EMA publishes guidance on declaring starting materials sourcing declarations

Pharmaceutical companies in the European Union (EU) have been given guidance on the information they should give regulators when declaring how they source starting material for manufacturing chemically active substances.

The European Medicines Agency (EMA) has released a guidance paper that clarifies some requirements within guidance from the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) on the development and manufacture of drug substances. The key issue is information having to be submitted in marketing authorisation dossiers by pharmaceutical companies when they justify the selection of starting materials.

The Agency noted that 'disagreements between applicants and quality assessors on the suitability of proposed starting materials have become more frequent in recent times'. This suggests that current guidelines, which cover a wide range of chemical syntheses, are open to interpretation. Noting a trend for some, or all, active substance manufacture to be outsourced to third parties, the EMA says this may lead to 'a higher degree of risk to quality of the active substance' than with in-house production or sourcing from one specialist active substance manufacturer.

Sourcing steps and quality control processes that should be noted in applications include:

• Those forming and purging key impurities;
• Steps which introduce key structural features of the active substance;
• Where careful control of stoichiometry, temperature, pH or other process variables is crucial for maintaining active substance quality;
• Steps which employ or generate genotoxic compounds;
• Those which employ Class I solvents and/or toxic metals;
• Complex chemical transformations where multiple variables could impact a reaction outcome, for instance the use of catalysts, and solvents; and
• Final purification.