Research and Development process for pharmaceuticals products
Each new medicine follows the same precisely defined development path right across the pharmaceuticals industry:
Global Discovery
Pharmaceutical research at Solvay Pharmaceuticals starts with the search for compounds which have a possible active effect, which implicates they may be able to cure causes of diseases. Solvay Pharmaceuticals’ Global Discovery is responsible for the finding of active compounds. We have 350 employees working in our Global Discovery (200 in Weesp and 150 in Hanover). They have modern laboratory facilities at their disposition.
We managed to organize our Global Discovery in such a way that the discovery process can easily be recognized.
The discovery process at Solvay Pharmaceuticals consists of four phases:
1. Target Biology
Target evaluation, -validation and -selection
In this first phase we look at new biological points of action in the body (receptors or enzymes) that are involved in processes of diseases. These points of action are also called ‘targets’. They form the starting point for the screening of potential medicines. Ideas for new targets may arise from internal research and via external sources, like scientific literature. With the present biotechnological knowledge we have a better understanding of the way cells should function as well as what goes wrong in case of a disease.
New genes and their functions are being detected and quickly become new targets for therapeutic intervention. The excellent skills of our biotech partner Innogentics in gene discovery help us choose our targets.
Assay-development and hit finding
The next step is the development of measurement systems or ‘assays’ for the selected target. Each year we aim to develop 15 assays. They are the starting point for our search for chemical compounds that are able to influence the target involved. With robots we test large numbers of chemical compounds on a possible effect. The High Throughput Screening (HTS) robots work day and night and are able to test thousands of compounds a day. If a compound is recognised with a certain activity we have a ‘hit’.
2. Chemical Design and Synthesis
Hit-to-lead
Based on the hits discovered in HTS, new variants of a compound are designed of which we change the chemical structure a little bit. A minor change in the chemical structure can lead to a major improvement of the biological activity of a compound. For the optimisation of molecules we use advanced three-dimensional computer models.
Thanks to the introduction of automated synthesis techniques, the number of chemical compounds that are synthesised each year has increased considerably. Our Automated Molecular Assembly Plant (AMAP) is capable to create tens of thousands of chemical compounds each year for further screening.
3. Lead Optimisation
Lead optimisation
On a yearly base we test 750 chemical compounds for their biological activity and availability. We call these compounds ‘verified hits’. For the investigation of the verified hits we have a great number of tests to our disposal. As we proceed further in the discovery process, the complexity of the tests increases: from a membrane or enzyme, to a single cell and from a cell to cell tissue, in which the effect of a compound is established. The remaining compounds are further tested in vivo (animal experiments). We investigate, for instance, the compound’s effect on the animal’s behaviour or on physiological parameters such as blood pressure. The biological availability is determined by studying the uptake of the compound by the body and its ability to reach the correct destination, in other words: its site of action.
In this phase of research a considerable number of compounds will be eliminated. Based on the test results, medicinal chemists will further “fine-tune” the chemical structure of the lead compounds. In the end about 10 – 20 compounds of the 750 verified hits remain. They show an effect over a certain time in the right place. These remaining 10 – 20 compounds are called ‘optimized leads’.
4. Preclinical drug development
Lead profiling and safety examination
Before a compound is administered for the first time to healthy volunteers we have to be absolutely sure that no harmful side effects will occur. Therefore a number of safety and toxicology experiments are carried out. Detailed efficacy studies in different disease models supply us with better information about the way a compound behaves in the body. The route of a compound in the body is examined as well as the amount and the speed of absorption. We want to know how the compound will be spread over the different organs, how the liver breaks it down and how it is excreted by the body.
In this phase of research we do pharmacological, toxicological and metabolic studies. Depending on the results we decide whether to develop the compound in clinical studies. A positive decision means that a new ‘clinical candidate’ is available.
Solvay Pharmaceuticals aims to produce three clinical candidates a year.
The role of Global Discovery ends here and the compounds are handed over to Solvay Pharmaceuticals’ Clinical Drug Development for further testing in humans.
Clinical Drug Development
For our clinical drug development we have entered a collaboration with Quintiles/ Pharmabio Development. Quintiles is the biggest Contract Research Organization worldwide. Their extensive experience and excellent facilities have already led to an important reduction in development time, shortening significantly our time to market.
Solvay Pharmaceuticals’ clinical drug development consists of four phases:
Phase I
Trials on limited, voluntary populations, aimed primarily at measuring safety and tolerance, rather than efficacy with an initial approach to dosages. These trials are usually executed in hospitals under close supervision of a doctor.
Phase II
Testing the effectiveness of the compound, measuring benefits against potential risks, and more precise defining of administration dosages. The compound is tested in 100 to 300 patients who are in need of treatment and have volunteered for the tests. All patients are carefully monitored by independent physicians.
Phase III
Worldwide large-scale trials on thousands of patients, principally in order to meet the requirements of the health authorities. Our product is compared to other existing drugs or to a placebo (fake drug). All study results have to be brought together in a registration file which we submit to the health authorities for registration. After approval, which usually takes one or two years, the drug is officially registered and we can introduce it for commercial use.
Phase IV
Additional trials aimed at fine-tuning the use of the medicine in practice. Additional dosage or administration forms are developed based on the experiences of our patients.