (1225) entitled Validation of Compendial Methods before the international harmonization effort began a... 

While compendial standards are available for some monographed article impurities, it may be difficult at times to obtain pure standards of impurities. Manufacturers of pharmaceuticals function as a potential source for obtaining reference standards of impurities, which may be synthesis precursors, process intermediates, or degradation products. The characterization and evaluation of these impurities reference standards should be constant with their intended use. In many cases, analytical procedures are developed and validated, where the response of an impurity is compared to that of the new drug substance itself. Response factor evaluation of impurities at the chosen detection wavelength is necessary to determine if a correction factor is needed (when the responses differ). Potentiometric detection, fluorescence/ chemiluminescence detection, and refractive index detection are some examples of detection modes available for compounds that may not be suitable for UV detection. 

Test methods—The analytical procedures used to test the finished API should be provided in the application. The level of detail is again subject to company philosophy however, sufficient detail should be included to provide the reviewer with a solid understanding of the method. In certain countries, the test methods may actually be run in an agency or contract laboratory, to confirm results on samples provided with the application. Certain tests can be performed using established compendial methods, with the compendial method referenced in the application. Often it is helpful to attach copies of these... 

Monographs provide specific tests, analytical procedures, and acceptance criteria for determining the strength, quality, purity, and potency for a given compendial article. Additional information such as storage conditions, nomenclature, chemical formulae, and the applicable USP Reference Standards are also included in the monograph. 

The validation requirements for USP monographs are addressed in General Chapters <1225> Validation of Compendial Procedures and <1227> Validation of Microbial Recovery from Pharmacopeial Articles. Chapter <1225> provides guidance for validating chemical and physical methods intended for submission as an official standard. The test is aligned with ICH documents Q2(R1), Q3A, Q3B, Q3C, Q6A, and Q6B [5-12]. The verification of the compendial procedure should be performed based on General Chapter <1226> Verification of Compendial Procedures and FDA guidances on analytical procedures, method validation, and CMC documentation. 

Transfers of analytical methods are also evaluated very critically, and analytical transfer plans with defined acceptance criteria are expected, as well as related transfer reports. On this topic, the USP <1224> Transfer of Analytical Procedures offers some guidance. For assistance on the confirmation of pharmacopoeia methods, the chapter USP <1226> Verification of Compendial Methods can be looked up. 

For non-compendial procedures, the performance parameters that should be determined in validation studies include specificity/selectivity, linearity, accuracy, precision (repeatability and intermediate precision), detection limit (DL), quantitation limit (QL), range, ruggedness, and robustness [6]. Other method validation information, such as the stability of analytical sample preparations, degradation/ stress studies, legible reproductions of representative instrumental output, identification and characterization of possible impurities, should be included [7], The parameters that are required to be validated depend on the type of analyses, so therefore different test methods require different validation schemes. 

Another useful pohcy type document is USP 37 monograph <1226> on Verification of compendial procedures [21], if you consider a pharmacopoeia as an analytical control laboratory transferring his methods to laboratories of companies. Documented evidence of suitability should be established under actual conditions of use. 

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