The wrong choice of excipient has led to delays or failures for many new drug candidates. A position brief from IPEC, which recently held a seminar on this subject, notes the need for
- Strong communication channels between suppliers and the pharmaceutical industry are pivotal for the development of innovative excipients that enhance drug efficacy and streamline manufacturing operations
- Close collaboration, to ensure that regulators take on board the concerns of all those involved in the use of excipients.
Below, verbatim, is IPEC's summary of some highlights from its recent seminar.
Carl Mroz, Chair of IPEC's European Regulatory Affairs Committee advised companies on how to expand their excipient business in markets such as China and Russia. He pointed out that Japan recently amended its 1948 Pharmaceutical Affairs Law to allow for the filing of an Excipient Master File (EMF) and that European stakeholders should focus on doing this in Europe as well.
Mroz said: "We want a mechanism that allows novel excipients to come faster to market in Europe. Without new excipients you are stifling innovation and there are many good ideas which never get off the drawing board because there is no system to introduce new excipients within Europe."
The EMF model is already in place in Japan and in the USA, and it is imperative that Europe catches up, added Mroz.
"If you are interested in a new drug delivery system that involves a new excipient, there is no impetus to invest in that sort of R&D at the moment because the regulatory hurdles are so high. If a DMF system were in place holding all confidential information safely, eliminating the need to submit sensitive data to every single potential customer to assess multiple times, the boost to the advancement of technology would be enormous."
Both patient need and process capability must guide excipient selection, seminar delegates said. However, as new legal requirements for Good Manufacturing Practice (GMP) in the production of certain excipients are introduced in Europe, suppliers will be required to offer excipients made to the similar GMP principles as active pharmaceutical ingredients (APIs).
To assess the impact of applying GMP regulations on excipients, Dr Rui Santos-Ivo, Enterprise and Industry Directorate-General at the European Commission, attended the IPEC Seminar and invited all stakeholders to take part in a public consultation and announced the launch of a questionnaire on the directorates website.
Dr Santos-Ivo said: We need high safety standards to promote patient safety and that is why we have identified some categories of excipients where legislation is required. Nevertheless, we also believe that adequate regulation is a tool for improving the competitiveness of companies, not only in Europe but worldwide.
We must also avoid placing unnecessary burdens on those affected by the new directive, without of course compromising patient safety. For me it is very clear that IPEC has ample knowledge in the field so it is very important that those who work directly with excipients offer their expert views in the consultation.
IPEC has already made a significant contribution to the debate by publishing a GMP guide for excipients, a practical authoritative document that not only helps excipient suppliers meet the increasingly stringent demands of the pharmaceutical industry, but also makes it easier for pharmaceutical companies to ensure their suppliers are meeting acceptable quality levels.
Impurities
Excipient suppliers are also faced with new rules on the acceptable limits for
genotoxic impurities in pharmaceuticals. Although new guidance from the European Medicines Agency (EMEA) that came into force on 1 January 2007 does not refer specifically to excipients, the regulator is expected to take into account the toxicological assessment of genotoxic impurities in excipients before granting marketing approval for new drugs.
This poses a great challenge for excipient suppliers because routine synthesis is not possible without the use of reactive materials which are potentially genotoxic, making the presence of genotoxic impurities in excipients inevitable in some cases.
Dr Peter Kasper, rapporteur for preparing the EU Guideline on the Limits of Genotoxic Impurities, told the IPEC seminar: A considerable proportion of all synthesis products in pharmaceuticals potentially contain genotoxic impurities, so this is certainly a major regulatory issue. Whether this poses a health risk is another question, because we are talking about very low levels and it is very difficult to quantify the risk.
Our guidelines help provide some much needed clarity to the assessment of genotoxic impurities. If companies are aware of this problem from the very start, most have the knowledge and the expertise to deal with it, so I dont think these new guidelines will have a negative financial impact.
According to the guidelines, published by the EMEAs Committee For Medicinal Products For Human Use (CHMP), a threshold of toxicological concern (TTC) of 1.5 µg/day intake is considered acceptable for genotoxic impurities without sufficient evidence for a threshold-related mechanism. Higher limits may be justified under certain conditions, such as short-term exposure periods.
Variability
It is often assumed that such demands for regulatory compliance will inevitably lead to less variability in the excipients used. But Janeen Skutnik, Director Technical Affairs at Pfizer and Chair-elect of IPEC-Americas, challenged the view that as pharmaceutical manufacturers in Europe concentrate on International Conference on Harmonisation (ICH) concepts, such as Design Space and Quality by Design, they will tighten their excipient specifications.
Skutnik said: A lot of pharmaceutical companies are having discussions with their procurement teams to help them understand the impact of these guidances and urge them to embrace scientific and risk-based discussion with excipient suppliers.
At the moment there is a lot of wastage in pharmaceutical manufacturing as the industry has not been continually improving and understanding process parameters, with the result that waste can be as high as 50% for some products, while factory usage rates can be as low as 15%. In most pharmaceutical companies manufacturing spending constitutes 25% of expenses which is equal to R&D investment.
Pharmaceutical manufacturing produces products of reasonable quality, but at great effort and cost, according to Skutnik. Through increased formulation understanding and efficient knowledge transfer, we can implement ICH Q8 Q9 and Q10 while bringing in new excipients that achieve better results for our processes and more effective medicines for our patients.
More extensive knowledge of critical product and process parameters and quality attributes should lead to more innovative use of excipients, yielding financial savings and better medicines, she said.
-AMS
