Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Monographs of the European Pharmacopoeia on medicinal products containing chemically defined active substances, Implications on marketing authorisation application, surveillance, and authorisations in the European Union

Dr. Peter Buschmann (Abschlußjahr: 2022)

Summary
Language: English
At its foundation in 1964, the European Pharmacopoeia (Ph. Eur.) was intended as a tool for the evaluation of the quality of medicinal products on a regional as opposed to a national level. Due to the early stage of common pharmaceutical legislation in the member states at that time, a strong focus on individual substances and analytical methods was prioritised. Pharmaceutical forms also received their own chapter but this was not directly linked to specific products but instead remained general and thus widely applicable. Unlike the internationally well respected US Pharmacopeia (USP) and British Pharmacopoeia (BP), the Ph. Eur. did not contain monographs for individual finished products with chemically defined active substances for more than 50 years. Since then, the regulatory framework and the structure of the pharmaceutical market have changed significantly. It has therefore been agreed by the Ph. Eur. Commission to extend the scope of the Ph. Eur. to finished products with chemically defined active substances.
Finished products unite the properties of their components so that the creation process of corresponding monographs is usually more complex than for individual substances. Compared to other regions of the world, the EU legislation allows a larger array of differences between two substances for them to still be regarded as "the same" (see Art. 10(2b) of Directive 2001/83/EC). The most common examples for this are different solvates and salts of an active moiety. If bioequivalence can be proven for them, they can usually be regarded as identical for regulatory purposes. Such properties are, however, out of scope of the Ph. Eur., which purely focuses on the quality of medicinal products. The applicability of existing finished product monographs on generics is consequently sometimes unclear, on which a discussion is provided in this thesis. Furthermore, the impact of new monographs on existing marketing authorisations will be investigated.
An important concern of the introduction of monographs for finished products with chemically defined active substances is the deterioration of the overall quality of medicinal products. This could be caused if several independent European marketing authorisations are used for the creation of a common specification, which is valid for all authorised products on the market. Strategies to counter the formation of "the lowest common denominator" are shown in this thesis so that negative impacts of the monographs can be avoided.
The results from the creation process, i.e. the implemented finished product monographs, impact work patterns of all concerned stakeholders in the area of validity of the Ph. Eur. However, the whole extent of this has not become clear yet in all its facets. Importantly, the relevant pharmaceutical legislation such as Directive 2001/83/EC and the Variations Regulation No 1234/2008 came into force before the decision to create monographs for finished products with chemically defined active substances was made in 2012. These new additions to the Ph. Eur. were, thus, not taken into consideration during the initial legislative process leading to so far unresolved regulatory and legal questions, which are explored in this work.
It was found that there are considerable overlaps between finished product monographs in the USP and Ph. Eur. Consequently, a closer look was put on differences in the respective creation processes, resulting qualitative differences and the potential roles of third country pharmacopoeias in Europe. Generally, only the Ph. Eur. provides legally binding monographs for finished medicinal products but certain limitations apply even to those. These as well as potential improvements of their handling are part of the discussion provided in this thesis.
Closely related, a detailed overview on the different expectations and interests is shown for the stakeholders of Ph. Eur. monographs on finished medicinal products with chemically defined active substances, such as authorities, innovators, generic manufacturers, and official medicines control laboratories. One of the key challenges is to manage the various desires appropriately so that timely contributions are made to have reliable compendial information available when it is needed.
Finally, the topic of market surveillance is briefly covered, which has so far been complicated particularly for pan-European studies. Finished product monographs have the potential to be a valuable tool for many efficient, large-scale tests with products from more manufacturers than ever before.
Pages: 80