Les 14: 6/12
- Key differences between pharmaceu5cals and biopharmaceu5cals?
o Manufacturing is the key
o PK is also completely different
o Immunogenicity
§ Small molecules o@en not immunogene5c
o Stability
§ Develop biological: quality control not only during the produc5on of the final
products, but also for tes5ng and evalua5ng the stability
Examples
Vaccines
- Biological, but it is not a classical interven5on
o Why are vaccines more complex then normal biologicals?
§ A vaccine is given before the disease while other drugs are given when you
already have the disease
• To minimize the poten5al impact of the disease
§ Vaccines are given to everyone -> to protect us to the poten5al impact of a
disease => complex situa5on
o We want to s5mulate the immunogenicity with vaccines and that is not the case
with an5bodies
- Most vaccines in the further will be given by nasal spray, by pills or intradermal -> so
no longer injec5ons
- Pox vaccine
o Based on cow pax vaccine
o Before that kind of vaccines were also already administered -> autologous
immuniza5on -> people inoculated with the disease causing agents
- Safety is important
- Most vaccines are prophylac5c, some of them are therapeu5c
o HIV vaccine, cancer vaccine
- Types of vaccines are quite large
o Killed/inac5vated (influenza, hepa55s A)
o AVenuated (measles, rubella, mumps)
o Toxoid (tetanus, diphteria)
o Subunit (Hepa55s B virus, human papillomavirus)
o Conjugate (Haemophilus influenzae type B)
§ Target the glycocalyx capsule; these sugars are important -> IS need to make
ab to bind to the capsule -> neutralize bacteria
§ If you inject saccharides -> not very immunogene5c -> to increase the
immunogenicity you make a conjugate by binding them to a protein
o DNA vaccines
o Vector vaccines
o DC vaccines
- Biological nature
o Star5ng materials
o Manufacturing process
, o Test methods needed to characterize batches
§ Batches in vitro and in vivo
- Vaccine produc5on
o Using prokaryo5c or eukaryo5c micro-organisms
o Subtle changes in these organisms may radically affect the vaccine product.
- Biological characteriza5on (biological assays) should complement physical and
chemical product characteriza5on since not completely understood rela5onships
between
o Physical and chemical characteris5cs
o Immunogenicity and efficacy of these products
o In vitro, but also in animal models
Characteriza5on
Produc'on
- manufacturing process/condi5ons must be highly controlled
o Characteriza5on of batches
o Seed lot system
- Consistency is essen5al
o Consistency is not the same as the exactly the same product
§ It’s need to be consistent for predetermined characteris5cs. You define
this in advance.
- Samples need to be stored from pre-clinical development for later comparison (during
clinical development, a@er upscaling produc5on...)
- Tes5ng physico-chemical parameters: amount of an5gen, size, protein content ~
measure for consistency, but NOT iden5cal
Potency tes'ng
- Measuring biological ac5vity of a vaccine -> look at the immune response
- Not always = mechanism of protec5on in humans
o Animal model -> look for ab induc5on; will it induce ab? How good are the ab?
Etc.
- Way of verifying consistency in manufacturing
o Best way is to use animal model for vaccina5on followed by challenge with
pathogen
§ Vaccinate animals -> challenge with pathogen -> you should see
protec5on
o If no good animal model available, measurement of immune responses
(serology)
§ Induces it a similar immune response as in vitro test?
o Interac5on with known an5bodies
Stability
- Very complex to study ~ complex biological material
o Threshold that you can not loose more then that because you will always loose
some ac5vity -> you need to take this account
- Potency tes5ng and physico-chemical evalua5on is essen5al part of stability tes5ng
- Normal storage temperature, long-term, real-5me storage
- ! Stability of standards and reference materials
o You need even controls for the reference materials -> you do this with other
biologicals
- Key differences between pharmaceu5cals and biopharmaceu5cals?
o Manufacturing is the key
o PK is also completely different
o Immunogenicity
§ Small molecules o@en not immunogene5c
o Stability
§ Develop biological: quality control not only during the produc5on of the final
products, but also for tes5ng and evalua5ng the stability
Examples
Vaccines
- Biological, but it is not a classical interven5on
o Why are vaccines more complex then normal biologicals?
§ A vaccine is given before the disease while other drugs are given when you
already have the disease
• To minimize the poten5al impact of the disease
§ Vaccines are given to everyone -> to protect us to the poten5al impact of a
disease => complex situa5on
o We want to s5mulate the immunogenicity with vaccines and that is not the case
with an5bodies
- Most vaccines in the further will be given by nasal spray, by pills or intradermal -> so
no longer injec5ons
- Pox vaccine
o Based on cow pax vaccine
o Before that kind of vaccines were also already administered -> autologous
immuniza5on -> people inoculated with the disease causing agents
- Safety is important
- Most vaccines are prophylac5c, some of them are therapeu5c
o HIV vaccine, cancer vaccine
- Types of vaccines are quite large
o Killed/inac5vated (influenza, hepa55s A)
o AVenuated (measles, rubella, mumps)
o Toxoid (tetanus, diphteria)
o Subunit (Hepa55s B virus, human papillomavirus)
o Conjugate (Haemophilus influenzae type B)
§ Target the glycocalyx capsule; these sugars are important -> IS need to make
ab to bind to the capsule -> neutralize bacteria
§ If you inject saccharides -> not very immunogene5c -> to increase the
immunogenicity you make a conjugate by binding them to a protein
o DNA vaccines
o Vector vaccines
o DC vaccines
- Biological nature
o Star5ng materials
o Manufacturing process
, o Test methods needed to characterize batches
§ Batches in vitro and in vivo
- Vaccine produc5on
o Using prokaryo5c or eukaryo5c micro-organisms
o Subtle changes in these organisms may radically affect the vaccine product.
- Biological characteriza5on (biological assays) should complement physical and
chemical product characteriza5on since not completely understood rela5onships
between
o Physical and chemical characteris5cs
o Immunogenicity and efficacy of these products
o In vitro, but also in animal models
Characteriza5on
Produc'on
- manufacturing process/condi5ons must be highly controlled
o Characteriza5on of batches
o Seed lot system
- Consistency is essen5al
o Consistency is not the same as the exactly the same product
§ It’s need to be consistent for predetermined characteris5cs. You define
this in advance.
- Samples need to be stored from pre-clinical development for later comparison (during
clinical development, a@er upscaling produc5on...)
- Tes5ng physico-chemical parameters: amount of an5gen, size, protein content ~
measure for consistency, but NOT iden5cal
Potency tes'ng
- Measuring biological ac5vity of a vaccine -> look at the immune response
- Not always = mechanism of protec5on in humans
o Animal model -> look for ab induc5on; will it induce ab? How good are the ab?
Etc.
- Way of verifying consistency in manufacturing
o Best way is to use animal model for vaccina5on followed by challenge with
pathogen
§ Vaccinate animals -> challenge with pathogen -> you should see
protec5on
o If no good animal model available, measurement of immune responses
(serology)
§ Induces it a similar immune response as in vitro test?
o Interac5on with known an5bodies
Stability
- Very complex to study ~ complex biological material
o Threshold that you can not loose more then that because you will always loose
some ac5vity -> you need to take this account
- Potency tes5ng and physico-chemical evalua5on is essen5al part of stability tes5ng
- Normal storage temperature, long-term, real-5me storage
- ! Stability of standards and reference materials
o You need even controls for the reference materials -> you do this with other
biologicals
