A matter of time

How to obtain growth through accelerating product and process development

In just three years, Avantium has become a company with more than 100 employees and gained a worldwide reputation as a research centre. But how?

Avantium is an advanced R&D company that has become internationally renowned in the fields of catalysis, high throughput experimentation, nanotechnology and the study of chemical processes. The company delivers these services in response to a definite market requirement. In order to remain ahead of the game, companies in the chemical and pharmaceutical industries have to speed up the development of new products, optimise production processes and shorten the time needed to get these products to market. But to constantly develop the technologies and competencies required for accomplishing this, each individual company would have to invest substantial amounts of extra money in R&D. The idea behind Avantium was to create a research centre to provide everything required for accelerated product and process development. This centre could then support industry on a commercial basis by means of contract research.

Rapid research
Avantium has three market-orientated business units of approximately the same size: chemicals, pharma and crystallics.

Crystallics focuses on quickly finding the best possible crystalline form of a substance for a certain application. In the case of many medicines, for example, the effectiveness of an active reagent depends heavily on the form in which it occurs. Crystallics is able to conduct a thorough investigation into the development of a substance’s various crystalline forms within six weeks. To complete this work, less than 5g of material is needed to conduct tests under more than a thousand different experimental conditions.

A similar system of rapid research is used in the other two business units. For example, finding just the right catalyst to accelerate a chemical process, to make it more specific, or to increase the yield of a reaction, is often a very prolonged and costly process. Also, the question is not limited to finding the most suitable catalyst, but also to finding the conditions under which it will function most effectively. Avantium provides answers to these questions within six weeks. During this time it makes use of its Quick Catalyst Screening platform which carries out many experiments automatically and with minimum material. Avantium stocks more than five thousand catalysts for use during these screening procedures. Finding combinations of process parameters for optimising specific steps in product synthesis can be done even faster and the Quick Process Screening service can provide this information within an incredible three weeks.

 Mettler Toledo's automated lab reactor

Investments in people and software
To make such high-speed research projects possible, heavy investment in people, software and hardware was required. Tom van Aken, vice president of Business Development for the company’s Life Sciences Division is clearly proud of what he calls “the gigantic amount of brainpower” within Avantium technologies. “The vast majority of our people,” he explains, “are university-educated mathematicians, chemists, pharmacologists, engineers and IT graduates specialised in software from all over the world.” The fact that the company has already invested in software can also be seen in the wide range of special packages they use for their projects. For research in catalysts, it has accumulated an extensive library of information about heterogeneous, homogeneous and biocatalysts from many different manufacturers which is used for quick access to existing information. Avantium also develops its own software. Its DAP package helps the chemist deal more efficiently with the vast amounts of data generated by high throughput experimentation. In addition, statistical packages help analyse this data and planning experiments - both useful for attaining a high degree of efficiency.

Obtaining results and conclusions is made faster by utilising software for modelling and simulating processes and reactions. Avantium not only utilises commercially available software but also VirtualLab, a package developed in co-operation with Mettler Toledo. This software solution offers the chemist an intuitive platform to design, conduct and analyse experiments, which are fully compliant with the traceability requirements stated in 21 CFR Part 11.

Investments in hardware
Avantium has invested in the FlexiWeigh instrument developed Mettler Toledo. It weighs solid substances from a dispensing vial and then dispenses them into destination tubes. The amounts weighed are mere milligrams of material.

The FlexiWeigh instrument is part of the workflow of Avantium’s High Throughput Experimentation platform. The other part, developed by Avantium, consists of a block in which 96 reactions can be conducted simultaneously – and under pressure if desired, in fact, finding optimum commercially feasible reaction conditions by means of this parallel processing technique is the first experimental step toward scaling up these processes.

 The lasentech FBRM systems allows users to see if and when particles form or dissolve in reaction vessels.

However scientists are not limited just to finding these optimum conditions – they can also study the robustness of a process. The more robust a process is, the less its yield will vary as fluctuations occur in the reaction conditions. This is valuable information for a manufacturing plant.

The further scaling up of reactions can be done in three successive steps. The second of these steps uses Mettler Toledo’s MultiMax multiple reactor system. This technology can utilise up to four reactor blocks, each containing either 16, 4 or 2 reactors, with a volume range of 10ml to 250ml. Step three uses LabMax - an automatic single vessel system that can contain up to 1000ml. An RC1 is also used with a volume, in this case, up to six litres.

Invested in in-situ technologies has also been strong, in order to further study what goes on in the vessel during a reaction. The Lasentec FBRM system allows scientists to see if and when particles form (crystallise) or dissolve in the reaction vessel. Raman, and the complementary Mid-IR technology, makes it possible to study how the concentration of chemical substances changes.

In addition to the RC1, Avantium uses thermal analysis equipment – a DSC unit and a TGA. Since 1998 Mettler Toledo and Avantium have developed a successful partnership through a shared interest in the field of parallel process development. This close co-operation has resulted in Avantium writing a supplement to the software package for the MultiMax reactor system.

The future
Avantium Technologies’ customer base has grown to more than 30 customers and its number of partnerships has also increased. In addition to its initial investors and Mettler Toledo, they now work with such organisations as Degussa and Engelhard in the field of catalysis, with Amcis in scaling up pharmaceutical processes and modelling production and with the University of Malaysia in developing high-grade products from palm oil. Avantium’s customers are very satisfied with the results the company has achieved in such a short space of time, and it looks as if they will continue to do so in the future.

By Robert van Geffen, Mettler Toledo, Netherlands