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Biologicals are becoming increasingly important to Boehringer Ingelheim

Biopharmaceuticals are playing an increasingly important role in Boehringer Ingelheim’s development pipeline. Visible evidence of this is the company’s Biologicals Development Centre (BDC) that is currently being constructed in Boehringer Ingelheim’s Biberach plant and will bring the company’s process development under one roof by early 2020. Walter Pytlik from BIOPRO talked with Dr. Ing. Ralf Schumacher about the new centre. Schumacher is responsible for the non-clinical development of biologicals at Boehringer Ingelheim.

Which biological molecules will be produced in the new centre?

Two years ago, Boehringer Ingelheim decided to completely separate contract manufacturing from its own biopharmaceutical development projects. The new building will house development projects for the company’s own NBEs1 and biosimilars.

Glossary

  • Antibodies are blood proteins (immunoglobulins) which are produced by the B lymphocytes in response to disease. They recognise foreign substances that have entered the body (e.g. bacteria) and help the body fight against a particular disease and develop an immunity to that disease.
  • Being lytic is the feature of a bacteriophage leading to the destruction (lysis) of the host cell upon infection.
  • Genetic sequences are successions of the bases adenine, thymine, guanine, and cytosine on the DNA (or uracil instead of thymine in the case of RNA).
  • The somatic gene therapy is used to compensate gene defects. Therefore, the correct form of the mutated gene is transferred into somatic cells.
  • A vaccine is a preparation of dead or weakened pathogens (or of derived antigenic determinants) used to induce immunity against the pathogen.
  • Biopharmaka are Drugs, which are produced with the help of biological systems.
  • Fermentation is the process of converting biological materials with the help of microorganisms or by the addition of enzymes. In its strictest sense, fermentation is the anaerobic oxidation of sugars for the purpose of energy generation of the metabolic organism.
  • A cell line is a permanently established cell culture that will proliferate indefinitely under defined conditions.
  • Expression means the biosynthesis of a gene product. Usually, DNA is transcribed into mRNA and subsequently translated into proteins.
  • kb is the abbrevation for kilobase. The unit kb describes the length of DNA or RNA molecules and corresponds with 1,000 bases or base pairs of the nucleic acid.
  • Cutanous means: belonging or affecting the skin.
  • T-Lymphocytes (also called: T-cells) are important cells of the immune defence (white blood cells), which recognize foreign particles (antigens) when they are bound to the surface of other cells. Together with the B-lymphocytes, T-lymphocytes participate in the aquired immune response, which means that they are able to respond specifically to a certain pathogen.
  • Aggregation is the forming of a functional cluster of cells or molecules.
  • Glycosylation is the addition of carbohydrate to an organic molecule, mostly proteins.
  • Biosimilars are drugs that mimic the effects of biopharmaceuticals.
  • Good Manufacturing Practise.
  • Biomolecules which can bind active agents are called targets. They can be receptors, enzymes or ion channels. If agent and target interact with each other the term agent-target-specific effect is used. The identification of targets is very important in biomedical and pharmaceutical research because a specific interaction can help to understand basic biomolecular processes. This is essential to identify new points of application.
  • Subcutaneous means: lying under the skin. The hypodermis or subcutaneous tissue named tissue lying immediately below the skin.

Four out of ten drug candidates in your pipeline are biologicals. 80 clinical and preclinical development projects were mentioned at Boehringer’s R&D press conference. Can you break this down?

Dr. Ralf Schumacher (55) has been responsible for the non-clinical development of biologicals since 2018. He held a similar position with Roche for many years and has accompanied the development of antibodies as a therapeutic from small beginnings to the present industrial dimension. © Boehringer Ingelheim

Let me clarify something first: we carry out the required non-clinical development work. We establish processes and develop techniques, scale them up and produce clinical material. That said, projects may during this time already be in Phase I or II of clinical development.

We have around 25 projects in various phases of development, ranging from preclinical stage to approval. Our focus is on classical antibodies, but we also have quite a few so-called "engineered" molecules, bispecific molecules referred to as T-cell engagers. These engineered molecules account for about 20 to 25 percent of the drugs we produce.

And the drug candidates are designed for therapeutic areas such as immunology and immuno-oncology?

That’s correct. We are specifically focused on antibodies that are directed at surface structures of tumour cells; but we also focus on checkpoint inhibitors. As far as the field of immunology is concerned, we are working on a classical antibody, an IL-36 receptor antagonist, which plays a role in the immunoregulation of psoriasis and other inflammatory diseases. We are also working on ophthalmologic approaches and antibodies for treating cardiovascular disease.

When the foundation stone for Boehringer Ingelheim Biologicals Development Centre was laid in June, you highlighted that it was necessary to combine biological analysis, process development and drug manufacturing for clinical trials departments under one roof. Why is this necessary?

Because we know from the biotechnological production of medicines that all process steps are both highly technological and mutually dependent. For example, if someone in the fermentation department comes up with the smart idea of growing the cells at 36.5 rather than at 37 degrees, this may entail a subtle, though decisive difference in the quality of the protein produced. The difference in quality might be due to a different glycosylation pattern. However, such process changes cannot be made in isolation. The ideas that fermentation, purification and analysis specialists come up with need to be discussed with scientists from other disciplines. Only when the analyst knows about the plan to change the fermenter temperature will he or she be able to assess and understand the change. We also generate tons of data. Each fermentation run generates a great deal of in-process data that needs to be interpreted and archived.

Could you explain what you mean by needing to use a complex network of technologies, perhaps by using your immunological beacon of hope, the IL-36 receptor inhibitor, as an example?

The complex process path from small bottles to 15,000-litre fermenters will be combined in the new biologicals development centre in Biberach. © Boehringer Ingelheim

Producing such a commonly produced classical antibody such as the IL-36 receptor inhibitor might be considered not particularly challenging. However, this is not the case. The individual amino acid sequences might contain elements, i.e. amino acid regions, with a hydrophobic structure. Some antibodies might therefore have an amino acid exposed on their surface that will undergo slight modifications, e.g. in the form of an oxidation or rearrangement.

This means that each antibody is in fact individual. Although a particular antibody has been produced before, each new one will nevertheless be different. We need to deduce from the molecular properties that determine the antibody sequence what is possible during fermentation without damaging the cells, which trace elements need to be added, which kind of media components the cells need, or what kind of growth properties the cell that was specifically produced for the production of the antibody has. This knowledge needs to be taken into account in the fermentation process. Harvesting needs to be optimised such that the subsequent purification process removes as many impurities as possible. We need to keep in mind that we are dealing with living cells that can make “mistakes”, which might lead to impurities and aggregation. As far as purification of the harvested cell culture fluid is concerned, we need to know what the harvested fluid contains. This knowledge needs to be combined with what we know about the amino acid sequence and the properties of the fluid (salts, pH value, additions) in order to avoid mistakes. This knowledge has to be accompanied by analytical processes, so that it is always possible to find out what is happening, for example whether the process is still in the “green area” or going through a phase where the proteins tend to aggregate.

As far as this particular antibody is concerned, we are targeting a relatively high concentration, in excess of 100 mg/ml, which is a prerequisite for later subcutaneous applications. Such a high concentration might cause the proteins to aggregate. It therefore goes without saying that the sequence of the antibody and hence purification properties need to be known in order to determine the concentration and the type of additives that are tolerated. All this is taken into account within the value creation chain.

The cell culture-based production of biologicals with Chinese hamster ovary (CHO) cells uses a decades-old technology. Will the new development centre also be used for producing ATMPs and the technologies needed to manufacture them?

ATMPs2 such as gene therapy, viruses or other vaccines may require expression systems other than CHO3. Although we will most likely not produce ATMPs here in Biberach because of special safety requirements, we will still focus on developing processes for producing these novel modalities.

Big pharmaceutical companies need to find answers to growing cost pressures. Can the new development centre help with this?

Boehringer Ingelheim is committed to developing first-in-class and breakthrough therapies. Breakthrough means that, during clinical development, it might turn out that the drug under development is the best and only available treatment option for a particular patient. The drug in question will then be given breakthrough therapy designation. Breakthrough therapy designation reduces a drug’s development and review time. We will also look at alternative development strategies so we can speed up commercial product development. We have to establish platforms that enable such acceleration. We will develop purification and analytical methods platforms for cell lines, fermentation and media in order to reduce development times and costs.

Will you also use single-use systems?

Yes, we will establish a manufacturing area called the Clinical Supply Center in this building, where we will manufacture the active ingredients that will later be used for human treatment under GMP conditions. We will use disposable fermenters for this purpose.

Boehringer Ingelheim does not yet have its own biopharmaceutical blockbuster. Does the new development centre increase the likelihood of manufacturing one?

We have some good products in the pipeline. I am sure that the new development centre will help us create the prerequisites necessary to develop significantly more blockbuster drugs, much better ones, and much faster. And yes, Boehringer Ingelheim will play a much bigger role in this area than before.

1 NBE: New biological entities
2 ATMPs: Advanced therapy medicinal products
3 CHO: Chinese hamster ovary

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