Efficiency of Lifecycle Management for Medicinal Products in the EU: Industry Experience with Variations to Implement a New European Pharmacopoeia Active Substance Monograph for a Generic Eye Drops Solution - A Case Study.

Background: While numerous efforts were taken by the regulators globally to have more streamlined and predictable post-approval CMC variation procedures, there are still areas where cumbersome and parallel assessments of variations may delay implementation of important CMC changes and bind resources in industry and regulatory authorities.

Methods: In this case study a switch from an ASMF (Active Substance Master File) to the CEP (Certification of Suitability to the monographs of the European Pharmacopoeia) for an already approved manufacturer used for a generic ophthalmic formulation with 38 licenses (Marketing Authorisations, MAs) in the EEA was selected to investigate time needed for generation, submission and approval of variations as well as consistency of variation classification by experienced regulatory professionals and Competent Authorities (CAs), respectively.

Results: Overall, four variations were needed for the change from an ASMF to the CEP to cover the concomitant changes that were required to fully align with the European Pharmacopoeia (Ph. Eur.) requirements for the active substance and consequentially for drug product. In one case the CA requested a 5th variation to cover the switch from in-house to Ph. Eur.

Requirements: While average CAs approval time was 4.6 (± 2.1) months (range 2-8 months), overall it took 15.2 (± 2.8) months (range 11-20 months) from data collection and variation generation by the CDMO (Contract Development and Manufacturing Organization) until approval by the respective CA. Good alignment was achieved for most of the aspects, however, when implementation of Ph. Eur. requirements included removal or widening of acceptance criteria, there were quite diverse opinions on the classification by regulatory professionals and CAs, resulting in the same change to be approved as Type IA, Type IB, and Type II variations, respectively, in the different EEA countries.

Conclusions: The long lead times and inconsistent variation classifications hamper switching to a new CEP or adding a new active substance supplier. More efficiency in variation regulations would be beneficial to allow for faster implementation of changes to assure the supply chain.