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Improving large-scale production processes for biological and pharmaceutical molecules were key topics of the plenary lectures at the ECCE/ECAB (September 2011, Berlin, www.ecab211.eu). This interview with Prof. Rolf Werner from Boehringer Ingelheim focuses on how to shorten the time from drug discovery to market approval by integrated process development. (See also interview with Dr. Konstantin Konstantinov from Genzyme on continous bioprocessing to streamline biomanufacturing platforms and to shorten production times [1]).

Plenary lecture

  1. Top of page
  2. Plenary lecture
  3. Interview
  4. REFERENCES

Biological pharmaceuticals, such as insulin, EPOs, the tissue plasminogen activator (tPA) as well as the many antibody-based anti-cancer therapeutics, present a successful revenue stream for pharmaceutical companies with about US$ 100 billion annual sales in 2009. For a drug with an average sales revenue of US$ 1 billion, a delay in product development is a loss in sales of US$ 80 million every month. Therefore, it is important to speed up the development and do it right the first time. Proving therapeutic efficacy and clinical safety is only one part of the story. The other part is the development of a production process as well as building of a production plant, which has to be available at the time of clinical phase III trials, when clinical efficacy remains to be established. Importantly, only 30% of all drugs entering clinical testing will ever reach the market. Needless to say, the financial risk is extremely high.

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The BI-HEX® Integrated Concept for Process Development at Boehringer Ingelheim.

In his keynote lecture at the ECCE/ECAB in Berlin (September, 2011) Prof. Werner, Senior Vice President Strategic Biobusiness Asia at Boehringer Ingelheim, impressively showed how fruitful collaboration between industry and academia is able to shorten the current time for market approval of biopharmaceuticals from 15 to 9 years. Boehringer Ingelheim in collaboration with Satorius Stedim has developed an integrated process development approach that can be done in parallel to first clinical testing, which can then be easily scaled up to a controlled production process. Process development mainly involves four steps: (i) upstream processes, i.e. strain development as well as fermentation optimization; (ii) downstream processing, including product separation as well as chromatography steps; (iii) formulation, such as new oral delivery systems or pulmonary inhaler devices; and (iv) development of accurate as well as cheap analytics, which are essential for quality and production control. Prof. Werner raised two main points that are essential for successful biopharmaceutical product development, on one hand the discovery of new target drugs, as well as their clinical validation and optimization, e.g., for the half life, and on the other hand the innovations in high-throughput bioprocess development for high titers and high yield.

“New targets are essential for the development of new therapeutics. I would like to encourage those working in this area”

Prof. Werner included many examples of how Boehringer Ingelheim drives innovation in pharmaceutical process development, either by in-house developments or strategic collaborations with external research institutions. For example the BI-HEX� platform for expression of proteins in CHO cells was developed in house, while the The Npro system and genome-integrated system for recombinant protein expression was developed externally together with Sandoz at the University of Natural Resources and Life Sciences (BOKU), Vienna, and the Austrian Centre of Industrial Biotechnology (ACIB). Many more examples of successful collaboration gave us a good insight on how Boeringer Ingelheim keeps up with technology development ensuring their position as market leader in the manufacturing of biopharmaceuticals.

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Interview

  1. Top of page
  2. Plenary lecture
  3. Interview
  4. REFERENCES

After this plenary lecture, Biotechnology Journal, represented by Prof. Alois Jungbauer (co-Editor-in-Chief) and Dr. Uta Göbel (Assistant Editor) had the pleasure of talking to Prof. Werner.

AJ:

Why is it so important to shorten the time for process development?

RW:

The biopharmaceutical industry has to invest about 1 500 to 800 million for the process engineering and plant construction. This usually has to be done right at the time of target drug discovery, to provide the material for clinical studies on time. Although, at this time it is unknown whether the product will ever reach the market. As I have shown in my talk, only 1% of new lead compounds for new targets will ever lead to a return of R&D costs. Ideally one would start investment into a commercial plant at the time when the phase III clinical study data become available, when we know that the drug can most likely be successfully delivered to the market; however phase III clinical material has to come from the commercial plant. The production process has to meet regulatory requirements and GMP standards. Therefore, we have developed this new concept that starts process development and engineering right after the first results of clinical phase I studies, when the toxicity studies have been completed, and when we can estimate a promising therapeutic dose.

AJ:

Can you explain in a bit more detail how the new concept works?

RW:

We developed a pilot plant with the same specificities and process parameters as required for the production plant, for example the same bioreactor geometry, kLa values, mass transfer and fluid dynamics coefficients. Here we receive the first results for pH and temperature optimums. Once the first statistical significant effects are shown in clinical studies, for example in phase II, we do a so-called bridging study for clinical production at larger scale.

UG:

Reducing the time to bring a biopharmaceutical to market from 15 to 9 years is an impressive achievement; however, 9 years remains a long time from a patient's perspective. What is the main problem?

RW:

We cannot reduce the times needed for clinical studies. A key problem is the recruitment of up to 10 000 patients in international multicenter studies, to reach the required statistically relevant results. At the same time, the regulatory requirements are actually growing, so the clinical testing time may even increase. Especially the time needed for phase III clinical development, where the therapeutical efficacy needs to be shown, depends on the type of the developed drug and the experimental readout. For tPA, for example, this is relatively quick. Whether the thrombus is dissolved and the patient survives the stroke/heart attack is definite within a few days. Oncological drugs present the other extreme, because clinical study results are mainly based on long term effects, such as 5-year patient survival rate.

Collaboration maximizes the outcome for all companies. We do not have the time for rivalry

UG:

In your talk you mentioned many collaborations with other companies and universities. Is this not highly unusual, because every company wants to keep its secrets?

RW:

Indeed this is quite special, but it maximizes the outcome for all companies. Usually every company has their own target drug and variant. We do not have the time for rivalry. Most of the newly developed target drugs are discovered via collaborations. We at Boehringer Ingelheim then try to enter a strategical cooperation or work on licensing the product. One further option is of course acquisition, although in most cases it absorbs the other company and the technology is no more available for broad application. The industry should rather foster collaborations. BI especially enjoys working with companies in Austria, for example at the ACIB, the Austrian Centre of Industrial Biotechnology. The country and cities in Austria are increasingly funding collaborative research between companies with academic research institutes.

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Time scale for process development and clinical testing. (A) Parallel process development (orange) to first clinical trial steps (blue). (B) New concept developed by Boeringer Ingelheim in collaboaration with Satorius Stedim. Pilot plant in parallel to clinical phase II trials, scale up and final process development steps in parallel to clinical phase III trials.

UG:

You mentioned that other companies are working together with Boehringer Ingelheim to speed up their production processes. How many processes are you currently developing?

RW:

Every year there are about 5–8 processes, for example when companies have problems with the capacities of the current process. Some companies do not invest into their own production plant, so we do the process development and the product production on a contract basis. For all of these companies we are minimizing their financial risk.

AJ/UG:

We thank you for taking the time to talk to us and for sharing with us the insights into successful current and future process development for biopharmaceutical drugs.

Alois Jungbauer, Co-Editor-in-Chief, Biotechnology Journal

Uta Göbel, Assistant Editor, Biotechnology Journal

REFERENCES

  1. Top of page
  2. Plenary lecture
  3. Interview
  4. REFERENCES