Groupe Novasep and its customer Provepharm of Marseille, which develops and markets drugs patented by its parent, the Provence Technologies Group, have successfully validated the cGMP manufacturing process for Provepharm’s Proveblue API. The two described this as “a major step in bringing compliant methylene-blue-based drugs to market”.

Proveblue is the first methylene blue-based API. It is also the first grade of methylene blue to comply with European Pharmacopoeia and ICH requirements and the European Medicines Agency (EMEA) Guideline on the specification limits for residues of metal catalysts.

Hitherto, methylene blue has been used mainly as a dye in therapeutic and diagnostic applications and as an antidote to blood poisoning, but it existed only in highly impure form, with excessive levels of heavy metals. As Novasep marketing director Jean Bléhaut told SCM at Informex USA 2010 in San Francisco, it is a strong chelatant that is hard to manipulate. The regulatory agencies were therefore keen to have a company come up with a purer product.

Novasep scaled up Provepharm’s original synthesis process, including the development and transfer of complex analytical methods, within the existing equipment at the former Finorga site at Chasse-sur-Rhône near Lyon, from February 2009. This was validated in September and a successful French Medicines Agency (AFSSAPS) followed in October. The process can reduce metal impurities by up to 99% and can yield “significantly improved” organic purity, it is claimed.

“This was a very typical project for Novasep and a very nice example of working with the chemistry a customer had developed,” said Bléhaut. “The customer came to us in dire straits, because they needed to find someone to scale the chemistry up.”

Simultaneously, the EMEA has accepted for rapid evaluation the Marketing Authorisation Application (MAA) for the methylthioninium chloride Proveblue solution for injection under the EU centralised procedure. This, if successful, could lead to a single authorisation in all 27 EU member countries.

The move also opens the way for R&D into more methylene-blue-based drug products in therapies such as urinary and ocular antiseptics, anti-malarial agents and treatments for neurodegenerative diseases, among others. Provepharm is also in discussion with the US regulatory agencies.