Part I. Introduction

Chapter 1.

What is a Bioprocess Engineer?

BIOPROCESS ENGINEERING

Textbook: Bioprocess Engineering Basic Concepts 2nd Edition

Instructor: Assistant Professor Yong Woo Cho, PhD

Office: Room # 38-411, The 4th floor, Engineering Building V

E-mail: ywcho7@hanyang.ac.kr

Tel: (OP) 031-400-5279, (CP) 010-4052-1012

TA: Hwa In Yoon, E-mail: fineyoon@gmail.com, (OP) 4712, (CP) 010-4744-6321

Homepage: http://www.biomedpolym.re.kr

Lecture: Monday 4:30 – 6:00 PM & Tuesday 4:00 – 5:30 PM

Text: Bioprocess Engineering Basic Concepts 2nd Edition (by M. L. Shuler and F. Kargi)

1 Midterm (40%), 1 Final (40%), and Assignments (20%).

Administrative Details

Part I. Introduction

Chapter 01. What is a Bioprocess Engineer?

Part II. The Basics of Biology: An Engineer’s Perspective

Chapter 02. An Overview of Biological Basics

Chapter 03. Enzymes

Chapter 04. How Cells Work

Chapter 05. Major Metabolic Pathways

Chapter 06. How Cells Grow

Chapter 07. Stoichiometry of Microbial Growth and Product Formation

Chapter 08. How Cellular Information Is Altered

Midterm Exam

Part III. Engineering Principles for Bioprocesses

Chapter 09. Bioreactors

Chapter 10. Scale-Up and Control of Bioreactors

Chapter 11. Recovery and Purification of Products

Part IV. Applications to Nonconventional Biological Systems

Chapter 15. Tissue Engineering and Gene Therapy

Final Exam

Course Outline

The Oldest Protocol for Yeast Production

Bread and Beer Manufacturing Process, the 5th. Dynastry (ca 2400 BC) Leiden Egyptian Museum, Holland

1.1. Introductory Remarks

Biological Revolutions

We can now manupulate life at its most basic level−the genetic.

Biological systems are very complex and beautifully constructed, but they obey the

rules of chemistry and physics.

The Job of the Bioprocess Engineer

Engineers should play an essential role in converting biological revolutions into

reality

The processes to use living cells can be rationally constructed on commercial scale.

Close the gaps between chemical engineering and biology

1.2. Biotechnology and Bioprocess Engineering

Researches at the interface of biology and chemical engineering

Biotechnology: Genetic manipulation / Applied biology

Bioengineering: Engineering with biotechnology

Biological Engineering: Emphasis on plants and animals

Biochemical Engineering: Emphasis on biological catalysts

Biomedical Engineering: Application of engineering principles and techniques to

medical fields

Biomoleucular Engineering: Focused at the molecular levels

Bioprocess Engineering

To apply processes based on using living cells or subcomponents of cells

Detailed equipment design, sensor development, control algorithms, and

manufacturing strategies

We will focus primarily on the application of chemical engineering

principles to systems containing biological catalysts, but with an

emphasis on those systems making use of biotechnology

1.3. Biologists and Engineers Differ in Their Approach to Research

Biologists

Strong with respect to laboratory tools

Weak with respect to physics and mathmatics.

Engineers

Good background in physics and mathmatics.

Unfamiliar with exprimental techniques and strategies used by life scientists

They are Complementary

To convert the promises of molecular biology into new processes to make new

products requires their Integration

1.4. The Story of Penicillin: How Biologists and Engineers Work Together

Antibiotics are one of the great marvels of modern medicine

Figure. The mold produces penicillin.The first antibiotic discovered was penicillin, which is made by the common mold Penicillium notatum, shown here growing on bread and in a close-up view. Alexander Fleming discovered penicillin in 1928. He was trying to grow bacteria (Staphylococus aureus), but the pesky mold Penicillium notatum had contaminated his bacterial cultures. Fleming noticed that bacteria did not grow near the mold. Fortunately, he recognized the value of an agent that could inhibit bacterial growth, and the age of antibiotic was born.

The discovery lay essentially dormant for over a decade

Staphylococus Bacteria

Figure. Fungal production of an antibotic. The mold Penicillium produces an antibiotic that inhibits the growth of Staphylococcus bacteria, resulting in the clear area between the mold and the bacteria

Staphylococus Bacteria

Staphylococcus bacteria cling to hairlike appendages called cilia on human skin cells

They cause boils

Penicillin Production by Fermentation

Low rate production per unit volume: 0.001 g/L in 1939 (Gold is more plentiful in see

water)

Penicillin is a fragile and unstable product

Development of a new medium (A corn steep liquor-lactose based medium): increased

productivity about tenfold.

Better producer strain: Penicillium chrysogenum − Superior to hundreds of other

isolates

A new manufacturing process: A submerged tank process − Reactor design

Special techniques for product recovery and purification: A combination of pH shifts

and rapid liquid-liquid extraction

Now, a production rate: 50 g/L

Multidisciplinary Work

This accomplishment required a high level of multidisciplinary work

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

available.

Merck assigned a chemical engineer and microbiologist together to each aspect of

the problem.

They planned, executed, and analyzed the experimental program jointly, “almost as

if they were one man”

Progress has involved better understanding of mold physiology, metabolic

pathways, penicillin structure, methods of mutation and selection of mold genetics,

process control, and reactor design.

1.5. Bioprocess: Regulatory Constraints

The primary concern is NOT reduction in manufacturing cost, but the production of a

product of consistently high quality in amounts to satisfy the medical needs of the

population.

US FDA

From the discovery stage through preclinical testing in animals: 6.5 years

Phase I clinical trials: Test safety, about 1 year, 20 to 80 volunteers

Phase II clinical trials: Efficacy and side effects, about 2 years, 100 to 300 patients

Phase III clinical trials: Efficacy and side effects, about 3 years, 1000 to 3000 patients

Data review: 1.5 years

Totally 15 years, $400 million

Only one in ten drugs that enter human clinical trials receives approval

1.5. Bioprocess: Regulatory Constraints

FDA approval is for the product and the process together

Drugs must come from facilities that are certified as GMP (Good Manufacturing

Practice)

Off-line assays done in laboratories must satisfy GLP (Good Laboratory Practice)

Procedures are documeted by SOP (Standard Operating Procedure)

GMP Concerns

The actual manufacturing facility design and layout

The equipment and procedures

Training of production personnel

Control of process inputs (e.g., raw materials and cultures)

Handling of products

Prevent contamination

Dictate flow of material, personnel, and air

Procedure validation: include not only operation of equipments but also cleaning and

sterilization

Key concepts: Written documentation, consistency of procedures, consistency of

product, and demonstrable measures of product quality (particularly purity and safety)