Bio-Engineering applied to the analysis and design of Bio-Processes

4-day course given at Department of Chemical and Biochemical Engineering, DTU

with John Villadsen and John M. Woodley as principal lecturers

Overall objective of the course

From the food industry to the production of fuels and solvents, commodity chemicals, and new drugs or cosmetics, the chemical industry is rapidly changing from raw materials of petro-chemical origin to raw materials of agricultural origin, mainly sugar and agricultural waste such as straw, or by-products from the forestry-based industries. Increasingly, the motivation is not only guided by “sustainability” of the processes, but also by the economic cost-efficiency of the bio-based industry. A market which was only about 1 billion US$ a few years ago has now grown to 20 billion US $ per year. 

This course addresses the key-issues of chemical engineering origin in particular, which any company must understand and apply in order to plan, and eventually to design and build an economically viable route to a desired large-scale bioprocess. Such processes use fermentation or alternatively enzyme-based processes (either isolated or operating in microbial cells) to synthesize new products. Although critical to the success of the venture, the molecular biology tools that must be implemented up-front of the actual production process are not central to the course, but will of course be cited as necessary. Many other courses address such topics and deliberately the focus here is on process engineering. The core-elements of chemical engineering: reaction stoichiometry, reaction kinetics (giving the required yield and productivity), the reactor design and control (assuring low production costs at a large scale), and to some extent the design of down-stream equipment, will be analyzed. The lectures will be supplemented by a large number of examples and exercises relevant to key-industrial bio-processes.

Who should participate in the course?

We hope to have participants who are employed in production and research at companies both in Denmark and in our neighboring countries. Also PhD-students from all Danish universities as well as foreign countries are invited. The course language is English. The course book, “Fundamental Bioengineering”, Wiley (2016), contains the examples taught in the course, but to inspire further studies it also contains detailed reviews by eminent bio-scientists of important subjects outside the course.

The teachers

John Woodley (jw@kt.dtu.dk) and John Villadsen (jv@kt.dtu.dk) are both professors at Department of Chemical and Biochemical Engineering, DTU. Their curricula can be found on the internet, and questions about the course can be addressed to either. To help solve exercises a number of PhD students from the bio- section of the department will offer assistance during the course (9 am to 4 pm) on each of the 4 days of the course.

Below is an overview of the four-day course, day by day. For each day text material, examples and problems (to be solved in class or between course days) are suggested. Contact time 9-12 and 13-16, counting lunch in between. Examples and problems take up about 60 % of the contact time.

Programme


Day 1: Mass balances, stoichiometry and reaction yield

Definition of (production) rates of bio-reactions, both for reactions catalyzed by enzymes and cell reactions, are introduced by means of mass balances for steady state operation of a stirred tank continuous reactor. The rates of reaction are defined both with respect to the reactor volume and with respect to the amount of catalyst available. The concept of yield, i.e. the ratio between production (or consumption) rates of two reaction species is introduced. This leads to the stoichiometry of the bio-reaction at a given feed rate v m3 h-1 per volume V of reactor. Using different values of v/V = D (h-1) one obtains experimental values for the productivity (kg m-3 h-1) of a given product per volume V of the reactor. This is used to design a reactor for a given annual productivity. When reaction kinetics (day 3) is introduced one can extrapolate process conditions, not yet studied experimentally.

Bio-reactions are (usually) carried out in an aqueous phase, but some substrates (e.g. O2) are available in a gas phase contacted with the liquid. Hence the transport rate of reactants from (or to) the gas phase must be combined with the rates of the liquid phase reactions. This gives rise to mass transfer limitations.

The concept of redox balancing is introduced as an instrument to evaluate experimental data and for both enzyme- and cell-reactions to suggest how the stoichiometry of the reaction can be changed to give a higher yield of a desired product. The application of redox balances will be illustrated by means of several examples, and it is shown how an optimal design of the stoichiometry can lead to considerable improvement of industrially important bio-reactions.

The topics introduced above are discussed in Chapters 2 and 3 of the course book “Fundamental Bioengineering”

Day 2: Metabolic pathways

The approach to construction of the stoichiometry of bio-reactions developed during the first day of the course is basically derived from experiments in a steady state continuous tank reactor. The enormous knowledge obtained during the last 100 years of research on biochemical pathways is, however, not used. We shall now stitch together the existing knowledge on individual reactions in biochemical networks to obtain the overall stoichiometry for a desirable bio-reaction. Using literature information on the bio-energetics of important networks together with redox balancing it becomes much easier to construct the overall stoichiometry – sometimes with a much smaller amount of experimental work. The resulting yield of desirable products from cell reactions can be improved by suitable genetic engineering of the production organism, and for complex enzymatic reactions the proper combination of enzymes is suggested by analogy with cell reactions.

Chapter 4 of the course book is used as background reading, and the examples to be discussed are all chosen from this chapter.

Day 3: Kinetics

On day 1 and 2 we have only studied bioprocesses in steady state. For each steady state (with given ratio D = v/V, given feed rate of substrate, given pH, reaction temperature etc.) the production rate could be found experimentally. In process design it is necessary to have a model that predicts the productivity, i.e. how much is produced per hour in a given reactor. Design of an optimal process requires both a good stoichiometric model, and a kinetic model. 

Kinetic models for enzymatic reactions were developed through the 20th century, and to a large extent they are mechanistic models, similar to those used for catalytic reactions in the chemical industry. Models for cell reaction kinetics are in comparison crude empirical analogues to enzyme kinetics.

The fundamental difference between enzyme kinetics and cell reaction kinetics is illustrated by two examples, one is for industrial production of succinic acid, a bio-process that in a few year has increased the annual production of this intermediate from 30 000 ton to about 200 000 ton.

Enzyme reactions are often carried out with the enzyme entrapped in a solid matrix to avoid wash out in a continuous process. Here transport of substrate into the matrix is a rate process that limits the overall production rate. A theoretical outlay of the double limited process kinetics is given with reference to a recently developed Novozymes process for a nutraceutical product.

Finally many-enzyme processes are treated with the objective of finding the optimal allocation of enzyme sequence of enzyme catalyzed reactions.

Chapter 7 of the course book treats these topics.

Day 4: Reactor design and scale-up

In a sense all the topics discussed during days 1 to 3 (including a fair amount of chemical thermodynamics) lead up to selection of the bio-reactor, the vessel in which the processes described convert substrates to products. Here different types of reactor design will be analyzed. The simple continuous stirred tank reactor (CSTR) operating in steady state is shown to be both simple and capable to reach a higher productivity than other modes of operation. Examples are given to show that CSTR´s operating in parallel or in sequence will greatly increase both the steady state productivity, but also the robustness of the total plant towards upsets in the operation. The fed-batch mode of operation is very popular in practice, but it suffers from low productivity compared to CSTR´s, and simulation of the operation often requires much more computation. 

The industrial reactor operates with a medium that is not necessarily homogenous, and vigorous agitation is therefore needed to avoid substrate variations over the medium volume, and the transfer of gaseous substrates to the liquid phase may become a limiting process. Here new types of reactor design, including many new mixing aggregates, are used to approach conditions of the “ideally mixed”, volumetrically homogenous reactor. In several examples the design of real reactors at different scale of operation is discussed, and rules for “best” operation of large reactors are introduced.

Chapters 10 and 11 of the course book serve as background material for design of reactors, especially for comparison of operation at different scales.

Course fee

The course fee is as follows (including coffee/cake and lunch):

  • PhD students from DTU:
    DKK 3.500

  • Participants from Danish universities:
    DKK 4.000

  • Participants from international universities:
    DKK 5.000

  • Participants from industry:
    DKK 16.000

Registration 
To enter the course, participants must register before July 1, 2016.

If a minimum number of 15 participants have not registered 30 working days before the course starts, the course may be cancelled. 


Refunds

If the course is cancelled it will be refunded. 

Deposits will not be refunded after August 1st, 2016 if participants wish to cancel a registration. 


Upon registration, an invoice will be issued in good time before the course starts.


More information
For more information, please contact John Villadsen.

Next course

August 23 to August 26, 2016 (course postponed)

Course responsible

John Villadsen
Professor emeritus
DTU Kemiteknik
45 25 26 68

Course co-responsible

John Woodley
Professor
DTU Kemiteknik
45 25 28 85

Registration

Anne Helene Juul
Studiesekretær
DTU Kemiteknik
45 25 28 36