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Biopharmaceutical Production: Value Creation, Product Types, and Biological Basics Introduction

1.1 Role of Production in Pharmaceutical Biotechnology

Over recent years, pharmaceutical biotechnology has developed very dynamically. An important driver for this success has been the enormous increase of scientific know-how in the areas of genetics and immunology, which has created huge expectations for the development of innovative medicinal treatments.

The scientific pioneer spirit has been fueled by public and private sponsorship, resulting in a biotechnological landscape that has long been dominated by highly innovative, venture capital-based, small- and mid-size companies. However, before patients can benefit from scientific achievements, it is necessary that the identified molecule is transformed into a medicine - fit for achieving the therapeutic target - and tested in comprehensive trials in the field. The production of such a medicine has to be carried out in officially licensed, often tailor-made technical manufacturing facilities.

From project to product

This path from project to product usually lasts several years and is associated with enormous costs and risks. On average, the development costs of a new compound are in the region of US$ 500-1000?million and only 10% of all projects that enter clinical trials find their way into the market.

Owing to these immense investments in drug development, the costs of drug manufacturing often seem acceptable, particularly as the costs are absorbed by sales of the marketed drug in the same accounting period; however, safe and efficient product supply is the cornerstone of a company's success. In biotechnology, the overlap between development and market launch is particularly intensive, motivating companies to take care of manufacturing early on:

• Many targets of process development result from requirements of large-scale manufacturing.
• The classical separation of development (pre-marketing) and production (post-marketing) does not work for biologics, as both the manufacturing process and plant are factors that determine the quality of the final medicinal product.
• Production is the basis for long-term market supply. Decisions about capital investment or outsourcing of manufacturing mostly have to be taken long before the market launch of the product.
• Biotechnological processes are much more difficult to control than small-molecule preparations. The limited ability to monitor and characterize the product results in increased manufacturing risks.

Significance of production in the value chain

The main target of production is to supply the product safely and cost-efficiently. It is positioned between the development and marketing of a product. Figure 1.1 illustrates its significance in the value chain.

The chain starts with research that has a clear focus on the identification of targets, which involves analyzing the interaction between the biochemical molecule and its potential therapeutic functionality. In the subsequent development phase, a process for the scale-up and more consistent manufacturing of the molecule is designed. Here, the target structure is developed into a pharmaceutical form and tested in animals and humans as to its safety and efficacy. Once this is achieved, production kicks in, taking care of a high-quality and profitable product supply, addressing the following main tasks:

• When, where, and in what quantities should the drug be produced? (Production concept)

  Figure 1.1 Role and tasks of production.

• How should market supply be organized? (Supply-chain organization)
• How should the quality of the product and Good Manufacturing Practice (GMP) compliance be assured? (Quality assurance)
• What are costs of manufacturing and how can these costs be controlled? (Manufacturing costs)
• How attractive is an investment in one's own facilities? (Investment decision)

The marketing of the product stands at the end of the value chain; from this position, essential goals are formulated for production: supply safety and cost efficiency.

Production is interdisciplinary

The integrated position of production in the value chain results in interdisciplinary tasks that are best treated by multilateral teams managed by experts in different disciplines such as biology, engineering, chemistry, economics, law, pharmacy, and medicine.

Figure 1.2 shows the subject areas that are important for the understanding and control of production processes and workflows. This volume provides an overview of these subject areas, while special emphasis is given to the interaction between these areas.

Figure 1.2 Subject areas in production. Inner circle = sections of this book; outer circle = subject areas treated in the sections.

Following this introductory part, Part II, "Technology," focuses on processes and analytics. This section illustrates why the manufacturing process plays such a large role in biotechnology, and to what extent product quality is determined by processes and analytics. Moreover, essential technologies for industrial manufacturing as well as methods and areas of application of analytical testing are described.

Part III, "Pharmacy," briefly elaborates on the basic principles of drug effects on humans and the essential steps of pre-clinical and clinical drug studies. The successful end of the clinical test marks the starting point of commercialization.

Product quality plays a crucial role in pharmaceutical manufacturing. Part IV, "Quality Assurance," elucidates the organizational and operative workflows for quality assurance, including the rules of GMP.

Almost all activities of commercial production happen in the framework of legal regulations. Part V, "Pharmaceutical Law," describes drug regulations and laws as well as institutions and enforcing official authorities.

The translation of process technology into large-scale manufacturing capacities is described in Part VI, "Production Facilities." Basic principles of the design of GMP-compliant manufacturing facilities are given and different building concepts compared. The planning process that leads to industrial plants is illustrated. Here, we include a brief look at the regulations regarding health, safety, environment, and construction that form the legal framework of industrial production facilities.

Commercial thinking is the spine of efficient production. Part VII, "Economy," introduces essential principles around product sales and cost of goods accounting. It compares concepts of in-house manufacturing with outsourcing strategies and elucidates the decision factors leading to capital investments in biotechnological plants.

The book closes with a Bibliography providing literature and web references and an appendix providing a list of abbreviations and an alphabetical index of keywords.

1.1.1 Relationship Between Production and Development

It is widely understood that production starts when development provides a marketable product and a commercially feasible manufacturing process. Ongoing market supply is secured by process optimization or the provision of additional manufacturing capacities, depending on how market demand develops. For biotechnological pharmaceuticals, the flexibility to react to demand changes is reduced due to the following reasons.

Drug application and the manufacturing process are described and fixed in the regulatory license. As the biotechnological manufacturing process is a quality-determining factor, it has to be finally defined at the time point of regulatory submission and can thereafter be changed only with relatively high effort. The market application contains proof of the safety and efficacy of the drug; it adds to the complexity that in biotechnology, this proof has to be made - at least partly - with material from the commercial process and manufacturing site. Changes to the process or site require comparability exercises that can be more or less complex depending on the risk associated with the change. All of this means that the manufacturing process is fixed at a relatively early time point during development and can only be changed with quite some effort.

Clinical and process development

This coherence is illustrated in Figure 1.3. Product development consists of clinical development, on the one hand, and development of the manufacturing process and the analytical methods, on the other hand. The clinical development renders proof of safe and efficacious use of the drug in humans. Ideally, this proof is generated with material from the process and the site designated for commercial supply. There is a challenge with this ideal approach: if the process would be finally established and only after that clinical development be initiated, the timelines of development would add up unacceptably. Therefore, the different branches in the development workflow occur in parallel; different stages of the clinical development are supplied with different development stages of the manufacturing process.

Figure 1.3 Relationship between production and development.

From lab to large-scale process

Validation and critical parameters

Coming...