biotech basics: fundamental principles of the biotechnology industry

Biotech Basics: Fundamental Principles of the Biotechnology Industry

Module 1: Basic Biotech Principles

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This ISPE course was developed by Jeffery Odum, a globally recognized instructor in the areas of facility design, GMP compliance, and aseptic manufacturing. Take a moment to get to know Jeff Odum by selecting the More Information icon. When you are ready, select Next to continue with the introduction.

Course Author

Jeffery Odum,Instructor

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Course Resources

• “Biopharmaceutical Manufacturing in the Twenty-First Century – the Next Generation Manufacturing Facility.”

• ISPE Baseline Guide: Pharmaceutical Engineering Guides for New and Renovated Facilities: Volume 6, Biopharmaceutical Manufacturing Facilities.

• “Trends in Biopharmaceutical Manufacturing Facility Design: What’s Hot!”

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Welcome to Basic Biotech Principles, Module 1 in Biotech Basics: Fundamental Principles of Biotechnology Industry.

This module focuses on the basic scientific principles of biotechnology and the bioprocess as well as providing an understanding of the basic elements of biology important to biotechnology.

Basic Biotech Principles

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• Recognize basic biotechnology principles

• Review the science of biotechnology

• Understand the basic elements of biology important to biotechnology

• Discuss the basic scientific principles of the bioprocess

Module 1 Learning Goals


Lesson 1: Recognize Basic Biotechnology Principles


What is Biotechnology?

While the science as we know it is new, the basic principles have been around for a very long time.


Biotechnology is the culmination of over 8,000 years of human experience using living organisms and the process of fermentation to make use products for mankind.

SME: Please confirm that the phrase “use products” is correct in the screen text and VO.

Modern Biotechnology

Modern biotechnology was first identified over 90 years ago. Karl Ereky was a Hungarian architect/engineer who envisioned a biochemical age similar to the stone age and iron ages.


Biotechnology is “all lines of work by which products are produced from raw materials with the aid of living things.”

-- Karl Ereky,1919

Useful Products from Biotech Applications


Beer

Wine

Cheese

Bread

Biotech Applications

Biopharmaceutical Drugs

Biotechnology Definition

Although this is a more modern definition, it is interesting that even this definition seems to be changing rapidly as the technologies continue to develop and advance within the industry.

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Biotechnology is a combination of advances in our understanding of molecular and cell biology and human genetics, and how the human immune system fights disease.

Bioscience Subsectors

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Therapeutics Industrial Products Devices Research and Development

• Industrial organic chemicals• Agricultural chemicals• Human health care

o Detection and treatment of diseaseso Human growtho Vaccines

• Forensics• Veterinary science• Organic chemicals• Fuels

• Agricultureo Crop yieldso Pesticideso Fertilizers

• Food processing• Aquaculture• Waste management

o Wastewater treatmento Bio-remediation

The industrial biotechnology applications listed below are particularly important.

Knowledge Check Directions

[placeholder for standard knowledge check directions]

The basic principles of biotechnology are relatively new concepts.

a) Trueb) False

Select the best response and then select Submit.

Knowledge Check

Submit

Which of the following are subsectors of the biosciences?

a) Therapeuticsb) Industrial productsc) Devicesd) Research and developmente) All of the above


Knowledge Check

Submit

Lesson 2: Review the Science of Biotechnology


This image is a cutaway of a mammalian cell. Cells have a common, basic structure. As you will see, the components of the cell are important to the understanding of the science.

Roll over each term to identify the cell structure.

Cell Structure

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The Cell as a Manufacturing Plant

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Polysomes

Mitochondrion

Endoplasmic reticulum

Vesticle

Nucleus

Pore

In simple cells like bacteria there are thousands of different pieces of “equipment” that must be linked together, regulated, and work in harmony for the cell to grow and reproduce.

Not only does this “chemical plant” make products, but it regularly replicates itself in rapid manner by dividing. Select each term to learn more about its function in the cell.

“The production plant” of the cell.

The “power station” of the cell.

The “roadways” of the cell.

The Cell as a Manufacturing Plant

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Polysomes

Mitochondrion

Endoplasmic reticulum

Vesticle

Nucleus

Pore

In simple cells like bacteria there are thousands of different pieces of “equipment” that all must be linked together, regulated, and work in harmony for the cell to grow and reproduce.

Not only does this “chemical plant” make products, but it regularly replicates itself in rapid manner by dividing. Select each term to learn more about its function in the cell.

The “command center” of the cell.

The “gateway” of the cell.

The “storage tank” of the cell.

DNA, Proteins, and Genes


DNA Proteins GenesDNA is genetic material that is contained in every living thing. All cells are programmed by DNA, which is basic genetic material.

Proteins are the building blocks of DNA and the major structural and regulatory molecules essential for life. Proteins are made up of 20 amino acids and each has its own chemical properties.

A gene contains the entire set of blueprints, specification, and procedures necessary to carry out life.

In addition to knowing the parts and functions of a cell, we also need to review three additional elements: DNA, proteins, and genes. We will address each topic in greater depth in this lesson.

• DNA is the basic genetic material.

• DNA consists of:o Sugaro Phosphateo Four nitrogen bases

DNA


The Four Nucleotide Bases of DNA


Adenine

Hydrogen bonds

Thymine

Guanine Cytosine

DNA Structure


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The DNA Language


The DNA alphabet has four letters:

A, G, C, T

Information

determined by letter

sequence

Sequence broken

into three-letter

“words,” or

codons

The codon

specifies 1 of the

20 amino acids

The DNA Code


A string of bases in DNA may look something like this:

AGCTTCCGATCGGTA

However, our DNA language is read in three-letter combinations. So the above bases would be read like this:

AGC, TTC, CGA, TCG, GTA

Each of the three letter words above is a codon that defines an amino acid:

Serine, Phenylalanine, Arginine, Serine, Valine

• DNA is universal code.

• Three-letter codon is the code for an amino acid. Same triplet of letters is always the code for the same amino acid.

• Amino acids used to build proteins, which are the building blocks of DNA.

• There are 20 amino acids, each with its own chemical properties.

DNA and Proteins


Chemical Properties and Protein Structure


Chemical properties of

a protein

Specific sequence of amino acids

The way the amino acid chain is twisted and folded in the three dimensional shape

Specific sequence of nucleotides

Chemical interactions between amino acids

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Roles of Proteins

Proteins have four major roles. Select the role below to learn more about what proteins do.


Provide structure

Provide transport

Act as catalysts

Control cellular processes

• The value of human proteins in treating disease has long been known.

o For example, some proteins are useful therapeutically and diseases caused by a protein deficiency can be treated with the human protein itself.

• Only tiny quantities can be extracted from human tissue.

• The goal of biotechnology is to produce sufficient amounts of human protein of high quality.

Therapeutic Applications of Proteins


• The chemical bonds that hold a protein together are weak and can easily be broken or altered by environmental conditions such as temperature, pH, and salt concentration.

• If a protein becomes denatured (loses its proper structure), then the protein product is ruined!

Denatured Proteins


The “Language of Life”

Language

Letters

Words

Sentences

Book

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The analogy of DNA to language makes it easier to understand the science.

Just like language has certain attributes, such as letters, words, and sentences, so does DNA with its nitrogen bases, amino acids, and genes.

History of Genetic Engineering

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Scientists discover genetic information is stored in the DNA.

Francis Crick, James Watson, and Maurice Wilkin received The Nobel Prize in Physiology or Medicines.

Scientists become “editors” to create solutions that target disease.

1944

1962

Today

While every cell in an individual organism has the same DNA units, different segments of DNA coding tell individual cells how to differentiate (what to do or what to produce, such as proteins, enzymes, etc.).

Coding the human genome was so important because scientists now know what each gene does, making genetic engineering possible.

Genetic Engineering


Genetic engineering uses recombinant DNA technology to transplant and/or combine genetic information from one organism to another.

Cells have a common basic structure.

a) Trueb) False


Knowledge Check

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Proteins are the major structural and regulatory molecules essential for life.

a) Trueb) False


Knowledge Check

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Proteins are made up of ______ amino acids and each has its own chemical properties.

a) 20b) 100c) 32d) 4e) 56


Knowledge Check

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Proteins:

a) Provide structure.b) Provide transport.c) Act as catalysts.d) Control cellular processes.e) All of the above.


Knowledge Check

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Lesson 3: Understand the Basic Elements of Biology Important to Biotechnology


What are Biologics?


Biologics are biological therapeutic products that generally encompass any protein, virus, vaccine, blood product, or gene transfer product.

We are going to focus on human therapeutics.

Therapeutic proteins are proteins that are produced in biological organisms or in recombinant DNA technology.

These proteins include: • Monoclonal antibodies.• Cytokines.• Growth factors.

Biologics vs. Small Molecule Drugs

It is important that we understand the difference between biologics and pharma-derived products. Most of you will have never taken a biologic drug, so your frame of reference will be tablets and pills.

Select each type of product below to learn more about how they are different.


Biologics Small Molecule Drugs

• Very fragile molecules that easily degrade in the digestive system

• Injected into bloodstream• Designed to interact with

molecules outside the cell• Typically more difficult and costly

to manufacture

• Compromise most traditional pharmaceutical drugs

• Developed via chemical synthesis• Taken orally• Absorbed through the intestine walls

into the bloodstream.• Usually designed to block targets

So, Why Biologics?


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Developing a Recombinant Protein


Create recombinant plasmid

Mix recombinant plasmid with host cells so transform-ation and cloning occur.

Grow small scale cell culture.

Conduct assay development and animal testing.

Grow large scale cell culture.

Conduct product recovery, formulation, and quality control.

Conduct aseptic filtration and processing for contamination control.

Create Recombinant Plasmid


Recombinant plasmid. Transformation and cloning. Small scale cell culture.

Assay development and animal testing.

Large scale cell

culture.

Product recovery,

formulation, and quality

control.

Aseptic filtration and processing

for contaminatio

n control.

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2

3

Transformation and Cloning




Large scale cell

culture.

Product recovery,


control.


for contaminatio

n control.

Small Scale Cell Culture




Large scale cell

culture.

Product recovery,


control.


for contaminatio

n control.

1.

Assay Development and Animal Testing




Large scale cell

culture.

Product recovery,


control.


for contaminatio

n control.

1.

Large Scale Cell Culture




Large scale cell

culture.

Product recovery,


control.


for contaminatio

n control.

1.

Product Recovery, Formulation, and Quality Control




Large scale cell

culture.

Product recovery,


control.


for contaminatio

n control.

1.

Contamination Control




Large scale cell

culture.

Product recovery,


control.


for contaminatio

n control.

Contamination is the presence of unwanted microbes that can have an adverse impact on the product. Contamination must be prevented in aseptic processing.

Aseptic Filtration and Processing

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Large scale cell

culture.

Product recovery,


control.


for contaminatio

n control.

Aseptic Filtration Aseptic Processing

• Used to sterilize products that cannot be terminally sterilized in their final container.

Aseptic Filtration and Processing




Large scale cell

culture.

Product recovery,


control.


for contaminatio

n control.

Aseptic Filtration Aseptic Processing

• Designed to achieve a sterile product, but this may not always be the end result.

• Techniques are often associated with the formulation, filling, and sealing of the drug product into its final delivery means.

Biologics are biological therapeutic products that generally encompass any:

a) Protein.b) Virus.c) Vaccine.d) Blood or gene transfer product.e) All of the above.


Knowledge Check

Submit

Match the terms with their correct description.

Drag each term to the best response and then select Submit.

Knowledge Check

Submit

o Biologics

o Small Molecule Drugs

o Very fragile molecules that easily degrade in the digestive system and are injected into the bloodstream.

o Most traditional pharmaceutical drugs; taken orally.

Aseptic processing is designed to achieve a final sterile product.

a) Trueb) False


Knowledge Check

Submit

Lesson 4: Discuss the Basic Scientific Principles of the Bioprocess


The Industrial Process


Like all industrial processes, the manufacture of biologic products requires inputs and activities to manufacture the product. The corresponding output will produce some form of waste.

SME: Please review slide and VO text to ensure it is accurate. Changed to ensure clarity.

Biotech Process Steps


Non-engineers will need to understand what a process is and how the unit operations integrate to produce the product. All biotech manufacturing processes have a general composition.

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Choosing the Right Material

Choosing the right starting material is vital to success. In a perfect world, the starting material should fit the following criteria, though not all production cell lines display all of these characteristics:


Able to make the product in large quantities

Stable in culture

Grow fast

Grow on inexpensive nutrients

Examples of Choosing the Right Material

Companies spend significant amounts of R&D money to make sure they select the right starting material. The right starting material is dependent upon the product being manufactured.

For example:


Chinese hamster ovary (CHO) cells grow well in culture and are used to manufacture many products such as human interferon (a protein).

E. coli bacteria are given the gene to make human insulin so that now diabetics no longer rely on insulin purified from animal carcasses.

Cell Growth Process

Culture Media preparation

Cell Growth Recovery

Purification Formulation


Stock selection & testing(covered in this lesson)

Food material for cell growth(covered in this lesson)

Production growth(covered in this lesson)

Removal of spent biomass(covered in module 2)

Purify product(covered in module 2)

Final dosage form(covered in module 2)

Culture: Processing the Cell Line

Cell Line Selection Cell Bank Development Scale-up

To promote the expected level of growth, cell lines need to: • Be easily reproducible.• Grow fast.• Use inexpensive medium.

This does not mean that every cell line meets these criteria. But the majority of cell lines that we see used in the industry:

• Produce high quality product.• Grow in inexpensive medium.

Culture Media preparation Cell growth

Recovery





Testing• The quality and viability of the cell line must be confirmed through testing. • Cell lines will be categorized as “master” and “working.”

o Using the original master cell line, subsequent working cell lines will be used to continue the manufacturing operations for years.

o The working cell banks are genetic equals of the master.

Storage• The storage and security of these cell banks is important. Millions of dollars have been

spent to genetically develop the master cell line. • Protection of this investment is not only good business, it is also a regulatory

requirement.


Recovery





• The processing of the cell line begins at a very small scale; a few milliliters of material are used to begin the growth process.

• As volumes grow, the scale of the process increases.

• With each scale-up step, the process grows closer to reaching the maximum volume needed to support the overall process.


Recovery



Just like people, cells need a balanced diet to provide them with energy and nutrients.

• Media broth• Metabolism

Media Preparation


Recovery



A Cell’s Diet

A Cell’s Diet

Carbon

Nitrogen

Oxygen and Hydrogen

Phosphorus

Other elements

Additives



Recovery


Carbon-containing compounds provide the chemical energy cells need to function.

Glucose is often the primary energy source. Starches or other sugars are also used.

Cells need a nitrogen source to make amino acids, nucleic acids, and other molecules. Sources are usually NH3 ( as a gas) and NH4 (solid form as a salt).

Cells get oxygen and hydrogen from air and water and also from carbon and nitrogen sources.

These are usually supplied from inorganic salts.

Cells also require sodium, potassium, and magnesium salts. Other metals such as zinc, iron, and manganese will also show as trace elements.

Sometimes cells can’t make all the biomolecules they need from raw materials. Additives such as amino acids, vitamins, antibiotics, and anti-fungal agents may be necessary.

Example of Media Recipes

Microbial (60,000L) Mammalian (10-20,000L)

• 65% glucose solution• Ammonium sulfate• Potassium and sodium salts• Protein hydrolysate• Growth factors• Water


Recovery



Example of Media Recipes

Microbial (60,000L) Mammalian (10-20,000L)

• Amino acids• Soy protein hydrolysate solution (heated)• Salts• Trace elements: iron and zinc• Sodium hydroxide• Methotrexate• Glucose• Amino acids• Potassium phosphate


Recovery



Media Recipes – Things to Watch Out For


Recovery


• Mixing mistakes can cause product failure.• Sequence of additions may be critical; following the

exact steps in the recipe will be a key element of success.

• All media must get into tank and be mixed.• Many mammalian media components are heat-sensitive

and must be filter-sterilized.• SOPs (the instructions on how to manufacture) may be

complex and must be followed.


Media Mixing


Recovery


Roll over each image and then select Next to continue.

As you can see from this graphic, the manufacture of media components is a major manufacturing operation.

There are numerous steps, extensive equipment needs, and possibly large volumes of materials and utilities that will be required just to provide the cells with the right diet. All of these operations are considered part of the overall product manufacturing process and thus under regulatory oversight.

Cells Affect Their Environment



Recovery


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[1]

[2]

[3]

[4]

[5]

[6]Death

Cell Culture Life Cycle



Recovery


All biotech manufacturing processes have a general composition of _________ operations and __________ operations.

Type your response in the question field, then select Submit to continue.

Knowledge Check

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____________ is the process in which cells break down ingredients in the growth media, release energy, and re-assemble elements into other molecules.

Type your response in the question field, then select Submit to continue.

Knowledge Check

Submit

Media mixing is not a major manufacturing operation and is, therefore, not under regulatory oversight.

a) Trueb) False


Knowledge Check

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Knowledge Check Summary

[placeholder for knowledge check summary]


You have completed this module.

For your review, here are the learning goals addressed in this module and the knowledge you should be able to demonstrate as a result:

• Recognize basic biotechnology principles

• Review the science of biotechnology

• Understand the basic elements of biology important to biotechnology

• Discuss the basic scientific principles of the bioprocess

Summary of Learning Goals for Module 1


Closing

If you have any questions about this module, please contact member services:

(813) [email protected]

When you are ready, navigate to Module 2 in the LMS.

Select Back to review this module or exit to the next module

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biotech basics: fundamental principles of the biotechnology industry

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