Industrial Microbiology INDM 4005 Lecture 1 090204

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Industrial MicrobiologyINDM 4005Lecture
109/02/04
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Overall Course aim

• Cover the basic science of bioprocessing
• Integrated approach to
• - Microbial physiology
• - Fermentation technology
• - Bioprocess engineering

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Learning Outcomes

• Understand the principles of bioprocessing which
  include bioreactor design and process
  optimisation
• Apply these principles to unit operations in the
  fermentation, brewing and antibiotic industries

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Process Design
UPSTREAM Stock culture Raw
material Seed Fermenter Shake Medium
preparation Flask Sterilisation
Bioreactor
DOWNSTREAM
Separation Biomass Supernatant
Product Purification
Inoculum
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1. MANAGEMENT OF MICROBIAL PROCESSES / QUALITY
ASSURANCE

• Overview
• ? Principles of GMP
• ? Process design / optimisation
• ? Economics

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DEVELOPMENT OF A MICROBIAL PROCESS

• The development of a new fermentation product is
  influenced by many factors including
• the market
• the regulatory environment
• the current level of scientific knowledge

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DEVELOPMENT OF MICROBIAL PROCESSES(Hulse, 2004)
Trends in Food Science Technology 15 p3-18

• Penicillin 1928
• Monoclonal antibodies 1970s
• Recombinant DNA technology 1980s
• The Future 2010 ???

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QUALITY ASSURANCE

• Any product released in the marketplace must
  conform to quality procedures
• - National and International regulatory
  requirements
• - Manufacturers guideline requirements
• - In house company standards
• Quality Assurance is defined as a program that is
  intended, by its actions, to guarantee a standard
  level of quality

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QUALITY ASSURANCE
Product Product Product Research Manu
facture Design Development Good
Manufacturing Quality Practices
Control
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GOOD MANUFACTURING PRACTICE

• GMP - is used internationally to describe a set
  of principles and procedures which, when followed
  by manufacturers of therapeutic goods, helps
  ensure that the products manufactured will have
  the required quality.
• A basic tenet of GMP is that quality cannot be
  tested into a batch of product but must be built
  into each batch of product during all stages of
  the manufacturing process.

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QUALITY CONTROL

• A system by which a desired standard of quality
  in a product or process is maintained.
• Quality control usually requires feeding back
  information about measured defects to further
  improvements of the process.
• Is concerned with sampling, specifications,
  testing, documentation

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MANAGEMENT AND GOOD MANUFACTURING

• Requires highest standards of process and product
  quality assurance.
• Recombinant products, cell culture products,
  drugs etc should generally possess attributes of
  purity, safety, potency, efficacy, consistency
  and stability.
• Determination of existing or potential risk
  factors associated with the process or product
  important in assurance of safety of product,
  process operators etc.

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• Reference
• For Introduction to Product development ,
  regulation and safety see Michael J. Waites,
  Industrial Microbiology an Introduction, Chp 8
  p124.

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1.1 MANAGEMENT AND GOOD MANUFACTURING

• Good Manufacturing Practice (GMP) pertains to all
  bioprocessing.
• Definition
• Term for technical procedures undertaken under
  recognised standards to ensure that products are
  consistently produced and controlled and that
  these products are appropriate to their intended
  use and product specification
• Relates to
• ? consumer
• ? worker
• ? product safety

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1.1.1 RISK FACTORS

• Must be clearly identified
• acceptable processing
• analytical methods and practices
• developed as a standardised process
  validation
• To minimise risk, manufacturing facilities and
  plant operations should conform with requirements
  for GMP, for example
• - Compartmentation of operations e.g.
  clean-room
• - Design of containment areas- Water quality
• - Design of Cell cultivation facility
• - Definition of work practices in different areas
• - Details of personnel allowed access to each
  area
• - Protocols for maintenance and cleaning
• - Protocols for staff training
• - Definitions of personnel roles - who is
  responsible for what ??
• - Definition of practices for record maintenance

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1.1.2 IMPLEMENTATION OF GMP

• Implications for all facets of bioprocess
• ? Microorganism / biological system
• ? Nature of processing steps used
• ? Equipment design
• ? Raw materials
• ? Operator training
• ? Analytical / laboratory procedures
• ? Product specification
• ? Product cost

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1.1.2 IMPLEMENTATION OF GMP

• IDENTIFICATION OF MAJOR SOURCES OF ERROR /
  CRITICAL POINTS
• 1. Materials - variation in specification
• 2. Equipment / facilities - variable operating
• 3. Procedures - lack of clarity / specificity
• 4. Personnel - lack of training / motivation
• MINIMIZE ERRORS / DEVIATIONS BY PROCESS
  VALIDATION
• Challenge to the process to determine whether
  pre-selected process variables are under control.
• To ensure high uniformity and reproducibility in
  process consistency and high quality of product.

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1.1.3. PROCESS VALIDATION -organisation

• Written documentation
• Manufacturing parameters
• Testing parameters
• In-process control
• Final product testing

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1.1.4. DESIGN OF FACILITY

• TASK 1
• Identify major objectives relating to each unit
  operation. Identify critical control points
  (CCP) in inoculum preparation, media preparation,
  fermentation step, product recovery/purification
  and in managing asepsis.
• CASE STUDY -Design of facility, for example, for
  production of extracellular soluble vaccine by a
  pathogenic organism
• Inoculum
• Fermenter design
• Cell recovery
• Finishing operations -Purification and packaging
• Asepsis / Sterility

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1.1.5. DIRECTIVES LEGISLATION

• Many manufacturers (e.g. Pharmaceutical, Food
  etc.) must conform to requirements /
  recommendations laid down
• ?EC, EU
• ?World Health Organisation
• ?US Food Drugs Administration
• ?Individual National Authorities
• See library for Directives Covers wide range of
  areas
• - Organisation and personnel - Buildings
• - Facilities and equipment - Control of
  components
• - Containers and closures - Process control
• - Packaging and labelling - Holding and
  distribution
• - Laboratory controls - Records of reports

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1.2. PROCESS DESIGN i.e. INDUSTRIAL FERMENTATION

• 1.2.1. DESIGN PARAMETERS RELATING TO
• ? MICROORGANISM
• ? RAW MATERIALS
• ? PROCESS
• ? PRODUCT
• see additional sheet for critical control points
• 1.2.2. Relate parameters to SPECIFIC INDUSTRIES
  already studied.

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• CASE-STUDY
• Identify relevant parameters (using above
  headings) FROM ONE of the following industries
• Brewing
• Pharmaceuticals
• Organic acids
• Fermented Foods
• Enzymes
• Waste treatment /environmental

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1.3. FERMENTATION ECONOMICS

• OBJECTIVE - yield a product at a competitive
  price
• 1.3.1. BASIC OBJECTIVES.
• ? Capital investment a minimum
• ? Inexpensive raw materials
• ? High yielding strain of microorganism
• ? Labour saving and automation
• ? Batch Production cycles as short as possible
• ? Recovery and purification - simple rapid
• ? Minimise waste streams
• ? Heat and power used efficiently
• ? Space requirement minimised

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1.3.2. MAJOR AREAS OF COST MINIMISATION

• 1. Isolation and handling of microorganism
• 2. Plant and equipment
• 3. Media
• 4. Air sterilisation
• 5. Heating and cooling
• 6. Aeration and agitation
• 7. Recovery cost
• 8. Process time and duration
• 9. Prevention of contamination
• See Stanbury and Whitaker p.231

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1.3.3. Calculation of productivity, cost, profit,
optimum production cycle.

• 1.3.3.1 PRODUCTIVITY
• In a batch process productivity must be
  calculated for the complete cycle. The total time
  (t) for a fermentation may be calculated
• t 1/?m? (ln Xf/Xo ) tT tL tD
• where ?m maximum specific growth rate
• Xo initial cell conc.
• Xf final cell conc.
• tT turn-around time (washing, filling,
  sterilisation, etc)
• tD delay time until inoculation
• tL lag time after inoculation

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PRODUCTIVITY

• The overall productivity P is given by P Xf/ t
• It will be possible from this equation to
  determine the effect of process changes on the
  overall productivity.
• For example, a larger initial inoculum would
  increase Xo and shorten the process time.
• Actively growing inocula would reduce the lag
  time (tL)

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1.3.3.2 OPTIMUM TIME FOR HARVESTING

• CASE STUDY
• Identify the
• (a) optimum harvest time
• (b) productivity of a fermentation cycle.
• SEE CHAPTER 12

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Effect of running time on productivity and cost -
optimum time of harvesting
In Stanbury and Whitaker
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Conclusion

• Understand the importance of being able to manage
  microbial processes
• What is quality assurance?
• How to implement GMP
• Fermentation economics
• How to calculate productivity