Quality Assurance of Pharmaceuticals - A Compendium of Guidelines and Related Materials - Volume 1
(1997; 248 pages) [French] View the PDF document
Table of Contents
Open this folder and view contentsIntroduction
Open this folder and view contents1. National drug regulation
Open this folder and view contents2. Product assessment and registration
Open this folder and view contents3. Distribution
Close this folder4. The international pharmacopoeia and related activities
View the documentGuidance for those preparing or commenting on monographs for preparations to be included in The international pharmacopoeia1
View the documentValidation of analytical procedures used in the examination of pharmaceutical materials1
Close this folderGeneral guidelines for the establishment, maintenance, and distribution of chemical reference substances1
View the document1. Criteria for determining the need for the establishment of chemical reference substances
View the document2. Evaluation of reference substances
Open this folder and view contents3. Chemical and physical methods used in evaluating reference substances
Open this folder and view contents4. Handling and distribution of reference substances
View the document5. Reference materials calibrated against International Chemical Reference Substances
View the document6. Means of promoting effective exchange of information and ensuring cooperation between organizations establishing reference substances
View the documentGeneral recommendations for the preparation and use of infrared spectra in pharmaceutical analysis1
View the documentList of available International Chemical Reference Substances1
View the documentList of available International Infrared Reference Spectra1
Open this folder and view contents5. Basic tests
Open this folder and view contents6. Laboratory services
Open this folder and view contents7. International trade in pharmaceuticals
Open this folder and view contents8. Counterfeit products
Open this folder and view contents9. Training
View the documentSelected WHO publications of related interest
View the documentBack cover

1. Criteria for determining the need for the establishment of chemical reference substances

The production, validation, maintenance, and distribution of chemical reference substances1 is a costly and time-consuming undertaking. It is therefore of great importance to limit the work involved by determining in a critical way whether a need for a given substance exists. Requests for new reference substances usually arise because a certain approach to the development of a specification for a new substance or product has been adopted. Methods may have been proposed in a specification that require the establishment of a reference substance for use as a comparative standard and the first matter that should be assessed, therefore, is whether some alternative procedure could be adopted that does not require a comparative standard and that might still be equally satisfactory. For example, an analytical procedure based on a stoichiometric relationship might be as valid, in a given context, as one based on ultraviolet absorption spectrophotometry and would obviate a possible need for a reference substance.

1 The term chemical reference substance, as used here, refers to an authenticated uniform material that is intended for use in specified chemical and physical tests, in which its properties are compared with the properties of a product under examination, and that possesses a degree of purity adequate for its intended use.

The types of analytical procedure at present used in specifications for pharmaceutical substances and products that may require a chemical reference substance are:

(a) infrared spectrophotometry, whether for identification or quantitative purposes;

(b) quantitative methods based on ultraviolet absorption spectrophotometry;

(c) quantitative methods based on the development of a colour and the measurement of its intensity, whether by instrumental or visual comparison;

(d) methods based on chromatographic separation for identification or quantitative purposes;

(e) quantitative methods (including automated methods) based on other separative techniques that depend upon partition of the material to be determined between solvent phases, where the precise efficiency of the extraction procedure might depend upon ambient conditions that vary from time to time and from laboratory to laboratory;

(f) quantitative methods, often titrimetric but sometimes gravimetric, that are based on non-stoichiometric relationships;

(g) assay methods based on measurement of optical rotation; and

(h) methods that might require a reference material consisting of a fixed ratio of known components (for example cis/trans isomers).

There is a consensus among experts that for certain of the above categories a reference substance is essential. For example, the use of thin-layer chromatography as a means of identification dictates the need for a reference material, because the migration of a substance relative to the solvent front is dependent on the operating conditions: certain of the conditions, such as temperature and composition of the mobile phase, are readily controllable; others, such as the precise thickness and the water content of the layer used and the degree of saturation of the tank, cannot be exactly reproduced. Other examples are non-stoichiometric procedures, such as the iodimetric titration of penicillins and the determination of ascorbic acid by titration with an indophenol.

In other cases, however, differences of opinion exist as to whether a reference substance is essential. It has been proposed, for example, that a reference sample might not be essential for infrared spectrophotometry; instead it might be possible to define certain characteristics of a spectrum or to provide a copy of an “authentic spectrum” that could be used for purposes of comparison. Differences in the mode of presentation of spectra by diverse instruments, differences in resolution between instruments, and problems associated with polymorphism and solvation make such an approach difficult in some instances at the present time. Nevertheless, this approach, implemented where feasible, would significantly reduce the number of reference substances needed and also reduce the extent of use of those substances required for other purposes.

The need for reference substances in ultraviolet absorption spectrophotometry has probably given rise to the greatest controversy. Certain compendia (for example, the United States Pharmacopeia) require comparison of observed spectral characteristics of the substance under examination with those of a reference substance similarly treated, while others (for example, the European Pharmacopoeia, the British Pharmacopoeia, and the third edition of The international pharmacopoeia) rely on comparison with quoted extinction values. Both of these methods have advantages, but neither is above criticism. A mere comparison of spectra obtained by an operator using poor technique and inadequately maintained equipment might lead to acceptance of a sample but might not constitute a valid assay. Conversely, the use of inadequate controlled conditions and a quoted extinction value might lead to rejection of a satisfactory sample. It must also be accepted that, despite considerable improvements in the stability, accuracy and precision of ultraviolet spectrophotometers during the past decade, variations between instruments still occur and may undermine the validity of using quoted extinction values.

These considerations, which also apply in some measure to other instrumental techniques such as infrared spectrophotometry, make it essential that adequate criteria for instrumental performance should be defined. This, in turn, suggests that a further class of reference materials, designed to assist in the calibration of instruments and the standardization of procedures, is also necessary. For example, The international pharmacopoeia (third edition, vol. 1, p. 35) prescribes the use of standardized didymium or holmium oxide filters for wavelength calibration and standardized potassium dichromate or potassium nitrate for absorbance calibration of ultraviolet spectrophotometers. In the field of standardization of procedures it is recognized that reference materials may be required to calibrate, for example, apparatus for dissolution testing. Such reference materials as these are, however, outside the scope of this present discussion of chemical reference substances.

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