Analytical validation reference standards

The benefits of producing good data are therefore broad and impinge on all of our daily lives, whether it is food, environment, health or trade. Laboratories that produce valid measurements have a higher status in the analytical world, since they produce data that are demonstrably traceable to a reference standard and reliable, with the cost of correcting bad data being lower. This means that such laboratories have a better chance of competing in the open market. 

A rationale should be generated to explain and support the reasoning for validating the selected parameters. The use of reference standards during validation helps to reinforce the reliability of the analytical method developed. The conditions of how a test is performed may have a strong influence on the results. These conditions have to be recorded and followed. 

Use of Standardized Methods The first level of AQA is the use of validated or standardized methods. The terms validated and standardized here refer to the fact that the method performance characteristics have been evaluated and have proven to meet certain requirements. At least, precision data are documented, giving an idea of the uncertainty and thus of the error of the analytical result. In both validated and standardized methods, the performance of the method is known. 

Analytical reagents used in testing the excipients should be prepared and labeled following established procedures. Retest or expiration dates should be used, as appropriate, for analytical reagents, or standard solutions. Analytical methods should be validated unless the method employed is set forth in the current revision of the United States Pharmacopeia/National Formulary, Association of Official Analytical Chemists (AOAC), Book of Methods, or other recognized standard references, or detailed in the Drug Master File or approved New Drug Application and are used unmodified. 

R, the NARL reference analytical value (accompanied by measurement uncertainty estimate) traceable to SI through the validated test method used and the pure substance reference standards used to calibrate the measuring instrument... 

Before an analytical method can be validated, it is necessary to qualify those materials that will serve as reference standards. To allow for expeditious validation, it is important to source and/or synthesize and characterize... 

Identify all samples being set aside for FDA validation. The samples should include drug substance, drug product, major impurities, and degradation products being controlled for, references standard, and internal standard (the latter is not required if commercially available but is recommended to facilitate FDA laboratory work). If appropriate, blanks and any other materials not commercially available but specified in the analytical procedures should be provided. The samples are to be maintained by the sponsor until the FDA s reviewing chemist provides instructions as to where they should be forwarded. The total quantities and the manner of their subdivision (e.g., 400 tablets, 4 x 100 tablets/ bottle) should be indicated. The amounts provided should be adequate to permit at least three separate determinations, excluding sterility, by two different laboratories. 

The validity of the method of standard additions depends on the forms of the analyte element in the sample and in the added standard responding in the same way during the atomisation step. This may not always be so in practice. For example, in determining lead in whole blood by this method it would have to be proved (or assumed) that lead added as a lead nitrate solution is atomised to the same extent as lead bound organically in the sample. This is most easily checked by running a certified standard material through the procedure. If no such reference standard exists, as with the above blood example, the sample should also be run after pre-treatment for removal of the matrix, e.g. wet or dry ashing, and the results compared. 

Some degradation products are either very polar or very nonpolar in nature this may present an issue in chromatography, where they may not be retained or strongly adsorbed on the column, respectively. One may also want to double check the reference standard for its purity, moisture content, and/or salt/ acid-base ratio for calculation. An analytical chemist must remember to explore all possibilities if mass balance issue is observed (either during method development, validation and/or stability testing). 

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. 

DNA technology, in particular, is having a revolutionary effect on a host of industrial and regulatory sectors. This area is rapidly developing and offers tremendous advantages and benefits to industry, but there is an urgent need for parallel validation of the analytical techniques employed in DNA-based measurements and development of tools to enhance validity such as suitable reference standards. Analytical molecular biology has typically been developed, and is most often employed, in academic and medical research environments where there is little need to consider the more routine applicability, reliability and reproducibility of the methods. Evaluation of these factors and further validation of the methods is therefore necessary, particularly when such techniques are applied to the analysis of real samples. 

Basic chemical data, identification, purity and test methods should follow the Guidelines Setting Specifications and Test Methods of New Drugs , notified in May 2001. Several others dealing with analytical validation, impurities or residual solvents were established on the basis of ICH agreements. When available, standards published in the JP or other quality standards (cf. section on Quality standards ) represent the references for specifications and test methods. 

In this section, guidance is given on the selection of reference standards and materials, as well as analytical method validation. 

Any discussion of the method development/validation process should consider obtaining a sufficient quantity of a qualified reference standard and appropriate samples to support the development and validation campaign. In most cases, the limit of the accuracy of the analytical test will be related to the correctness of the standard s assay. There is little consensus on the common requirements of reference standards as outlined by the regulatory authority typical practice favors an approach of thorough analytical characterization of the standard supported by adequate documentation. 

Information on impurities, including their structure, acceptance limits, and control, is to be briefly described. For control of a drug substance, specifications (including justifications) and analytical procedures (including validation information) used for testing are to be summarized. Data on reference standards or reference materials used for drug substance testing are to be provided. Information on batches and the results of batch analyses are to be described. 

Using tables and graphs as appropriate, control of a drug product is to be briefly described and is to include information on specifications and their justification, analytical procedures and their validation, and characterization of impurities. Also, information on reference standards or materials used for control of a drug product should be provided. 

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