Pharmacopoeias play an important role in quality control. They define important standards and framework conditions for tests; they contain requirements for reagents and reference materials as well as specifications for active substances (APIs), excipients, packaging materials and medicinal products. In addition, pharmacopoeias also contain descriptions of all relevant test methods.
As a rule, authorities expect products and materials to meet the requirements of pharmacopoeia monographs during their storage life. In the context of the differentiation established in Europe into release and shelf-life specifications, specifications in pharmacopoeias are therefore to be seen as shelf-life specifications. This means that if changes occur during storage, specifications for release may need to be made more stringent.
However, this does not mean that the performance of all tests set out in a monograph is always a mandatory prerequisite for the release of a product batch. For example, the manufacturer can ensure that a product meets the requirements of the monograph on the basis of data from validation studies of the manufacturing process and in-process controls, such as online or at-line monitoring. In some circumstances, such data may provide a better guarantee that a batch meets a specific requirement of a monograph than test data from the examination of a small number of units taken from that batch. Control of synthetic by-products after the production of the active substance may eliminate the need for testing for these impurities in the medicinal product. This of course only applies to impurities from the production of the active substances which cannot be degradation products at the same time.
Furthermore, under conditions considered appropriate by the regulatory authority, parametric release is not excluded by the need to comply with the requirements of the pharmacopoeia.
In most pharmacopoeias, the tests and assays described in a monograph are official methods on which the pharmacopoeia standards are based. After regulatory approval (included in the submission to the authority), alternative analytical methods may be used for routine control purposes. However, this only applies on the condition that a clear decision is possible on the basis of the methods used as to whether fulfilment of the monograph standards would also be possible using the official methods. In case of doubt or dispute, the analysis methods set out in the relevant monograph are binding.
Monographs for pharmaceutical active substances contain a section on description or characters, which also includes solubility data. These are informative in nature and do not constitute a requirement.
Pharmacopoeias contain general monographs whose requirements for reagents, reference standards, packaging, excipients and active substances and/or medicinal products should be met. Individual monographs contain specific requirements for an article, including additional points, and may extend limits for the requirements of a general monograph or provide for exceptions. The exact application of the general monographs is handled differently in the various pharmacopoeias. The USP provides for more comprehensive definitions in the individual product monographs.
Biological macromolecules produced from cell cultures, such as monoclonal antibodies, represent a challenge for a pharmacopoeia.
In addition to the specifications, these substances are significantly characterised by the manufacturing process. Because pharmacopoeias are primarily based on specifications, a different approach with regard to monograph content is required for biological medicinal products, and this is still in development.
Markus Veit, PhD
i.DRAS GmbH, Planegg | Alphatopics GmbH, Kaufering
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