INTRODUCTION TO

BIOCHEMICAL
ENGINEERING
 LEARNING OBJECTIVES
• General definitions

• Research approach of biologists vs. engineers

• Example: Penicillin

• Regulatory constraints
 BIOPROCESS ENGINEERING
What is it?

Bioprocess engineers are in charge of using cells on commercial scales in

a purposeful, predetermined manner, obeying the rules of chemistry and
physics, for:

New medicines

More nutritious foods

Pollutant removal

Novel consumer products

Sustainable energy sources

 GENERAL DEFINITIONS
Related fields…

Biotechnology

Use/development of methods of direct genetic manipulation for a socially desirable goal

Key element: sophisticated techniques outside the cell for genetic manipulation

Bioengineering

Broad field, includes work on medical, agricultural, environmental systems

Practiced by agricultural, electrical, mechanical, industrial, chemical engineers
Subfield: biological engineering  applications to plants and animals
 GENERAL DEFINITIONS
Related fields…

Metabolic engineering

Design of cells with genetically altered pathways to make new products

Biochemical engineering

Chemical engineering principles to systems using a biological catalyst

Biomedical engineering

Application of engineering principles from different disciplines to design: medical devices, synthetic organs,
drug delivery systems, diagnostics, instrumentation…
 GENERAL DEFINITIONS
Related fields…

Biomolecular engineering

Research at the interface of biology and chemical engineering and is focused at the molecular level

Bioprocess engineering

Includes mechanical, electrical, environmental, industrial and chemical engineers to apply principles to different
disciplines to processes based on using living cells
Detailed equipment design, development of sensors, control algorithms, manufacturing….
 ENGINEERS & BIOLOGISTS
Distinct differences

Biology research

Mathematical theories and quantitative methods play a secondary role

Progress based on improvements in experimental tools
Qualitative results and good interpretation of complex lab data

Engineering research

Solid background in physical and mathematical science

Develop theories that lead to mathematical formulations validated with experiments
Quantitative models and approaches
 PENICILLIN

• Discovered by accident by Alexander Fleming in 1928

• “The staphylococcus colonies became transparent and were obviously undergoing lysis …
the broth in which the mold had been grown at room temperature for one to two weeks had
acquired marked inhibitory, bactericidal and bacteriolytic properties to many of the more
common pathogenic bacteria.” Article published by Fleming in the British Journal of
Experimental Pathology in 1929
Penicilium
• Penicillium notatum  Isolated the secreted material and demonstrated its antimicrobial
colony properties and named it penicillin
Lysed bacteria
• He preserved the culture, but the discovery lay dormant for more than a decade
Healthy
bacteria
 PENICILLIN

• WWII provided a huge incentive to scale up production  Most deaths in war are from
infection
• Production of penicillin was incredibly difficult and was done in very small quantities,
product was really unstable and did not last long
• Penicillin was scarce, resulting in deaths at the hospitals
• Chemical synthesis was attempted by hundreds of chemists, it was extremely difficult
Penicilium • In 1940, fermentation to produce a pharmaceutical was an unproved approach
colony
Lysed bacteria • In 1939, the titer in a typical fermentation broth was 1 mg/L, and very unstable, placing
significant constraints on approaches used for recovery
Healthy
bacteria
CHEMICAL ENGINEERS TO THE RESCUE!
During WWII, the US and UK governments
approached the largest US chemical and
pharma companies to enlist them in the
race to mass produce penicillin.

One of these companies, Pfizer, succeeded

in producing large quantities of penicillin
using deep-tank fermentation, making
penicillin available to Allied soldiers by the
end of the war.

Pfizer’s plant started operating on March

1944. It contained fourteen 7,500-gallon
tanks. Working 24/7, the increase in
penicillin production was dramatic. During
the fall, one day’s production exceeded the
entire production of 1943.
 CHEMICAL ENGINEERS TO THE RESCUE!

Alexander Fleming and the discoverers of other antibiotics

deserve all the credit they have won. But their work would
have remained on the laboratory shelf if not for the
development of deep-tank fermentation. As David Wilson
wrote in his book In Search of Penicillin (Knopf, 1976), “It is
the biggest single failing of the myth about penicillin that it
ignores the technological breakthrough of deep fermentation,
a breakthrough that was every bit as vital to the successful
development of penicillin as any of the more dramatic
laboratory work.”

https://www.acs.org/content/acs/en/education/whatischemistry/landmarks/penicillin.html
 CHEMICAL ENGINEERS TO THE RESCUE!

Summary…

From “bottle plants”  Large scale fermenters

Titer from 0.001 g/L  50 g/L

US had the capacity by the end of WWII to produce penicillin to treat 0.1 million patients/y

Merck realized that men who understood both engineering and biology were not available

Before the penicillin process, no chemical engineers sought specialized training in life sciences

With the advent of modern antibiotics, the concept of bioprocess engineer was born
 REGULATORY CONSTRAINTS
US FDA  Ensure safety and efficacy of medicines

Primary concern of bioprocess engineer: Production of a high-quality product in the amount needed to satisfy
medical needs of the population

Drug development:

- How much time does it take from discovery to animal testing?? 6,5 y
- Human clinical trials:
Phase I) test safety (1 year, 20-80 volunteers)
Phase II) test efficacy (2 years, 100-300 patients)
Phase III) test efficacy and side effects (3 years, 1000-3000 patients)
FDA review (18 months)

Takes 12-15 years and $5 billion

Exception?
Only 10% of drugs that enter human clinical trials are approved
Both product and process need to be approved – why?
 REGULATORY CONSTRAINTS
GMP  Good manufacturing practice

GMP concerns facility design and layout (flow of material, personnel and air), equipment and procedures
(including cleaning and sterilization), training of personnel, control of input materials, product handling, process
monitoring and control (computer software), etc.

GLP  lab assays

SOP  procedures

FDA provides extensive information and guidelines

Bioprocess engineers often find that much of their work is to satisfy regulatory requirements