The 2013 biennial meeting of the European Society for Animal Cell Technology (ESACT) was in Lille, France this past June. While there, BPI editorial advisor Miriam Monge (vice president of Biopharm Services Ltd.) interviewed ESACT executive committee member Hitto Kaufmann, PhD (vice president of biopharmaceutical process sciences for Boehringer Ingelheim). They talked about some scientific developments being discussed at this year’s ESACT conference as well as Boehringer Ingelheim’s recent announcement about setting up in China and Kaufmann’s own thoughts on the key future trends for biopharmaceutical development and manufacture.

Hitto Kaufmann is currently heading a department that develops drug substance and drug product manufacturing processes and operates a clinical supply facility including fill and finish. Previously he was responsible for upstream development at BI’s Biberach site as director of upstream development and later as global head of mammalian cell culture processes. He joined Boehringer Ingelheim in 2003 as associate director of cell biology. Before that, he worked on identifying novel drug targets involved in apoptosis at the Walter and Eliza Hall Institute in Melbourne, Australia — after receiving his doctorate from the Eidgenössische Technische Hochschule Zürich (ETH Zürich) in Switzerland, where he worked on improved production processes using Chinese hamster ovary (CHO) cells. Kaufmann is coinventor on more than 100 active intellectual property rights and is an active member of several national and international committees.

ESACT 2013

Monge: How did the ESACT committee decide on the title of this year’s conference — “Better Cells for Better Health” — and how did you select the scientific content?

Kaufmann: We wanted to continue on the ESACT theme of cells in a therapeutic context, either in terms of a manufacturing facility producing therapeutics (mainly recombinant proteins) or of the drugs themselves (e.g., stem cell therapy). We tried to get that concept across through the title. The themes/topics covered range from stem cell therapy manufacturing to antibody manufacturing in a 20,000-L bioreactor. It is also a continuing tradition at ESACT to integrate basic and fundamental research that elucidates cellular mechanisms all the way to applied sciences that are relevant for fields covered by the pharmaceutical industry to produce drugs for treatment of various diseases. The scientific committee took great care to ensure that the presented stories represented significant progress in the field. We were lucky to have a large number of abstracts to choose from and thus create a program of high scientific quality.

Monge: What do you consider to be the greatest breakthrough research presented at ESACT this year?

Kaufmann: A number of studies represented significant progress in their particular fields. Some of the most remarkable for me were those related to tissue engineering and designing cellular systems that resemble the complexity of such systems in human bodies. That research is moving forward pretty rapidly. To put it into context: Two or three years ago, studies in the field seemed far away from application, almost artificial. But this year we have seen significant progress.

Another thing that may be obvious with regard to biopharmaceutical manufacturing is increasing focus on the relationships between cellular systems and the quality coming out of them. This is especially important inbiosimilars manufacturing: We really need to understand much better than we previously did how process parameters (such as cell lines or media) influence different product quality attributes (PQAs) that you have to achieve if you want to develop a biosimilar.

For example, a mammalian cell performs about 100 different types of posttranslational modifications, adding all kinds of modifications to proteins. This is an entire field of science on its own: to understand the relationship between protein molecules, bioprocesses, and posttranslational modifications attributed to them.

Another exciting field involves better understanding of RNA biology, its implications for therapy, and applications in regulating cells and growth. We have seen many exciting studies of inhibitory RNAs, including micro-RNAs. Especially in light of new possibilities for high-throughput sequencing methods, this field seems to be progressing quite rapidly.

Boehringer Ingelheim and China

Monge: Let’s talk about your company, Boehringer Ingelheim. It has put forth a number of exciting announcements recently, notably with regard to moving into the biosimilars space and opening a new facility in China.

Kaufmann: Yes, but those two are not linked! With regard to biosimilars, it is publicly known that we have three molecules in clinical studies at the moment. Regarding the biopharmaceutical facility in China: We wanted to set up a modern high-tech plant that meets 100% of the quality and reliability standards of Boehringer Ingelheim’s global biopharmaceutical network and therefore fulfills all national and international regulatory standards.

Monge: When you decided to set up the facility in China, what were the key objectives, and what were the key obstacles you needed to overcome to achieve them?

Kaufmann: In general the Chinese pharmaceutical/biopharmaceutical market is growing rapidly. To give you one number for BI: If we combine our three businesses in China — the prescriptive medicine, consumer healthcare, and animal health — we had a growth in 2012 of about 30%. In addition, it is very clear from the five-year plans of the Chinese government that the country has a strong focus on new high-tech industries, which the government wants to establish in China. The focus currently is on biopharmaceuticals and biopharmaceutical manufacturing.

It is on that basis that BI, as a producer of biopharmaceuticals, has worked out a strategy to enter China initially with a GMP [good manufacturing practice] manufacturing facility to supply materials for clinical studies (on the Chinese market) for Chinese clients. So this project was recently initiated. We will provide to local clients process transfer possibilities and some process development possibilities and production of GMP material to supply clinical studies. Obviously because the concept of contract manufacturing organizations [CMOs] is new to China, we need to work closely with local authorities to establish a legal route for contract manufacturing of biopharmaceuticals there. We have started talking to them, and so far the initial feedback we have received is positive.

Hitto Kaufmann, PhD ()

Monge: Is it a challenge to recruit a highly qualified local workforce?

Kaufmann: We have started recruiting staff. Boehringer Ingelheim has a strong presence in China already, especially in Shanghai, which is where we have chosen to locate our biopharmaceutical facility. Our site will be part of the Zhangjian Base Company science park in Pudong, Shanghai. The new site will provide a full range of development and clinical services to Chinese and international customers. It will become the first facility established by a leading international biopharmaceutical manufacturer in China using mammalian cell-culture technology. The project will create up to 65 job opportunities with high qualification standards. We will have some key scientific experts supporting the project management from our cell culture facility in Biberach, Germany. In addition, we will hire people locally and collaborate with Chinese universities — specifically Shanghai University. We will also foster exchange between the University of Applied Biotechnology in Biberach and the East China University of Science and Technology in Shanghai.

Monge: How does education compare between Chinese and European universities? Would you say it is comparable in terms of the science, or is it a very different approach?

Kaufmann: I think it’s quite remarkable to see that the top universities in China provide very good training in terms of biologics. In applied biology, we would like to use exchange programs to invite Chinese students to our established site in Biberach. That way, they can add to that know-how some practical experience within our world-class biopharmaceutical development and manufacturing facility.

Monge: Is it not a concern that by transferring knowledge and expertise, you will be creating future low-cost competition for the European biologics manufacturers?

Kaufmann: We see China as a fast-growing market that will add business opportunities rather than competewith business opportunities in the CMO market we have in Europe. We also see a strong push by the Chinese government to guarantee protection of intellectual property for the future. It is apparent that China will base its future on developing innovation in high-tech industries. We will take care to protect intellectual property, but we see the market evolving in a way that could be very different in 10 years from now from what we see today.

Monge: You will be working to the same standards as in Europe, but presumably the cost of goods (CoG) for drugs manufactured in China will be substantially lower than CoG in Europe or the United States. What sort of reduction in CoG for drug substances are you expecting to see?

Kaufmann: It is too early to come up with a figure here. But as we see it at the moment, the main driver is not so much to reduce manufacturing cost as it is to manufacture the drugs for the local market.

Monge: What are BI’s greatest strengths in terms of platforms and technologies?

Kaufmann: One of our key differentiators in the market is our track record. BI started really early in providing services, and we have brought 22 products with our clients to the global market. We have transferred more than 150 processes from clients to our own development and manufacturing sites. BI has experience in mammalian cell culture, yeast cultures, and microbial cultures. The other important point is that we operate for our clients as a “one-stop-shop.” We manufacture drug substances and drug products. We can support clients from DNA work to formulations to setting up an economical fill–finish process for a drug product.

Beyond that, in the mammalian cell culture field we have our own BI-HEX expression system, which comes royalty free to clients and has been available for over 10 years. It has a proven track record of providing high yields. We have our own media and feed platform that has evolved over the years, and our clients have access to that as well. We can easily modify media and feed compositions according to the needs of a specific cell line in transfer to our facilities. We also offer services worldwide, with development and manufacturing on three different continents now: in Asia, in America (the United States), and in Europe. So we can offer services wherever clients need them.

In microbial manufacturing, we have a number of platforms. One worth mentioning is our proprietary pDNA platform that delivers high-quality DNA for gene therapy or DNA vaccination approaches.

We always make sure that we offer technologies that we have extensively tested in house and with which we have experience (including scale-up — regardless of whether the technology has been developed in-house or has been in-licensed by our experts. We make sure that in-licensed technologies are adapted sufficiently to our hardware. We do more than just offering them to clients; we offer those technologies and the experience in how to handle and implement them. BI has its own technologies that are unique for drug formulations: for example, our state-of-the-art, dual-chamber cartridges.

We have a global center of excellence for cell-line development where we can rapidly generate cell lines and rapidly screen them for productivity and yield. We look at how a product behaves with each cell line and check product quality. We offer highly automated, fully integrated cell-line development with insight into how a protein coming out of a given cell line will look. Consider a situation in which after clinical phase 1 you have to redevelop your cell line, but at the same time you have to meet a certain product-quality standard. You need to select not only for product titer or cell growth or a robust and stable cell line, but also for a clone that yields product of appropriate quality. We have more than one CHO cell line that is fully adapted to our platform. So we can start cell-line development with more than one host cell if a client wants that, then generate material in slightly different but distinct product qualities and see what matches best.

Industry Trends

Monge: There is much talk in the industry about developing a fully continuous processing train. Do you see this as being the future manufacturing platform of choice?

Kaufmann: For mammalian cell cultures, fed-batch is still the industry standard and is likely to be for some time. It is very reliable, and you can optimize the throughput of your facility with it very easily. Over the past few years, there has been tremendous progress in generating high cell densities on these fed-batch processes, and it’s very scalable.

Nevertheless, there will be certain applications in the future for which other process formats may be more suitable, and that could include all forms of continuous processing. For example, if you set up a facility that supplies a smaller market or a smaller indication, at the same time it should be highly automated and flexible in terms of modules. We are closely following the progress that has been made in establishing facilities with either fully continuous manufacturing or continuous downstream processing.

Monge: Continuous upstream is well established. But there is still much work to do in establishing and demonstrating proven technologies and economic benefits of continuous downstream processing.

Kaufmann: This is true. However, the progress that is being made is not only driven by developing smart solutions around technologies that already exist, but also in establishingdisruptive technologies. Think of a purification process that could be independent of any chromatography column. That could open up new ways of establishing a continuous purification processes.

Monge: How do you go about optimizing CoG for your processes in development? How do
you manage facility fit when bringing processes into existing facilities — particularly stainless steel facilities? How do you manage to ensure an optimized, cost-effective process?

Kaufmann: That question comes up when a client’s project has reached the clinical proof-of-concept stage, when the focus can be on optimizing the economic parameters of the process. We try to identify the major drivers for process development and commercial costs: e.g., optimizing expression titers, for which our latest media platform is a big asset. Other technologies can improve seed trains, leading to higher cell densities in final-stage bioreactors, along the harvest and purification stream. For IgG processes, BI has shown many times that it can optimize yields quite dramatically — sometimes increasing DSP [downstream process] yield to >90%, whereas the average industry yield is much lower.

In addition to DSP yield, something that is very important for economic efficiency or high-titer processes is the overall buffer volume that you need to run a process. In a couple of cases, we have been able to significantly reduce the overall buffer volume needed to run that process. By optimizing and fine-tuning all the steps of chromatography purification, you can use less and less buffer. To achieve that, you need to increase your process understanding — which we do with our small-scale, high-throughput systems — and then implement at large scale. In some cases, we have cut down buffer volumes by over 50%.

Monge: Once you have an optimized process, how do you manage and optimize facility fit?

Kaufmann: We do so at the beginning of process optimization for commercial processes. Some work can be done on paper, some through experimentation and small-scale modeling of the large-scale facility. That may also include, for example, the optimal point of harvest. For a short fed-batch process, you can harvest more each time. Depending on the titer curve, that can be more economical than running the same process for a long period.

Monge: With regard to optimization and flexibility, I understand that BI has recently been through a significant disposables implementation project at clinical manufacturing scale. Do you expect to integrate disposables more actively into your future commercial manufacturing?

Kaufmann: What BI has established is a fully disposable drug substance manufacturing process. Only when a facility is fully disposable can you run that facility without cleaning and steaming in place, which is key to bringing down overall facility and capital costs. We have used disposables in some process steps for several years now, but only recently have we set up a fully disposable process train for drug substance. The key here was to run the systems first in a non-GMP area and thereby discover the pros and cons of the disposables from different vendors.

We have now implemented a unique, interchangeable disposable platform concept in Fremont, California, and in Biberach, Germany. And we plan to implement the same in Shanghai, China for GMP clinical manufacturing. The key benefits of these disposable-based facilities is clearly demonstrated when supplying material for clinical phase 1 or clinical phase 2, when you don’t have time-consuming, labor-intensive change-overs while bringing many different projects into the same facility.

However, one trend is making it likely that we will see commercial products supplied from disposable manufacturing facilities in the future. This will be driven by the diversification of biopharmaceuticals, mainly due to the need for smaller quantities of drugs for smaller indications and patient groups defined by a certain biomarker, for example, or because of highly potent drugs that require smaller doses of product. An example of a highly potent biopharmaceutical would be an antibody that has been modified to be highly efficient in activating patients’ immune systems to kill cancer cells. This subfraction of biopharmaceuticals probably will be the first group to be launched from fully disposable commercial manufacturing facilities.

I foresee for many years to come a coexistence: high-throughput, stainless steel facilities (for antibodies or other recombinant proteins that are large-volume biopharmaceuticals applicable to a broad spectrum of patients) and highly flexible smaller-scale facilities based on disposables (supplying highly potent drugs or those for personalized medicine in smaller indications). Linked to that will be a need to characterize and understand all these facilities really well from a regulatory point of view. Many projects will transfer from small-volume disposable facilities to larger stainless steel facilities. We have studied that type of transfer in great depth and have compared product quality data to show that we can reproduce the same quality of product in either type of system.

Monge: Thank you for your time, Dr. Kaufmann. See you at the next ESACT in Barcelona in May 2015.

About the Author

Author Details
BPI editorial advisor Miriam Monge is vice president of sales and marketing at Biopharm Services Ltd., Lancer House, East Street, Chesham, Bucks, HP5 1DG, United Kingdom; 44-1494-793243, fax 44-1494- 785954; [email protected]; www.biopharmservices.com.