Pharmacopoeial monographs

Chemical and pharmaceutical manufacturers must establish their own internal reference materials, when no pharmacopoeial monograph exists, to satisfy the requirements of Good Manufacturing Practice (European Commission 1997). 

The harmonized general chapters on CE in the European, Japanese, and United States Pharmacopoeias are discussed. In addition, specific pharmacopoeial monographs prescribing CE methods in the current pharmacopoeias are described and the analytical instructions evaluated. 

During the last few years, a number of specific monographs for different pharmaceutical products have appeared in pharmacopoeias in which CE is prescribed as one of the analytical procedures. Several comparative studies have been reported in which established analytical procedures described in pharmacopoeial monographs were compared with capillary electrophoretic methods or in which CE was evaluated as a valuable additional technique.Based on the results, some analytical procedures have been replaced by CE-based alternative methods in a number of monographs. For other products, CE has been included in the monograph from the initial version onwards. In addition, CE has been applied... 

FIGURE I Structural formulae of different compounds for which CE is prescribed in the pharmacopoeial monograph. 

At present a number of specific pharmacopoeial monographs exist in which CE is prescribed as analytical procedure for identification or (chiral) purity determination. 

Despite some distinct advantages of CE for pharmaceutical analysis, the current number of pharmacopoeial monographs which prescribe CE is rather limited. Although it is difficult to point out the exact reason for this, an appropriate training for pharmaceutical analysts in CE-specific analytical characteristics certainly plays an important role. We do hope that this book may provide a contribution in this respect. 

It has been discussed before that CE has several particular advantages making it useful in drug analysis and the need for CE methods in Pharmacopoeial monographs is discussed by the same author in Chapter 11. 

There is a practical distinction between pharmacopoeia standards and manufacturers release specifications, although both comprise sets of tests to which a given product should conform. Release specifications are applied at the time of manufacture of a pharmaceutical product to confirm its appropriate quality but they also need to have a predictive value, to support the notion that the manufacturer is responsible for the product during its entire shelf-life. In many cases pharmacopoeial monographs are based on the specifications developed by the manufacturers of innovator (originator) products. 

If a laboratory was fully confident in a particular assay it might submit it for testing by several laboratories, which would give a measure of how reproducible the assay was in a wider sense with different operators and equipment. For an as.say to succeed in this type of exercise it would have to very robust. For example pharmacopoeial monographs are designed, in theory, to be sufficiently robust to be reproduced relatively easily by many laboratories. Flowever, the tolerances for the precision of such assays might be quite wide. 

When the lactam ring is open it will react with iodine. 1 mole of the ring open form of penicillin will react with 8 equivalents of iodine, the intact lactam ring will not react. In this type of titration excess iodine solution is added to a sample of the penicillin and the iodine which is not consumed in the reaction is estimated by titration with sodium thiosulphate. The value obtained for the amount of hydrolysed penicillin in the sample should be no more than 5% of that obtained when all the penicillin in the same amount of sample is completely hydrolysed to the ring-opened form and then reacted with iodine. Most of the pharmacopoeial monographs for penicillins indicate that this test should be carried out. 

Table 13.4 Some examples of identity tests based on TLC described in pharmacopoeial monographs...

Table 13.5 shows some BP limit tests for known impurities used in pharmacopoeial monographs. 

Table 13.6 shows some of the other limit tests set in pharmacopoeial monographs ranging from a simple test for a known impurity to tests in which limits are set for more than one known impurity plus any unknown impurities which might be present. 

Pharmacopoeial monographs on medicinal substances describe basic requirements that need to be met to assure appropriate quality of the product. Most of the monographs indicate purity at the 98-99 % level, which means that a content of 1-2 % impurities is allowed. In cases of medications used in high doses, such as vitamins or antibiotics, which have daily doses from few hundred milligrams up to a few grams, a 1-2 % level of impurities can have serious consequences for patients. 

Reference to pharmacopoeial monograph for medicinal plant included in recognised pharmacopoeias or submissions of a monograph. 

Control of the excipients in the composition of the product—indication of the pharmacopoeial monograph and/or presentation of a quality specification. 

Because many vaccines are derived from basic materials of intense pathogencity — the lethal dose of tetanus toxin for a mouse is estimated to be 3 x 10-5pg— safety testing is of paramount importance. Effective testing provides a guarantee of the safety of each batch of every product and most vaccines in the final container must pass one or more safety tests as prescribed in a pharmacopoeial monograph. This generality does not absolve a manufacturer from the need to perform in-process tests as required, but it is relaxed for those preparations that have a final formulation that makes safety tests on the final product either impractical or meaningless. 

Specifications for starting materials (and also of primary or printed packaging materials) should include, if applicable, reference to a pharmacopoeial monograph. 

Reference to pharmacopoeial monographs or similar official references. 

Where no pharmacopoeial monograph exists, manufacturers must supply their own comprehensive specification which should include the following ... 

Even though the product has not yet been developed, a high-quality product specification can be proposed with tests and limits that the product should meet at the time of manufacture and at the end of shelf life. For the intravenous product example, tests might include appearance (clear, particle free), pH, osmolality, particulate levels, sterility and endotoxin levels. Appropriate standards or limits can also be proposed based on the knowledge of similar types of products that have already been developed and from standard pharmacopoeial monographs. 

---