Compendial analytical

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. 

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. 

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... 

There are occasions where new analytical methods have to be developed specifically for testing raw materials, intermediates, and finished products that are not covered by compendial methods. In these situations, the analytical methods are required to undergo a validation process to ensure they are suitable. One or more of the following parameters as defined in Exhibit 9.10 must be validated for newly developed analytical methods ... 

Where the specific impnrity is unavailable or is too costly, the use of composite or degraded samples is possible. This approach involves the nse of a dirty sample of a drug substance or the creation of a mixture of impurities through the in situ forced degradation method. Both of these approaches are best nsed for qualitative uses. In each of these mixtures, the impurities are present in unknown quantities. The real benefit of this type of impnrity standard is the low cost and the ability to unequivocally identify the peak loci of the impurities. When these mixtures are used in conjunction with a compendial standard and a well-developed set of relative response factors the resnlts will meet most analytical needs. 

It is not required to have prior FDA approval to use an alternative method to a compendial test. According to 21 CFR 314.70 Supplements and Other Changes to an Approved Application, the addition or deletion of an alternative analytical method does not require prior approval and may be filed in the Annual Product Report. However, the equivalency of the alternative method needs to be documented... 

Guidance can be found regarding the validation of chemical methods applicable to mierobial testing. Examples inelude the USP Chapter (1225) Validation of Compendial Methods, and a recent publieation by the International Conference on Harmonization (ICH) Validation of Analytical Methods. These publications provide specific instruction regarding the demonstration of new ehemical analytical methods and then-equivalence to existing methods. 

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. 

When the specification for a compendial excipient differs from the compendial monograph (e.g., additional tests, different analytical methods, or different acceptance criteria) the test results will be accepted from the excipient manufacturer s COA. However, the excipient should still conform to the monograph in an official compendium if there is such a monograph otherwise, justifications must be provided, and labeling needs to be changed to state plainly that the article does not meet the compendial requirement. 

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. 

In 1970, scientists from the Pharmaceutical Analysis Section of the Academy of Pharmaceutical Sciences began to plan a cooperative venture to compile and publish a series of volumes entitled the Analytical Profiles of Drug Substances. The aim of the series was to provide information not available in the official compendial monograph of a drug substance, such as physical or chemical data, methods of synthesis, and pathways of physical or biological degradation and metabolism. Klaus Florey became the first editor of the series, and between 1972 and 1991 he edited the first 20 volumes in the Analytical Profiles series. 

Optical rotation has the dual advantages of historical use and widespread recognition in the compendia. For an enantiopure material, it defines its configuration when used in conjunction with other valid chemical tests. However, optical rotation has been used ineffectively when the primary analytical goal is the determination of stereochemical purity. The limits selected for the specification seem to be unrelated to the purity required by other methods. For example, the compendial monograph for naproxen requires that the drug substance meet a specification of "between -f-63.0 and -1-68.5"" in a chloroform solution. Based on the published specific rotation, this corresponds to a stereochemical purity of 95.5 to 103.7%, compared to the assay limits of 98.5 to 100,5%, determined by titration with sodium hydroxide (5). 

Method validation is a process by which documented evidence is prepared and provided to show that the method meets the intended need. Highly regulated pharmaceutical analytical laboratories perform method validation and generate data on the following parameters, to comply with the compliance requirements of government agencies such FDA, EPA and/or to provide data for compendial agencies like USP, BP, etc. 

Analytical method validation should track closely to the stages of development of the method itself However, it is not realistic to expect complete and thorough validation of the method until its development cycle is complete. An exception to this would be a situation where an accepted compendial method is applied to clinical material (such as a dissolution test or release testing of a compendial component). In these cases, companies must be prepared to demonstrate that consistent acceptable results can be obtained when using the compendial method in the company s laboratory (also known as methods verification). The obvious... 

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... 

An interesting historical change in the orientation of the USP is implicit in this discussion. Until the age of instrumentation, there was an expectation that compendial methods could be performed in a community pharmacy. What became possible decided where it could be done, and the focus moved out of the pharmacy and into the central analytical laboratory. 

The advance of pharmaceutical technology ever forces forward new or refined excipients, some with heretofore unexploited properties. Polymers are a case in point and have been central to many of the technological advances of recent years. New and different challenges for compendial standards are offered by materials used in new wave formulations. Modern analytical chemistry allows rather thorough evaluation of materials. 

Then a known concentration of each analyte is prepared. The absorbance of these solutions are measured at each of the two wavelengths. Solving the two simultaneous equations, two equations for c and C2 are obtained. Then the known values of individual concentrations and calculated values of the four molar extinction coefficients are substituted in the derived equations to arrive at the unknown concentrations of the two components in the mixture. Multicomponent analysis is normally used in the dissolution testing of tablets. Standard hardware and software components for multicomponent dissolution testing based on compendial method are available from instrument manufacturers. 

It is generally expected that an analytical method will perform in an acceptable manner each time it is used. While a consideration of method ruggedness is a necessary part of any method s validation, it is a critical issue for compendial methods because of their widespread use in many different laboratories. 

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. 

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