Masterarbeit

Impact of polymorphism of active pharmaceutical ingredients on the development of generic medicinal products ***

Dr. Florian Herb (2014)

Summary
Language: English
Polymorphism of active pharmaceutical ingredients (APIs) could have a major impact on quality, safety and efficacy of a drug product. Especially if the polymorphic form used during drug product development or in clinical trials converts unexpectedly to a different even unknown polymorphic form during life cycle of the product.
Consequently, demand of taking the most stable polymorphic form for drug product development could be made. However, this is sometimes not desirable as the most stable form does not always have an appropriate bioavailability.
Furthermore, for generic companies it is sometimes unavoidable to switch to other most likely disadvantageous forms in order to provide generic market entry at the time of basic patent expiry and not several years later after additional patents on distinct polymorphic forms filed by originator have expired.
This master thesis summarizes the current regulatory framework on polymorphism in European Union (EU) and United States (US). ICH Q 6 A on test procedures and acceptance criteria for new drug substances and new drug products and US guidance ANDAs: Pharmaceutical Solid Polymorphism Chemistry, Manufacturing, and Controls Information do both include decision trees to evaluate the need for control of polymorphic form.
Knowledge from regulatory guidance is strengthened with information from scientific publications. Focus has been put on the potential impact of drug product manufacturing on phase transition of polymorphs.
Based on regulatory framework and scientific review, a new decision diagram has been created by combination and extension of the existing decision trees from regulatory guidance documents. The newly proposed decision diagram should enable a generic pharmaceutical company to define the necessary steps for handling an API that is available in different polymorphic forms.
Furthermore, critical questions as inclusion of different polymorphic forms is one generic dossier will be discussed.
Pages: 61