What do the European Congress of Applied Biotechnology (ECAB, www.ecab2011.eu) and the Berlin marathon have in common? All those who attended the Tuesday plenary lecture at the ECAB would answer: Konstantin Konstantinov.
In this plenary lecture, introduced graciously by Prof. Thomas Scheper (University of Hanover, Germany), Dr. Konstantinov (Vice President, Commercial Process Development at Genzyme) brought to the attention of the audience, the importance and value of continuous bioprocessing, both up and downstream.
Dr. Konstantinov discussed the importance and value of continuous bioprocessing
Economic advantages aside, the modular nature of continuous bioprocesses means that industry is able to adapt more rapidly to changing market demands. Dr. Konstantinov discussed continuous biopharmaceutical manufacturing in the context of other industries that have already successfully adopted continuous processing. He showed that factors, other than scientific ones, are the barriers to change from batch to continuous production. Dr. Konstantinov gave an excellent example of the manufacturing strategies of the steel industry in the 20th century, when this industrial sector incrementally switched from batch to continuous operations. He emphasized that biopharmaceutical industry has reached a stage that requires a change in the production paradigm. For a certain class of biopharmaceutical products upstream continuous manufacturing has always been applied: for example, unstable proteins that rapidly degrade in the culture broth. In order to obtain a high quality product, the residence time in the reactor must be minimized. This can only be achieved with continuous cultivation and preferably with perfusion reactors. In his presentation, Dr. Konstantinov also gave a brief overview on the types of cell retention devices currently used in biopharmaceutical industry. He furthermore emphasized that this is a universal production platform that can be extended to other classes of products, such as antibodies, which are relatively stable molecules. He presented several examples where continuous manufacturing is as productive and with a much smaller footprint of the manufacturing plant, avoiding multiple non-value added unit operations. In essence, the investment for a continuous plant is much smaller compared to a batch-operated one. A platform process for a fully integrated continuous fermentation and continuous capture of the product was described. The process consists of a stirred tank reactor with a cell retention device, the reactor is continuously harvested and the cell-free effluent captured by a continuous chromatographic process. In such a process, the culture supernatant is loaded to full saturation on a chromatography column and after breakthrough, the column effluent is loaded on a second column. After full saturation the column is disconnected from the second column and product is recovered, whereas the second one is loaded to full saturation. After breakthrough of the second column the effluent is loaded onto a third column. The second column is disconnected again and product is recovered. This process is also known as countercurrent chromatography and has been implemented at pilot scale in Genzyme. The system is more complex than a typical batch chromatography process, but fully automated and with higher productivity. Dr. Konstantinov also showed several examples of how high product quality can be maintained during long-term steady state operation of the integrated continuous system. In light of the current transition of biopharmaceutical industry towards Quality-by-Design and real-time product release, continuous manufacturing technology is a big step in getting closer to this ambitious goal.
Biotechnology Journal, represented by Prof. Alois Jungbauer (Editor-in-Chief) and Dr. Judy Peng (Managing Editor) took the opportunity to interview Dr. Konstantinov on the occasion and asked him a few questions of interest to our readers:
Why do you think American pharma are seeking talent from Europe when unemployment rate is relatively high in the US and therefore theoretically a large labour pool to choose from?
We always seek for the best and brightest scientists and engineers. As you may know, we have recently become part of Sanofi, which definitely extends our global reach and strengthens our possibilities.
The main message of your lecture was the benefits of continuous processing in biotechnology and biopharmaceuticals. You also mentioned that continues processing is well-established in the steel, food, petrochemical and chemical industries, why do you think it has yet to become a routine practice in biopharmaceutical production?
I think a good answer to this is the concept “Disruptive Innovation” from Clayton Christensen of Harvard Business School, who has written many books on this topic. It is natural to transfer successful concepts and approaches between industries. However, for various reasons, bioprocessing has been rather conservative and inward looking, implementing mostly incremental changes. It is always difficult to initiate “disruptive” change from within.
You mentioned also that regulatory agencies, such as the FDA, are becoming more receptive to continuous processing. How do you think regulatory authorities have influenced technological advancements?
Regulatory authorities are increasingly recognizing that a partnership between government and the private sector is essential to meet the demands of public health, in the sense that regulations have to be flexible in a responsible way in order to respond with reasonable speed to the public's needs and also open the door for innovations. Recently, FDA representatives have repeatedly discussed the advantages of continuous processing in the pharmaceutical industry. We are extremely pleased with their encouragement, as it applies to the biopharmaceutical sector as well.
Another aspect that influences technology development and implementation of new processes is patent regulations - do you think that our current country/region-specific patent laws remain applicable in a global economy and how do you think this has affected technological developments?
I am not closely involved in patent law, but believe that harmonization of patent laws across various regions would make life easier from a scientist/engineer's perspective. Even more important for the biopharmaceutical sector is the worldwide harmonization of the regulatory requirements.
Much attention has been placed recently on academia/industry collaboration. What do you think needs to be in place for such a collaboration to be successful?
As with all collaborations, the fundamental basis should always be respect for one another's work and also trust. With this in mind, it is important to lay down concrete plans and to have a strategic fit: for example, at Genzyme, we have a pool of funds for such collaborations, but in order for this to be spent in a meaningful manner, we must also have a concrete, specific plan in place. From a technical standpoint, I have always tried to keep in touch with leading academic authorities worldwide. This is important both in terms of innovation and as a source of top students from the corresponding departments.
Thank you very much Konstantin for taking the time to talk to us today, we highly appreciate your insight.
Alois Jungbauer, Co-Editor-in-Chief, Biotechnology Journal
Judy Peng, Managing Editor, Biotechnology Journal