Regulatory classification of API co-crystals in the US Approval Procedure

Active pharmaceutical ingredients (APIs) appearing in a co-crystalline shape have a significant advantage compared to the native form: their solid-state properties such as solubility, fluidity, compressibility, etc. can be altered by choosing a suitable excipient, so as to provide optimum processability and stability. This procedure of co-crystallisation is mainly used in cases where active substance molecules contain no ionic groups and can therefore not form salts or where molecules generally possess unfavourable solid-state properties. Co-crystallisates are compounds in which the active substance and excipient exist in a defined stoichiometric ratio and do not form covalent or ionic bonds.

But how is a co-crystalline API to be classified in a marketing authorisation application? Must this co-crystallisate be described as a drug product intermediate or is it merely to be viewed as a polymorph of the active substance?

The FDA clearly answered this question in their revised Guidance for Industry "Regulatory Classification of Pharmaceutical Co-Crystals" published in February 2018: co-crystals are the polymorphic form of an active substance and therefore not an intermediate. This significantly reduces the "GMP effort" and the complexity during the approval procedure. The guideline's revision is the FDA's response to the feedback given by the industry on the earlier version of the document from 2013, in which co-crystals had still been classified as a product intermediate. The revised draft guideline was published in 2016 and has now been finalised two years after. The described classification of co-crystalline APIs is in line with the EMA's reflection paper on the use of co-crystals of active substances in medicinal products from May 2015.

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