Novel Excipients: A Rare Species

What is the current situation regarding innovation in excipients

Have you ever heard the wording of A.T. Florence, former president of the Controlled Release Society, regarding new excipients, which he made in the 90s? "Where are the new excipients, where are the new solubilizers, sustained release excipients...?"

This is, of course, a rhetorical question indicating that, at the time, there had been no major advances in this field. The situation has improved slightly in the last decade, but is still far from satisfying because few novel excipients have entered the market.

Every year, numerous activities generate progress in drug therapy, but this does not hold true for excipients, which means that pharma companies are lacking new opportunities for drug delivery systems with unique characteristics. Of course, old excipients can be combined in a synergistic manner, but this usually only leads to incremental progress as quantum leaps cannot be made by this approach. Generally speaking, we are still lacking innovation in excipients.

For excipient suppliers, however, developing a novel excipient is not very attractive because of the long development times, high costs and risk of failure. In addition, pharma companies are often reluctant to use novel excipients. Thus, only a few excipient suppliers are active in this field.

Why is the pharma industry reluctant to use novel excipients?

As everybody knows, new drug developments are expensive and risky. Pharma companies do not want to add additional risks to their developments by, for instance, using a novel excipient; the authority might not approve the drug because of the new excipient so it's important to check whether all relevant toxicology studies have been conducted. From the view of pharma companies, there may also be a risk of reliable supply from GMP production because the excipient supplier will lack experience in manufacture in the early days.

Excipient suppliers should do everything they can to minimise the risks and toxicology studies should be conducted according to current guidelines. It’s also beneficial to validate manufacturing in the final plant for the batch size prior to launch. At BASF, we also have stability data of novel excipient available. If everything is done properly, using a novel excipient is no more risky than an established one. Our own novel excipient, Kollicoat IR, was approved by the EMA, the FDA and the Japanese Pharmaceutical and Medical Devices Agency on the first attempt.

Are novel excipients safe?

According to current guidelines, a novel excipient needs to be toxicologically tested as a new drug. This requires acute toxicity studies, subchronical and chronical studies, genotoxicity studies, reproductive toxicity studies and ADME. If a novel excipients has been tested in such a way, I think this material is as safe as old excipients — or even safer because the studies will have been performed according to the current state of the art. In addition, polymers of a molecular weight exceeding 5000 dalton are usually not absorbed by the intestinal tract and so, principally, cannot generate systemic effects. Novel excipients are also tested in stability studies under ICH guidelines and ICH climate zones. Generally, polymers are much more stable than actives.

Can you briefly describe the development process of a novel excipient?

Here, we have to distinguish between two kinds of developments: one where a new product is a derivative or a successor of an already known excipient, and the other where the product is completely new with no predecessor. An example for the first kind are the developments of hydroxypropyl betacyclodextrin and sulfobutyl betacyclodextrin, which are derivatives of the already known and approved betacyclodextrin. By introducing or changing functional groups, drawbacks can be eliminated and new properties created.

Developing a completely new excipient is more challenging because no base structure exists. At our company, after having identified an interesting target, we start with a screening period of approximately 2 years where we test numerous polymer classes, such as polyurethanes, polyacrylates, polyesters and polyamides, for their suitability. Having found a promising polymer class, the polymer structure is optimised at laboratory scale—mainly regarding co-monomers, co-monomer ratio and molecular weight. The optimised polymer is then scaled up to pilot plant scale. Subsequently, toxicological testing begins and will generally take around 3 years. In parallel to testing, the production is transferred to production scale and detailed physicochemical data and application data are generated, as well as the Drug Master File. Overall, the development of a novel excipient takes 6 to 7 years.

Principally, as outlined above, there are large similarities between the development of a new active and a new excipient.

What changes do you propose to ease the use of novel excipients?

To say it like Martin Luther King, I have a dream... one day, excipients will have their own approval process and will not need to be approved in combination with drugs only. This individual approval has various benefits because every pharma company will then know that the use of a novel excipient in a certain dose is safe. This process would ease the use of novel excipients and also strongly support innovation in excipients by enabling novel excipients to more quickly penetrate the market. Subsequently, suppliers would also invest more money in new developments. As a result, we will see more modern drug delivery systems with unique properties.

All parties would benefit from such an approach: the pharma company, the excipient supplier and, finally, the patient by receiving a unique medicine.

Karl Kolter Head of R&D Pharma Ingredients at BASF.