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Biotechnology Drugs. Part I Basic concepts Part II Process: Quality & Safety issues Part III A checklist for inspection. Synthetic Drugs Small molecules Easy synthesis Aspirin Oligopeptides Hemi-synthesis Need of active stereo-isomers Steroids Anticancer Antimetabolites cyclosporin.

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biotechnology drugs
Biotechnology Drugs
  • Part I Basic concepts
  • Part II Process: Quality & Safety issues
  • Part III A checklist for inspection
why are biotechnology products different from simple organic chemicals
Synthetic Drugs

Small molecules

Easy synthesis




Need of active stereo-isomers





Extraction Biologicals

Complex & rare molecules

Animal source possible



Human source necessary


Coag. Factors


Why Are Biotechnology Products Different From Simple Organic Chemicals?
biotech drugs
Biotech Drugs

Better yield & better safety

  • Insulin
  • HGH

Modified molecules

Extraction impossible

  • Erythropoietin
  • Interferon
  • Interleukin
  • Growth factors
manufacturing processes are different
Biotech Products

Produced by purification

Starting material variable

Many in-process tests

End-product tests complex

Process is product-specific

Batch sizes small (g or kg of finished product)

Conventional drugs

Produced by formulation

Starting material defined

Few in-process tests

End-product tests simple

Process is product type specific (generalizations possible)

Manufacturing Processes Are Different
biotechnology drugs5
Biotechnology Drugs
  • Use of micro-organisms (procaryotic or eucaryotic) genetically modified for production of complex molecules
  • After purification, the products are used in human or animal therapeutics
medicinal products derived from recombinant dna
Medicinal Products Derived From Recombinant DNA
  • Insertion of naturally occurring or synthetic nucleotide sequence into a vector
  • Introduced into a suitable host organism to ensure the efficient expression of the desired gene product
five features for a biotechnology drug
Five Features For a Biotechnology Drug
  • Expression system of the gene
  • Production system compatible with the microorganism
  • Purification system
  • Nature of the active product
  • Pharmaceutical formulation and presentation
five features for a biotechnology drug 1 expression system vector host
Five Features For a Biotechnology Drug1. Expression System: Vector + Host

Identify, isolate and clone the gene coding for the desired protein

Construct a vector containing:

  • The gene
  • The expression controls (promoter, secretion signal…)

Insert the vector into the selected micro-organism

  • Escherichia coli
  • Saccharomyces cerevisiae
  • Mammalian cells
  • Genetically modified plants
five features for a biotechnology drug 2 the production system
Five Features For a Biotechnology Drug2. The Production System


  • Optimize survival conditions for the genetically modified microorganism
  • So that it produces the desired protein
  • With acceptable yield

Materials & Methods

  • Selection of cell culture medium
  • Selection of culture conditions
  • Selection of culture equipments:fermentor, cytocultor
five features for a biotechnology drug 3 the purification system
Five Features For a Biotechnology Drug3. The Purification System


  • extract protein from a complex growth medium
  • Achieve close to 100% purity
  • Without altering the protein

Materials & Methods

  • Sequence of purification steps
  • Filtration/ultrafiltration
  • Precipitation/resolubilization
  • Chromatography (ion-exchange, affinity, etc.)
five features for a biotechnology drug 4 nature of active product
Five Features For a Biotechnology Drug4. Nature of Active Product


  • Chains of amino-acids
  • Sequence of amino-acids encoded by genes
  • Folded into 3-D conformation
  • To obtain biological activity
  • Host-dependent post-translational modifications (sugars…)
five features for a biotechnology drug 5 pharmaceutical formulation and presentation
Five Features For a Biotechnology Drug5. Pharmaceutical Formulation and Presentation


  • Maintain biological activity
  • By maintaining active protein conformation in solution

Materials & Methods

  • Stabilization (albumin, glycerol)
  • Storage at low temperature
biotechnology drugs14
Biotechnology Drugs
  • Part I Basic concepts
  • Part II Process: Quality & Safety issues
  • Part III A checklist for inspection
process flow chart
Process Flow-Chart









a cell bank
A Cell Bank
  • A collection of ampoules of uniform composition stored under defined conditions, each containing an aliquot of a single pool of cells
the master cell bank mcb
The Master Cell Bank (MCB)
  • Generally derived from the selected cell clone containing the expression construct.
  • The MCB is used to derive all working cell banks.
the manufacturer working cell bank mwcb
The Manufacturer Working Cell Bank (MWCB)
  • Derived by expansion of one or more ampoules of the MCB under defined culture conditions
  • The working cell bank is used for the production of the batches.
the late expanded cell bank lecb
The Late Expanded Cell Bank (LECB)
  • Obtained in multiplying the cells used for the production of the recombinant protein, several passage after the passage of production.
  • It is used to reveal a potential low viral contamination and to study genetic stability of the transgene.
cell bank system
Cell Bank System



Parental cell line

Master cell bank (MCB)




Manufacturer working

cell bank (MWCB)


Production substrate


Late expanded cell

bank (LECB)

process flow chart22
Process Flow-Chart



  • Various expansion systems
  • (fermentor, roller bottle, fermenting flasks,
  • Cell culture systems, airlift, hollow fiber
  • Various culture media
  • (totally synthetic or containing components
  • of animal origin)



process flow chart23
Process Flow-Chart






  • Discontinuous production system
  • (from fermentor)
  • Continuous production system
  • (several harvests of culture supernatant)
process flow chart24
Process Flow-Chart







  • Various extraction strategies
  • (from supernatant or cell disruption)
  • Various purification methods
  • (according to potential contaminants)
purification potential contaminants
Purification: Potential Contaminants
  • What contaminants may be encountered?
  • What is the source of the contamination?
  • How hazardous are they?
  • How can they be removed?
  • How can we ensure their removal?
purification potential contaminants26
Process-related impurities

Cell substrate derived

Cell culture derived

Downstream derived

Product-related impurities

Truncated forms

Other modified forms


Purification: Potential Contaminants
purification potential contaminants27
Purification: Potential Contaminants

Microbiological contaminants:adventitious agents

  • Prevent in the original cells or in the master cell bank
  • Adventitious viruses introduced during production
purification potential contaminants28
Purification: Potential Contaminants


  • Toxicity
  • Heavy metals, cyanogen bromide, antibiotics, organic solvents…
  • Altered pharmacological activity
  • Aggregates, breakdown products
  • Immunogenicity
  • Oncogenicity
  • Infectious diseases
  • Mycoplasmas, yeasts, viruses
purification contaminant removal
Purification: Contaminant Removal

A sequence of several methods:

  • Precipitation
  • Filtration
  • Liquid chromatography based on different physical or chemical principles
  • Affinity, hydrophobicity, molecular weight, electrical charge…
biotechnology drugs30
Biotechnology Drugs
  • Part I Basic concepts
  • Part II Process: Quality & Safety issues
  • Part III A checklist for inspection
purification system should be
Purification System Should Be:
  • Appropriate
  • Justified
  • Validated
process flow chart32
Process Flow-Chart









  • Stabilization
  • (according to protein and delivery mode)
  • Storge
a checklist for inspection
A Checklist For Inspection
  • Focus on changes in the manufacturing process
  • Do not classify a priori a change in the process as minor or major
  • Consider the potential consequences on the drug product in terms of :
  • Quality
  • Safety
  • Efficacy
changes in the manufacturing process
Changes In the Manufacturing Process

Main reasons for introducing changes

  • Improvement of product quality
  • Increase of production yield
  • Global productivity
  • Cost savings
  • Production scale-up
  • New production sites
a checklist for inspection35
A Checklist For Inspection

1.Cell bank system

2.Fermentation/culture process

3.Purification process

4.Drug substance

5.Formulating and filling

6.Drug product

issues for inspection 1 cell bank system
Issues For Inspection:1.Cell Bank System
  • GMP compliant plant design
  • Documentation of cell origin
  • Setup conditions for the (Master), (working) and (late expanded) cell banks:
  • Documentation of viral safety
  • Documentation of expansion conditions
  • Storage conditions
  • Measures taken against contamination
issues for inspection 2 fermentation culture process
Issues For Inspection:2.Fermentation/Culture Process
  • Starting material (cells)
  • New supplier
  • Specifications
  • Additions/substitution of new material
  • Cell culture conditions
  • pH, oxygen, temperature, time, % of reagents, formulation of culture media…
  • Scale of fermentation/cell culture mode
  • Equipment
  • Change of additional fermentation site or facility
issues for inspection 3 purification process
Issues For Inspection:3.Purification Process
  • Column/resin change
  • Size of column, supplier, cleaning conditions, storage conditions
  • Reagents
  • New supplier, specifications, replacement of raw material
  • Purification protocols
  • Addition/substitution/elimination of specific steps
  • Scale of the downstream processing
  • equipment
issues for inspection 4 drug substance active principle
Issues For Inspection:4.Drug Substance(active principle)
  • Batch definition
  • Storage conditions
  • Pooling strategy
issues for inspection 5 formulating and filling
Issues For Inspection:5.Formulating and Filling
  • Excipient
  • Equipment
  • Manufacturing process
  • Scale
  • Change of site/facility
  • Storage & shipping conditions
issues for inspection 6 drug product final product
Issues For Inspection:6.Drug Product (final product)

Control of :

  • Identity
  • Purity
  • Activity
  • Stability
  • General safety
  • Sterility
  • pyrogenicity
issues for inspection summary
Issues For Inspection:Summary
  • Clean starting material
  • Well-characterized cell-line
  • (cell bank) system
  • Validated production & purification processed
  • (In-process) controls
  • Specific final products testing
  • Compliance to GMPs

The growing number of biotechnology products requires highly skilled professionals to inspect complex and changing production processes