ADVANCED BIOTHERAPIES
,1. LEGAL FRAMEWORK 1
2. PATHOGEN REDUCTION OF BLOOD PRODUCTS & PLASMA-DERIVED MPS 5
3. NUCLEIC ACID THERAPEUTICS 11
4. COLLECTION & HANDLING OF CELLS 21
5. LABILE BLOOD PRODUCTS 27
6. GENE THERAPY 33
7. DONOR ELIGIBILITY 41
8. SOMATIC CELL THERAPY 47
9. HISTOCOMPATIBILITY 53
10. HAEMATOPOIETIC STEM CELL TRANSPLANTATION 63
11. CANCER ANTIGENS 67
12. IMMUNOTHERAPY OF CANCER 73
13. PLASMA-DERIVED DRUGS & RECOMBINANT ANALOGUES 79
14. SAFE HANDLING OF MABS IN THE HEALTHCARE SETTING 87
, 1. LEGAL FRAMEWORK
- Cell engine therapy: (experimental) for a child with acute leukaemia: altered immune cells
→ child became very sick → after couple of weeks: no leukaemic cells left = very successful
- Products for therapy:
- Blood products (labile) = red cells, platelets, plasma
- Tissues & cells (human body material)
(SOHO = substances of human origin; blood products, tissues,… everything will merge in the
future & will fall under 1 legislation, not yet right now)
- Organs
- Drugs / medicinal products
1.1 LABILE BLOOD PRODUCTS
= Products that are 1. derived from blood and 2. used for transfusion
- Red cells → oxygen transport
- Platelets → coagulation
- Plasma → coagulation
- Not: cord blood (used for transplantation), hematopoietic stem cells collected by apheresis
(tissues and cell)
- Not: albumin, immunoglobulins, viro-inactivated plasma (after pooling)
(= stable blood products: you can keep them for longer)
- Manufacturer & distributor: blood bank (bloedtransfusiecentrum)
- Distributor in hospital: hospital blood bank
- European Legislation: more or less uniform in Europe
- No market autorisation required: you don’t need to describe the products as much = easier,
more exible; you can alter production process, product characteristics easily
- Licensing, inspection by local authorities (i.e. FAGG in Belgium)
- Donor criteria → which donor did you select
- Quality controls on blood products
- Quality system
- Hemovigilance → do you follow up if there are adverse e ects
- Traceability → that you know which patient got blood from which donor
- Today: by far the most used products of human origin = blood products: public health is at risk
due to the constant threat of spread of communicable diseases
- Huge amount of blood transfusion every year → if a virus enters there (AIDS) = major problem
→ very tightly controlled by the authorities
1.2 TISSUE & CELLS (HUMAN BODY MATERIAL)
= Products that are
1. derived from humans (from animals = pharmaceutical product)
2. non vascularized (otherwise = organs)
3. minimally manipulated (only phisical methods can be uses, otherwise pharmaceutical)
4. not used for transfusion (otherwise labile blood product)
- Includes:
- Cord blood (tissues, cells)
- Hematopoietic stem cells collected by apheresis
- Bone, bone fragments
- Cornea
- Skin, tendons, heart valves, ..
- Gametes: sperm, oocytes and embryos (in vitro fertilization)
- SOHO includes also human breast milk, human feces
1
fl ff
, - Not: cells expanded by culture (= more than minimal manipulation)
→ pharmaceutical product!
- Manufacturer & distributor: tissue establishment (bank vr hematopoëtische stamcellen,
weefselbank, bank vr reproductieve cellen)
- European Legislation: more or less uniform in Europe
- No market authorisation required: you can alter production process, product characteristics
easily
- Licensing, inspection by local authorities (i.e. FAGG in Belgium)
- Donor criteria: no remuneration allowed (e.g. sperm)
- Traceability
- Quality controls on tissues
- Quality system
- Biovigilance → follow up
- Volume: limited compared to blood products
- How do they get the cells from the patients? (Expanding → cell bank
→ legislation of pharmaceutical products) → they get the cells from a tissue bank!
→ transfer these cells to a GMP production site for pharmaceutical manipulation
→ transfer to hospital pharmacy to administer to the patients
- Nr of transplants using cells & tissues << than for transfusion
→ most frequent transplants = whole bone or bone fragments used in orthopedic surgery
- Note that storage of gametes & embryo’s is a booming business, partly for medical reasons
(infertility, chemotherapy), partly for social reasons (women postponing pregnancies until in
their forties) (they freeze sperm cells for later ivf when young people need chemo)
1.3 ORGANS
- Separate legislation for international exchange of donor organs
- Xenotransplants: transplantation of pig kidneys / hearts to patients: not yet applicable:
- Innate immunity directed against di erent sugar chains on the cells make it impossible to
transplant successfully (compare with ABO incompatibility, which is also caused by non-self
sugar chains on cells)
- Threat of endogenous retroviruses → may transmit to humans
- Minipigs = genetically engineered to make more human polysaccharides, until now with
insu cient success (survival of days now in stead of minutes 20 yrs ago)
- Minipigs = generated with the endogenous retroviruses deleted
= progress but not yet applicable
- Incompatible transfusion → immediate problems: patients can die because of antibodies
= inmate (aangeboren) immune reaction: companies try to remove the enzymes that make
the sugar chains with little success + everyone has retroviruses in the genome, some get
activated and may be able to transmit diseases: concern that if we use pig organs these can
get activated: progress but not yet applicable
- Transplantation: liver has 2 lobes → 1 lobe can be transplanted:
- Cadaveric donors: from patients that are brain death (heart-beating), from trauma
- Living donation = accepted for liver & kidneys when there is an emotional relationship
(→ very high need for organs) (not paid!!!!)
- Organs can be preserved for hours (heart) to days (kidneys): logistics are though
→ stored on ice
→ perfusion pumps: heart, arteries & veins connected: delivers oxygen & nutrients = better
2
ffi ff
,1. LEGAL FRAMEWORK 1
2. PATHOGEN REDUCTION OF BLOOD PRODUCTS & PLASMA-DERIVED MPS 5
3. NUCLEIC ACID THERAPEUTICS 11
4. COLLECTION & HANDLING OF CELLS 21
5. LABILE BLOOD PRODUCTS 27
6. GENE THERAPY 33
7. DONOR ELIGIBILITY 41
8. SOMATIC CELL THERAPY 47
9. HISTOCOMPATIBILITY 53
10. HAEMATOPOIETIC STEM CELL TRANSPLANTATION 63
11. CANCER ANTIGENS 67
12. IMMUNOTHERAPY OF CANCER 73
13. PLASMA-DERIVED DRUGS & RECOMBINANT ANALOGUES 79
14. SAFE HANDLING OF MABS IN THE HEALTHCARE SETTING 87
, 1. LEGAL FRAMEWORK
- Cell engine therapy: (experimental) for a child with acute leukaemia: altered immune cells
→ child became very sick → after couple of weeks: no leukaemic cells left = very successful
- Products for therapy:
- Blood products (labile) = red cells, platelets, plasma
- Tissues & cells (human body material)
(SOHO = substances of human origin; blood products, tissues,… everything will merge in the
future & will fall under 1 legislation, not yet right now)
- Organs
- Drugs / medicinal products
1.1 LABILE BLOOD PRODUCTS
= Products that are 1. derived from blood and 2. used for transfusion
- Red cells → oxygen transport
- Platelets → coagulation
- Plasma → coagulation
- Not: cord blood (used for transplantation), hematopoietic stem cells collected by apheresis
(tissues and cell)
- Not: albumin, immunoglobulins, viro-inactivated plasma (after pooling)
(= stable blood products: you can keep them for longer)
- Manufacturer & distributor: blood bank (bloedtransfusiecentrum)
- Distributor in hospital: hospital blood bank
- European Legislation: more or less uniform in Europe
- No market autorisation required: you don’t need to describe the products as much = easier,
more exible; you can alter production process, product characteristics easily
- Licensing, inspection by local authorities (i.e. FAGG in Belgium)
- Donor criteria → which donor did you select
- Quality controls on blood products
- Quality system
- Hemovigilance → do you follow up if there are adverse e ects
- Traceability → that you know which patient got blood from which donor
- Today: by far the most used products of human origin = blood products: public health is at risk
due to the constant threat of spread of communicable diseases
- Huge amount of blood transfusion every year → if a virus enters there (AIDS) = major problem
→ very tightly controlled by the authorities
1.2 TISSUE & CELLS (HUMAN BODY MATERIAL)
= Products that are
1. derived from humans (from animals = pharmaceutical product)
2. non vascularized (otherwise = organs)
3. minimally manipulated (only phisical methods can be uses, otherwise pharmaceutical)
4. not used for transfusion (otherwise labile blood product)
- Includes:
- Cord blood (tissues, cells)
- Hematopoietic stem cells collected by apheresis
- Bone, bone fragments
- Cornea
- Skin, tendons, heart valves, ..
- Gametes: sperm, oocytes and embryos (in vitro fertilization)
- SOHO includes also human breast milk, human feces
1
fl ff
, - Not: cells expanded by culture (= more than minimal manipulation)
→ pharmaceutical product!
- Manufacturer & distributor: tissue establishment (bank vr hematopoëtische stamcellen,
weefselbank, bank vr reproductieve cellen)
- European Legislation: more or less uniform in Europe
- No market authorisation required: you can alter production process, product characteristics
easily
- Licensing, inspection by local authorities (i.e. FAGG in Belgium)
- Donor criteria: no remuneration allowed (e.g. sperm)
- Traceability
- Quality controls on tissues
- Quality system
- Biovigilance → follow up
- Volume: limited compared to blood products
- How do they get the cells from the patients? (Expanding → cell bank
→ legislation of pharmaceutical products) → they get the cells from a tissue bank!
→ transfer these cells to a GMP production site for pharmaceutical manipulation
→ transfer to hospital pharmacy to administer to the patients
- Nr of transplants using cells & tissues << than for transfusion
→ most frequent transplants = whole bone or bone fragments used in orthopedic surgery
- Note that storage of gametes & embryo’s is a booming business, partly for medical reasons
(infertility, chemotherapy), partly for social reasons (women postponing pregnancies until in
their forties) (they freeze sperm cells for later ivf when young people need chemo)
1.3 ORGANS
- Separate legislation for international exchange of donor organs
- Xenotransplants: transplantation of pig kidneys / hearts to patients: not yet applicable:
- Innate immunity directed against di erent sugar chains on the cells make it impossible to
transplant successfully (compare with ABO incompatibility, which is also caused by non-self
sugar chains on cells)
- Threat of endogenous retroviruses → may transmit to humans
- Minipigs = genetically engineered to make more human polysaccharides, until now with
insu cient success (survival of days now in stead of minutes 20 yrs ago)
- Minipigs = generated with the endogenous retroviruses deleted
= progress but not yet applicable
- Incompatible transfusion → immediate problems: patients can die because of antibodies
= inmate (aangeboren) immune reaction: companies try to remove the enzymes that make
the sugar chains with little success + everyone has retroviruses in the genome, some get
activated and may be able to transmit diseases: concern that if we use pig organs these can
get activated: progress but not yet applicable
- Transplantation: liver has 2 lobes → 1 lobe can be transplanted:
- Cadaveric donors: from patients that are brain death (heart-beating), from trauma
- Living donation = accepted for liver & kidneys when there is an emotional relationship
(→ very high need for organs) (not paid!!!!)
- Organs can be preserved for hours (heart) to days (kidneys): logistics are though
→ stored on ice
→ perfusion pumps: heart, arteries & veins connected: delivers oxygen & nutrients = better
2
ffi ff
