Future market: biotechnology
Demands on the conception of biotechnological plants

In search of new drugs the pharmaceutical industry today is profiting greatly from the dynamic growth in knowledge of genetics and cell biology. Innovative drugs are produced for example by genetically modified cells and permit completely new therapeutic approaches. Culture of such cells and recovery of their products on an industrial scale place complex demands on the conception of biotechnological plants.

Biotechnology belongs to those future technologies, which owing to the potential for innovation and the bright prospects of the market will leave their imprint on the technological face of the world in coming decades. In pharmaceutics, biotechnology is presently bringing about a qualitative change: Innovative drugs, which are produced by means of genetically modified cell systems, permit new therapeutic concepts. In the future, it is hoped, drugs will act specifically on for example cancer cells and therefore will have fewer side effects on healthy tissue than chemotherapy, radiation or surgical removal of tumors.

The therapeutic strategies and, starting from there, the development of drugs with specific action on cancer cells, was only possible as a result of great innovative activity in associated fields of knowledge. The following examples may be mentioned here:
molecular cell biology and genomics, which elucidated the mechanisms regulating growth and reproduction of living cells, as well as basic medical research resulting in precise descriptions of the body’s immune system and of tumorigenesis;
nanotechnology for the visualization of structures and mechanisms in living cells on a molecular or macromolecular level;
gene technology, which by means of recombination is able to modify genes and insert new genes into cells thus permitting tailor-made development of drug substances in line with therapeutic strategies;
new production methods, which make it possible to produce these novel drug substances on an industrial scale.
The greatest change in the pharmaceutical industry has been the switch from chemically synthesized to biotechnologically produced drug substances in the last five to ten years. Currently, erythropoietin (EPO) is the first biotech product to capture the top position as the best-selling pharmaceutical product in the world.
Trends in product development by geneic engineering
Characteristic milestones in the use of genetically modified cell systems for the production of active pharmaceutical ingredients (APIs) were:
“Imitation“ of human biosynthesis of insulin in systems with genetically modified cells. Via the technique of genetic recombination, the DNA fragment, which in human cells contains the production code for insulin, was inserted in bacteria.
“Modification” of the DNA of the human insulin gene and thereby modifying the molecular structure of the insulin protein with the objective of altering the profile of action in the patient’s body by producing especially fast-acting or especially longacting insulins. Thus, more closely adapted therapies for the individual patient are possible, and the insulin level can be kept uniformly high, which among other things results in greater wellbeing of the patient.
Use of mammalian cells, normally CHO (Chinese hamster ovary) cells, as host cells for human DNA fragments. Because of the closer “similarity” of CHO cells to human cells, the range of possibilities for the development of new medicinal drugs and/or mechanisms of action was increased. At the same time, the technological difficulties of maintaining the conditions for life and growth of these highly sensitive cell systems increased. An example of this product category is EPO.
Development of monoclonal antibodies
The qualitative step of gene technology from DNA-based imitation of human substances to initiation mechanisms in the immune system was taken with monoclonal antibodies (MABs). MABs are the basic elements for a high-tech scientific answer with adequate active principles to, among other things, the extremely complex disease-related defects in the genome of man. Antibodies have “search systems” of their own for foreign substances in the body—including those on the surface of cancer cells—and act via activation of the immune system. Today genetic methods allow MABs to be altered or specifically constructed in such a way that they can also recognize endogenous substances in the body. These properties have made MABs the great bearers of hope in the fight against cancer. An example of this product category is Avastin, which was recently approved for the treatment of colon cancer.
A special group of biotech products consists of herbal substances. Because of the limited natural resources of rare or slow-growing plants these substances are nowadays produced biotechnologically as well. For this purpose, the corresponding plant cell is isolated and propagated in bioreactors under suitable culture conditions. The slow growth of plant cells places great demands on the sterile processing technology of the production facility. Plant cells are used for example for making special products for the chemotherapeutic treatment of tumors.
The observation of trends in biotechnology enables the plant designer in the pharmaceutical industry at an early stage
to identify and work on innovative projects and technologies with future potential, thus achieving a leadership position in this field of engineering, with respect to market share and references;
to adapt its personnel profile, personnel training, design algorithms and design tools to market conditions;
to focus its acquisition activities on companies with high development and market potential.
Strategic environment of the pharmaceutical industry
Entrepreneurial decisions have become increasingly difficult for pharmaceutical companies active in biotechnology in recent years. On the one hand, the dimension of decision-making relates to the success of the company in its core: The costs of product development up to start of production are exceptionally high and in some cases amount to more than a billion Euro. Thus, only a few products can be developed all the way to approval and registration. However, they may then have the prospect of sales volumes of more than a billion Euro per year. On the other hand, the fundamentals for decision-making are often hard to assess, since decisions to prepare for production must be taken exceptionally early because of the “time to market” situation and the long product development time. Making this more difficult is the fact that at this point in time no reliable data exist as to costs and time schedule of the development phase and as to the prospects of efficacy and regulatory approval of the product. In addition, the competitive situation with respect to products of competing companies with either identical mechanism of action or competing mechanism but possibly better therapeutic results is not clearly known. Uncertainty also often prevails concerning the availability or the status and quality of licenses—in the end, European pharmaceutical companies are largely dependent upon know-how from the USA, due to the latter’s head start in the field of genetically modified production systems. As a result, a small number of risky product developments determine the success or failure of even large companies.
Strategies for plant design and construction
For a plant designer, who is only brought in to the picture at the end of the long and hard-to-predict chain of decisions, there is a high risk in the evaluation of the likelihood of success of projects as well as in the development of its own planning strategy for biotechnological plants. This risk can only be dealt with by accurate knowledge and correct assessment of the interrelationships and influences involved. This includes consideration of the distinctive features of biotech plant design.
Development and design in parallel: Because of the innovative character of the products being developed and the “time to market” pressure, process and product development proceed in parallel with design. The classic model of plant design and construction with established and proven processes as a prerequisite for the start of basic engineering is thus invalid per principle. With regard to biotech know-how transfer from the licensor to the plant designer during concept and basic engineering, this approach requires close collaboration—usually at the customer’s site—among licensor, ultimate plant operators, customer’s engineering specialists and plant designer. The smooth transfer of know-how into the project during ongoing design and the compliance with the project objectives are thus ensured.
Customized solutions: Each project is unique, frequently with new technologies and unit operations for which only limited process information is available. Therefore new solutions have to be worked out during the design phase.
Task profile: front-end engineering
For these reasons, the plant designer is being brought into the project by the customer earlier and earlier and now collaborates already in the preparation of investment decisions (feasibility phase). There, questions of process risk, scale-up, cost estimates and time schedules up to start of production come to the fore. The plant designer’s experience is also being used more and more frequently to assess biotech investment projects or to evaluate and compare locations on an international level. Last but not least, the customer
often wants strategic support in project management. Linde-KCA-Dresden has summarized this task profile under the term “front-end engineering”. Today front-end engineering is an important and successful marketing and sales tool for an early entry into customers’ projects. Linde-KCA-Dresden now generates most of its pharmaceutical projects in this way.
Integrated step for quality assurance
Additionally and carried out in parallel to other disciplines, a step for quality assurance of the finished pharmaceuticals is integrated into the design and execution phases of biopharmaceutical projects. Quality assurance is carried out according to strict international rules and is a requirement for the approval and registration of drugs. Quality assurance includes definite rules for design and testing of plants as well as, in particular, the documentation of work steps. Very high demands are also placed at the IT level, in order to ensure complete traceability of all raw material, intermediate product and finished product batches for a ten-year period of record-keeping. Thus, the automation, control and information systems of biotechnological plants have higher requirement levels and a larger scope than large industrial plants.
Linde-KCA-Dresden has been technologically associated with the development of biotechnology from the early stage products such as insulin through the fractionation of blood plasma all the way to demanding projects with genetically modified systems with bacteria, yeasts and animal cells. Thus, Linde is main contractor for one of the largest and technologically most advanced European projects for monoclonal antibodies and hence is active at the very forefront of biotechnological development, design, and production of drugs for the fight against cancer.
A great market potential can be predicted for pharmaceutical biotechnology. The reasons for this are multiple: Since the mid-nineties, the values of investment in biotech plants have risen from e10 to e20 million, predominantly for pilot plants and small scale production plants, to about e300 million for large scale production plants today. Along with this, there are a large number of biotech products in the pipeline of pharmaceutical companies and the areas of application are expanding beyond pharmaceuticals up to food. In addition, the market conditions for plant design with respect to split of work have improved. This results from deeper knowledge of the special requisites and basic conditions governing pharmaceutics, on the part of both investor and plant designer. Additionally, the trend in plant design goes to an extension of the value chain along
with increasing project size, broader scope of work and constantly increasing and changing technological requirements.