Beccy Bell, associate director of Laboratory Services at testing and regulatory consultancy Broughton, outlines the challenges of interpreting the guidance, and measures that can be put into place to ensure pharmaceutical products are compliant with the guidance outlined in several jurisdictions.
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Pharmacopeias contain the official standards for the quality of substances in medicines and how to make them. There are four Pharmacopeias: British, European, U.S. and Japanese. While the four sets of standards are largely harmonised, there are nuances that are open to interpretation.
All four Pharmacopeias share the same purpose and goal to ensure that there is quality and consistency of medicines, and it’s fundamental that a product developer follows the guidance set out in the relevant jurisdictions. They provide the quality standard for pharmaceutical substances and medicinal products, including the specifications materials or products must meet – covering everything from Active Pharmaceutical Ingredients (API) to excipients, formulated preparations and more.
The Pharmacopeia you follow depends on where you want your product released, i.e. for the United States you must follow the U.S. Pharmacopeia. While there is a lot of similarity with the U.S. compared to those of Britain and Europe, there are differences. Users may find the U.S. document is a lot more wordy, for example. A more obvious difference might be the methods that are applied to achieve the same end goal.
In Britain, for example, testing for ethylene oxide and dioxan can be done with a combined test using gas chromatography, the sample preparation is straightforward. The U.S. equivalent has these as two separate tests one of which requires a complex distillation with heating and electric currents prior to passing through glassware as part of the sample preparation. In essence, it’s the same tests with the same specification applied, but a very different method to follow.
Interpreting the documents, therefore, can have their challenges, and opting for the simplest way is usually the most efficient but, as outlined, that isn’t always possible. Interpretation isn’t just about different geographies. While there is an understanding as to what they are, and why they exist, wider information in the Pharmacopeias are not as obvious to those with limited exposure to the subject.
There is a level of understanding that is required when using the Pharmacopeias to ensure all requirements are captured. The British Pharmacopoeia has a general principles section and offers help on how to interpret and use the information provided within a monograph. But a monograph is not the only consideration.
While it contains the specifics for the substance or product, you must apply general chapter considerations – located separately – though it has become easier to locate these now the Pharmacopeia is an online resource. Additionally, supplementary chapters also provide a lot of information on general standards, and what aspects you might be allowed to change that don’t affect any previous validations.
It's important to note that Pharmacopeias in different jurisdictions continue to evolve and in different ways. The US pharmacopeia updates continuously while the British version updates every six months. Both systems allow comment and opinion, including from contract research organisations. This is something that, at Broughton, we have used to pre-empt any changes to our testing procedures, while also highlighting areas for potential improvement if we believe a process as set out in the Pharmacopeia doesn’t work in practice.
Taking all of this into account, Pharmacopeias can be difficult to interpret and to follow their testing procedures, especially for new scientists. At Broughton, we developed our own training systems to address some of the common misinterpretations associated with Pharmacopeia. We saw it as an opportunity to develop our own resource while improving to make our scientists as familiar with Pharmacopeia as they could be.
Pharmacopeia isn’t as straightforward as reading a preparation. Language within the text is defined elsewhere in other supplementary documents and full detail of everything you require isn’t provided, as it assumes that all of the guidance notes have been read, and the definitions have been applied to how you’ve interpreted it.
For example, for high-performance liquid chromatography (HPLC), the Pharmacopeia will have all the parameters that are required, but if you have not read the supplementary chapters for HPLC analysis, you will be unable to perform the system suitability testing that is expected. This is because Pharmacopeia doesn’t define it as part of the individual monograph because it is applied to every HPLC method. There are a base set of standards that are applied everywhere, and then there are individualised parameters on top of that. Scientists should spend the time going through these volumes in the Pharmacopeia to be aware of exactly how it should be applied.
Working with an experienced contract research organisation with in-depth knowledge of Pharmacopeia is crucial to ensuring your drug substance or product meets the required standards.