Download delivery of proteins using biodegradable polymers

Development of
Biopharmaceuticals and Biosimilar
Drug Delivery
Dr. Basavaraj K. Nanjwade M.Pharm., Ph.D
KLE University’s College of Pharmacy
Belgaum-590010
E-mail: [email protected]
Cell No: 00919742431000
Development of NDA and BLA
24 Jan. 2010
Modern College of Pharmacy, Pune
2
What are Biopharmaceuticals
• Biopharmaceuticals are defined as pharmaceuticals
manufactured by biotechnology methods, with the
products having biological sources, usually
involving live organisms or their active components
• Biopharmaceuticals are protein or nucleic acid
based pharmaceuticals (substance used for
therapeutic or in vivo diagnostic purpose), which
are produced by mean other than direct extraction
from a native biological source.
24 Jan. 2010
Modern College of Pharmacy, Pune
3
Pharmaceutical Biotechnology
• The methods and techniques that involve the use
of living organisms (such as cells, bacteria, yeast
and others) are tools to perform specific industrial
or manufacturing process are called biotechnology
• Pharmaceutical Biotechnology will continue to
provide new breakthroughs in medical research in
the years to come, leading to treatment in field
which have previously eluded us (including AIDS,
cancer asthma, Parkinson’s disease, Alzheimer
disease)
24 Jan. 2010
Modern College of Pharmacy, Pune
4
Pharmaceutical Biotechnology
• Biotechnology offers better product-targeting for
specific diseases and patient groups, through the
use of innovative technologies, in particular,
genetics. Examples include, amongst others,
treatment for rare diseases and cancers.
• Some products are not naturally created in
sufficient quantities for therapeutics purpose.
• Biotechnology makes large-scale production of
existing substances possible, for example, insulin
in the field of diabetes treatment
24 Jan. 2010
Modern College of Pharmacy, Pune
5
Biopharmaceuticals history
24 Jan. 2010
Modern College of Pharmacy, Pune
6
Protein and peptide
 Proteins - Chains of amino acids, each joined together
by a specific type of covalent bond
 Proteins formed by joining same 20 amino acids in
many different combinations and sequences
 Protein > 50 amino acids
 peptide < 50 amino acids
 Function of a protein determined by its non-covalent
3D structure
24 Jan. 2010
Modern College of Pharmacy, Pune
7
Covalently linked Amino Acids
O H
H3N+
O
H3N+
H R1
O
H R
N
H
R2 H
N
O H
O H R3
N
H
R4
O
O
Polypeptides
Amino Acids
24 Jan. 2010
Modern College of Pharmacy, Pune
8
Peptide Synthesis
24 Jan. 2010
Modern College of Pharmacy, Pune
9
Protein Structure
Lactate Dehydrogenase:
Mixed a / b
24 Jan. 2010
Immunoglobulin
Fold: b
Modern College of Pharmacy, Pune
Hemoglobin B
Chain: a
10
Classification of Proteins
• According to their biological roles
- Enzymes – Catalyses virtually all chemical reactions i.e. 6GDH
- Transport proteins i.e. Haemoglobin of erythrocytes
- Contractile or Motile proteins i.e. Actin and Myosin
- Structural proteins i.e.Collagen
- Defense proteins i.e. Immunoglobulins and Antibodies
- Regulatory proteins i.e. insulin
- Nutrient and storage proteins i.e. Ovalbumin
24 Jan. 2010
Modern College of Pharmacy, Pune
11
Protein Therapeutics
• Proteins/peptides are gaining prominence
• Proteins - ideal drugs as they carry out
essentially all biologic processes and
reactions
• Recombinant DNA, hybridoma techniques,
scale fermentation and purification processes
brought new series of Proteins/peptides
24 Jan. 2010
Modern College of Pharmacy, Pune
12
Protein Pharmaceuticals
• Insulin (diabetes)
• Interferon b (relapsing MS)
• Interferon g (granulomatous)
• TPA (heart attack)
24 Jan. 2010
Modern College of Pharmacy, Pune
13
Protein Pharmaceuticals
• Actimmune (If g)
• Epogen
• Activase (TPA)
• Regranex (PDGF)
• BeneFix (F IX)
• Novoseven (F VIIa)
• Betaseron (If b)
• Intron-A
• Humulin
• Neupogen
• Novolin
• Pulmozyme
• Pegademase (AD)
• Infergen
24 Jan. 2010
Modern College of Pharmacy, Pune
14
Protein Pharmaceuticals
• 77 FDA approved protein drugs
• 66/77 are recombinant proteins
• Protein pharmaceutical sales currently
approach $25 billion/yr
• By 2012 they are expected to reach $60
billion/yr
24 Jan. 2010
Modern College of Pharmacy, Pune
15
Challenges with Proteins
• Very large and unstable molecules
• Structure is held together by weak non-covalent
forces
• Easily destroyed by relatively mild storage
conditions
• Easily destroyed/eliminated by the body
• Hard to obtain in large quantities
24 Jan. 2010
Modern College of Pharmacy, Pune
16
Problem with Proteins
(in vivo – in the body)
• Elimination by B and T cells
• Proteolysis by endo/exo peptidases
• Small proteins (< 30 kD) filtered out by the
kidneys very quickly
• Unwanted allergic reactions may develop (even
toxicity)
• Loss due to insolubility/adsorption
24 Jan. 2010
Modern College of Pharmacy, Pune
17
24 Jan. 2010
Modern College of Pharmacy, Pune
18
Problem with Proteins
(in vitro – in the bottle)
Noncovalent
Covalent
- Denaturation
- Deamidation
- Aggregation
- Oxidation
- Precipitation
- Disulfide exchange
- Adsorption
- Proteolysis
24 Jan. 2010
Modern College of Pharmacy, Pune
19
Noncovalent Processes
Denaturation
24 Jan. 2010
Adsorption
Aggregation Precipitation
Modern College of Pharmacy, Pune
20
Covalent processes
• Deamidation - conversion of Asn-Gly sequences to
a-Asp-Gly or b-Asp-Gly
• Oxidation - conversion RSR’ to RSOR’, RSO2R’ or
RSO3R’ (Met & Cys)
• Disulfide exchange - RS- + R’S-SR’’ goes to RSSR’’ + R’S- (Cys)
• Proteolysis - Asp-Pro, Trypsin (at Lys) or
Chymotrypsin (at Phe/Tyr)
24 Jan. 2010
Modern College of Pharmacy, Pune
21
How to Deal with These Problems
 Storage
Formulation
Delivery
24 Jan. 2010
Modern College of Pharmacy, Pune
22
Storage
• Refrigeration
• Packaging
• Additives
• Freeze-Drying
24 Jan. 2010
Modern College of Pharmacy, Pune
23
Storage (additives)
• Addition of stabilizing salts or ions (Zn+ for insulin)
• Addition of polyols (glycerol and/or polyethylene
glycol) to solubilize
• Addition of sugars or dextran to displace water or
reduce microbe growth
• Use of surfactants (CHAPS) to reduce adsorption and
aggregation
24 Jan. 2010
Modern College of Pharmacy, Pune
24
Storage (Freeze Drying)
• Freeze liquid sample in
container
• Place under strong vacuum
• Solvent sublimates leaving
only solid or nonvolatile
compounds
• Reduces moisture content to
<0.1%
24 Jan. 2010
Modern College of Pharmacy, Pune
25
How to Deal with These Problems
Storage
 Formulation
Delivery
24 Jan. 2010
Modern College of Pharmacy, Pune
26
Protein Formulation
• Protein sequence modification (site directed
mutagenisis)
• PEGylation
• Proteinylation
• Peptide Micelles
• Formulating with permeabilizers
24 Jan. 2010
Modern College of Pharmacy, Pune
27
Site Directed Mutagenesis
E343H
24 Jan. 2010
Modern College of Pharmacy, Pune
28
Site Directed Mutagenesis
• Allows amino acid substitutions at specific
sites in a protein
• i.e. substituting a Met to a Leu will reduce
likelihood of oxidation
• Strategic placement of cysteines to produce
disulfides to increase Tm
• Protein engineering (size, shape, etc.)
24 Jan. 2010
Modern College of Pharmacy, Pune
29
PEGylation
30
Modern College of Pharmacy, Pune
24 Jan. 2010
CH-CH-CH-CH-CH-CH-CH-CH-CH-CH
| |
| | |
| |
| | |
OH OH OH OH OH OH OH OH OH OH
+
PEGylation
• PEG is a non-toxic, hydrophilic, FDA
approved, uncharged polymer
• Increases in vivo half life (4-400X)
• Decreases immunogenicity
• Increases protease resistance
• Increases solubility & stability
• Reduces depot loss at injection sites
24 Jan. 2010
Modern College of Pharmacy, Pune
31
Peptide-PEG monomers
Hydrophobic block
Hydrophobic block
Peptide
O H
H3N+
H
R1
24 Jan. 2010
N
H
R2 H
N
O H
Peptide
O H
R3
N
H
R4
O
O H
O H3N+
H
R1
N
H
R2 H
N
O H
Modern College of Pharmacy, Pune
O H
R3
N
H
R4
O
O
32
Proteinylation
+
Protein Drug
24 Jan. 2010
ScFv (antibody)
Modern College of Pharmacy, Pune
33
Proteinylation
• Attachment of additional or secondary
(nonimmunogenic) proteins for in vivo
protection
• Increases in vivo half life (10X)
• Cross-linking with Serum Albumin
• Cross-linking or connecting by protein
engineering with antibody fragments
24 Jan. 2010
Modern College of Pharmacy, Pune
34
Peptide Micelles
24 Jan. 2010
Modern College of Pharmacy, Pune
35
Peptide Micelles
24 Jan. 2010
Modern College of Pharmacy, Pune
36
Targeted Micelles
24 Jan. 2010
Modern College of Pharmacy, Pune
37
Formulation with permeabilizers
• Salicylates (aspirin)
• Fatty acids
• Metal chelators (EDTA)
• Anything that is known to “punch holes” into
the intestine or lumen
24 Jan. 2010
Modern College of Pharmacy, Pune
38
How to Deal with These Problems
Storage
Formulation
 Delivery
24 Jan. 2010
Modern College of Pharmacy, Pune
39
Drug Delivery
• Non-conventional way of administering
drugs (novel drug delivery)
• Conventional way
• Oral (Tablets, Capsules)
• Parenteral (IV injections)
24 Jan. 2010
Modern College of Pharmacy, Pune
40
Conventional
• ORAL
• INTRAVENOUS
– Ease of administration
– Patient Compliance
– Fast action
– No absorption issues
– Exposure to extremely
acidic pH
– Poor absorption of
larger drugs
– Degradation by
enzymes
– Lesser patient
compliance
– Fast clearance of drugs
24 Jan. 2010
Modern College of Pharmacy, Pune
41
Parenteral Delivery of Proteins
• Intravenous
• Intramuscular
• Subcutaneous
• Intradermal
24 Jan. 2010
Modern College of Pharmacy, Pune
42
Parenteral Delivery of Proteins
•
•
•
•
•
Route of delivery for 95% of proteins
Allows rapid and complete absorption
Allows smaller dose size (less waste)
Avoids first pass metabolism
Avoids protein “unfriendly zones”
• Problems with overdosing, necrosis
• Local tissue reactions/hypersensitivity
• Everyone hates getting a needle
24 Jan. 2010
Modern College of Pharmacy, Pune
43
Drug Delivery
DRUG DELIVERY CLASSIFICATION
Drug Delivery
Route of Administration
Pulmonary
Parenteral
Transdermal
Implants
24 Jan. 2010
Drug Modification
Miscellaneous
Ocular
Oral
PEGylation
Pro-drug
Polymer depot
Nasal
Modern College of Pharmacy, Pune
44
Novel Drug Delivery
• Useful for following types of drugs:
– Short half-life
• Insulin
• Growth hormone
t1/2 < 25 min
t1/2 < 25 min
– High systemic toxicity (causing side effects)
• Carmustine
causes nausea, hair loss
– Frequent dosing
• Growth hormone
Daily dosage required
– Expensive drugs
24 Jan. 2010
Modern College of Pharmacy, Pune
45
Novel Drug Delivery
• Adverse Drug Effects
– 15 % of hospital admissions
– 100,000 deaths
– $136 billion in health care costs
• Less patient compliance
– 10 % hospital admissions
• Novel Drug delivery sales
– $14 billion in 1997 & $53 billion in 2002
24 Jan. 2010
Modern College of Pharmacy, Pune
46
Polymeric Drug Delivery
•
•
•
•
Frequency of doses reduced
Drug utilized more effectively
Drug stabilized inside the polymer matrix
Reduced side effects
• Possibility of dose-dumping
• De-activation of drug inside polymer
24 Jan. 2010
Modern College of Pharmacy, Pune
47
Polymeric Drug Delivery
• Controlled Release of drugs
Plasma concentration
60
50
40
Conventional
30
Controlled release
MEC
20
MTC
10
0
0
1
2
3
4
5
6
7
8
Time
24 Jan. 2010
Modern College of Pharmacy, Pune
48
Polymeric Drug Delivery
• Polymers should be:
– Biodegradable
– Bio-compatible
– Non-toxic
• Examples:
– Polylactides/glycolides
– Polyanhydrides
– Polyphosphoesters
24 Jan. 2010
Modern College of Pharmacy, Pune
49
Polymeric Drug Delivery
• Diffusion of drug out of the polymer
• Governing equation: Fick’s laws of diffusion
• Drug release is concentration dependant
o o o
o o o
o o o
o
o o o
o o
• Less applicable for large molecules
24 Jan. 2010
Modern College of Pharmacy, Pune
50
Polymeric Drug Delivery
• Drug Release by Polymer Degradation
• Polymer degradation by:
• Hydrolysis
• Enzymatic (Phosphotases; Proteases etc.)
24 Jan. 2010
Modern College of Pharmacy, Pune
51
Microsphere Encapsulation
100 mm
24 Jan. 2010
Modern College of Pharmacy, Pune
52
Encapsulation
• Process involves encapsulating protein or
peptide drugs in small porous particles for
protection from “insults” and for sustained
release
• Two types of microspheres
– nonbiodegradable
– biodegradable
24 Jan. 2010
Modern College of Pharmacy, Pune
53
Types of Microspheres
• Nonbiodegradable
– ceramic particles
– polyethylene co-vinyl acetate
– polymethacrylic acid/PEG
• Biodegradable (preferred)
– gelatin
– polylactic-co-glycolic acid (PLGA)
24 Jan. 2010
Modern College of Pharmacy, Pune
54
Microsphere Release
• Hydrophilic (i.e. gelatin)
– best for burst release
• Hydrophobic (i.e. PLGA)
– good sustained release (esp. vaccines)
– tends to denature proteins
• Hybrid (amphipathic)
– good sustained release
– keeps proteins native/active
24 Jan. 2010
Modern College of Pharmacy, Pune
55
Polymer Scaffolds
• Incorporate drug into polymeric matrix
• Protection of drug from enzymatic degradation – particularly
• Applicable to peptide and protein drugs
• Release drug at known rate over prolonged duration
• Drug dispersed or dissolved in suitable polymer
• Release
- diffusion of drug through polymer
- diffusion through pores in polymer structure
- therefore different release profiles result (dissolved or
dispersed)
24 Jan. 2010
Modern College of Pharmacy, Pune
56
Release Mechanisms
Drug Release
Diffusion
Polymer Degradation
Combination
Enzymatic degradation
Hydrolysis
Combination
Bulk erosion
24 Jan. 2010
Surface erosion
Modern College of Pharmacy, Pune
57
Magnetic Targeted Carriers (MTCs)
• Microparticles, composed of
elemental iron and activated carbon
• Drug is adsorbed into the MTCs
and transported
• The drug attaches to the carbon
component
• The particles serve as delivery
vehicles to the area of the tumor for
site-specific targeting
24 Jan. 2010
Modern College of Pharmacy, Pune
58
Magnetic Targeted Carriers (MTCs)
Source: http://www.magneticsmagazine.com/e-prints/FeRx.htm
24 Jan. 2010
Modern College of Pharmacy, Pune
59
Magnetic Targeted Carriers (MTCs)
• FeRx Inc. is the leader in the development in this
innovative technology
• Founder of FeRx and pioneer of magnetic targeted drug
delivery is Dr. Kenneth Widder
• Began with albumin microspheres containing
encapsulated drugs, and lead to present MTC
technology
• Present clinical trials by FeRx show that drug remains
for 28-days with no redistribution from the targeted site
24 Jan. 2010
Modern College of Pharmacy, Pune
60
Liposomes
Spherical vesicles with a phospholipid bilayer
Hydrophilic
Hydrophobic
24 Jan. 2010
Modern College of Pharmacy, Pune
61
Liposomes Drug Delivery
• Potential of liposomes in drug delivery has now realized
• Bloemycin encapsulated in thermosensitive liposomes
enhanced antitumor activity and reduced normal tissue
toxicity
• S.C injection of negatively charged liposomes produced a
prolonged hypoglycemic effect in diabetic dogs
• Liposomes have recently been used successfully as
vehicles for vaccines
24 Jan. 2010
Modern College of Pharmacy, Pune
62
Hydrogel Based Drug Delivery
Hydrogels are three dimensional networks of hydrophilic
polymers that are insoluble
24 Jan. 2010
Modern College of Pharmacy, Pune
63
Hydrogel Based Drug Delivery
Hydrogels can swell as a result of changes in pH, Temp.,
ionic strength, solvent composition, pressure and the
application of electric fields
R
O
O
O
N
N
H
H
H2O
R
R
NH2
O
+
H
H
R = polymer backbone
Insulin has been one drug that has been incorporated in
hydrogels and investigated by researchers extensively
24 Jan. 2010
Modern College of Pharmacy, Pune
64
Proteins in Pumps
Infusaid Model 400 Implantable Pump
24 Jan. 2010
Modern College of Pharmacy, Pune
65
Proteins in Pumps
Mechanical Insulin Pumps
24 Jan. 2010
Modern College of Pharmacy, Pune
66
Proteins in Pumps
• Formulation is the beginning of successful drug
delivery
• Multiple potential interactions between the
protein and the pump
• Control of the material interface is most
important
• Device design and formulation need to work
together and be regulated together
24 Jan. 2010
Modern College of Pharmacy, Pune
67
Oral Protein Delivery
24 Jan. 2010
Modern College of Pharmacy, Pune
68
Oral Insulin
• Buccal aerosol delivery system developed by
Generex
• Insulin is absorbed through thin tissue layers in
mouth and throat
• Insulin is formulated with a variety of additives
and stabilizers to prevent denaturation on
aerosolization and to stabilize aerosol particles
24 Jan. 2010
Modern College of Pharmacy, Pune
69
Oral Delivery by Microsphere
pH 2
24 Jan. 2010
pH 7
Modern College of Pharmacy, Pune
70
pH Sensitive Microspheres
• Gel/Microsphere system with polymethacrylic acid +
PEG
• In stomach (pH 2) pores in the polymer shrink and
prevent protein release
• In neutral pH (found in small intestine) the pores swell
and release protein
• Process of shrinking and swelling is called
complexation (smart materials)
24 Jan. 2010
Modern College of Pharmacy, Pune
71
Nasal Delivery of Proteins
• Extensive microcirculation network underneath the nasal
mucosa
• Drug absorbed nasally can directly enter the systemic
circulation before passing through the hepatic circulation
• The nasal administration of peptides has attracted much
interest now a days due to
- Relatively rapid absorption of drug
- Little metabolic degradation
- Relative ease of administration
- Selective to peptide structure and size
24 Jan. 2010
Modern College of Pharmacy, Pune
72
Nasal Delivery of Proteins
• Enhancement of nasal absorption of insulin using
polyacrylic acid as a vehicle
• Enhancement in the nasal absorption of insulin entrapped
in liposomes through the nasal mucosa of rabbits
• Administration of insulin (1 IU/ kg) via the nasal route
caused a significant decrease in the plasma glucose level
• The nasal route appears to be a viable means of
systemically delivering many small peptides
24 Jan. 2010
Modern College of Pharmacy, Pune
73
Pulmonary Delivery
• Deep lung, an attractive site of protein delivery due to
- Relatively large surface area (100m2)
- Rapid absorption of drug into the blood stream through the alveoli
• Dura and Inhale developed dry powder delivery systems
for proteins
• 40% of the insulin administered in an aerosol, to the
trachea of anaesthetized rabbit was absorbed
• Albumin was largely absorbed within 48 hours of
instillation into the lungs of guinea pigs and dogs
24 Jan. 2010
Modern College of Pharmacy, Pune
74
Rectal Delivery
• The rectal delivery offers many advantages
- Avoidance of drug dilution prior to reaching the systemic
circulation
- Reduction in first-pass metabolism
- Rapid systemic absorption
- Safe and convenient especially in case of neonates and infants
- Greater dose may be administered
- Withdrawal of drug is possible in case of adverse effects
• Administration of insulin using the rectal route shows
systemic absorption
24 Jan. 2010
Modern College of Pharmacy, Pune
75
Occular Delivery
• Gelfoam eye device enhances the absorption of sodium
insulin with an absorption enhancer
• Many proteins and peptides that have been investigated
for ocular delivery
- Enkephalins
- Thyrotropin releasing hormones,
- Leutanizing hormone-releasing hormone,
- Glucagon and Insulin
• All these peptides were absorbed into the blood stream to
some extent
24 Jan. 2010
Modern College of Pharmacy, Pune
76
Patch Delivery
24 Jan. 2010
Modern College of Pharmacy, Pune
77
Mucoadhesive Patch
• Adheres to specific region of GI tract
• Ethylcellulose film protects drugs from
proteolytic degradation
• Composed of 4 layers
–
–
–
–
Ethylcellulose backing
Drug container (cellulose, citric acid)
Mucoadhesive glue (polyacrylic acid/PEG)
pH Surface layer (HP-55/Eudragit)
24 Jan. 2010
Modern College of Pharmacy, Pune
78
Patch Delivery
24 Jan. 2010
Modern College of Pharmacy, Pune
79
Transdermal Patches
Micro fabricated needles to facilitates permeation of peptide drugs
24 Jan. 2010
Modern College of Pharmacy, Pune
80
Transdermal Patches
• Proteins imbedded in a simple matrix with
appropriate additives
• Patch is coated with small needles that
penetrate the dermal layer
• Proteins diffuse directly into the blood stream
via capillaries
• Less painful form of parenteral drug delivery
24 Jan. 2010
Modern College of Pharmacy, Pune
81
Role of a Pharmaceutical Engineer
• Modeling of drug delivery systems
• Prediction of kinetics/thermodynamics
• Novel polymer research
• Temperature sensitive polymers; pH sensitive polymers
• Development of new drug delivery techniques
• Novel techniques for new therapies
• Development of purification processes
• Solvent Removal; Removal of impurities etc.
• Process development
• Design & Development of robust processes; GMP Validation
• Scale-up of processes
24 Jan. 2010
Modern College of Pharmacy, Pune
82
Protein X
• Natural protein
• Specific enzymatic activity
• Negligible side effects
• Frequent injections (up to twice a day)
• Expensive
24 Jan. 2010
Modern College of Pharmacy, Pune
83
Protein X delivery
• Applicable alternative techniques
• Pulmonary delivery
• Non-invasive; Good patient compliance
• Poor efficiency; Requires patient training
• PEGylation
• Improved stability; reduced frequency of injections
• Protein X activity?
• Polymeric delivery
• Long-term delivery;improved patient compliance
• May improve protein X utilization
• Stability of protein X in polymer?
24 Jan. 2010
Modern College of Pharmacy, Pune
84
Protein X delivery
• Improved protein utilization
– Less protein gets wasted
– Drives down product cost
Plasma concentration
• Economical advantages
60
50
40
Conventional
30
Controlled release
20
MEC
10
0
0
1
2
3
4
5
6
7
8
Time (days)
• Improved patient compliance
60
Plasma concentration
– Reduced frequency of dosing
– Improved patient compliance
– Less medical expenditure from
events due to missed doses
50
40
30
20
10
0
0
1
2
3
4
5
6
7
8
Time (days)
24 Jan. 2010
Modern College of Pharmacy, Pune
85
BIOSIMILARS
24 Jan. 2010
Modern College of Pharmacy, Pune
86
What is a biosimilar medicine
• A biosimilar medicine is a medicine which
is similar to a biological medicine that has
already been authorized (the ‘biological
reference medicine’)
• The active substance of a biosimilar
medicine is similar to the one of the
biological reference medicine
24 Jan. 2010
Modern College of Pharmacy, Pune
87
What is a biosimilar medicine
• Biosimilar and biological reference
medicines are used in general at the same
dose to treat the same disease
• Since biosimilar and biological reference
medicine are similar but not identical
• The name, appearance and packaging of a
biosimilar medicine differ to those of the
biological reference medicine
24 Jan. 2010
Modern College of Pharmacy, Pune
88
What is a biosimilar medicine
• As biosimilars are not generics, the generic
substitution rules should not apply to
biosimilars
24 Jan. 2010
Modern College of Pharmacy, Pune
89
Characteristics of therapeutic proteins
• Size
- 100 – 500 times larger than classic drugs
- Can not be completely characterized by physicochemical methods
• Immunogenicity
• Structural heterogeneity
• Relatively high biological activity
• Relatively unstable
24 Jan. 2010
Modern College of Pharmacy, Pune
90
Factors influencing activity of
therapeutic proteins
•
•
•
•
•
•
•
Gene and promotor
Host cell
Culture conditions
Purification
Formulation
Storage and handling
Unknown factors
24 Jan. 2010
Modern College of Pharmacy, Pune
91
What is in a name
•
•
•
•
•
•
•
•
Biogenerics
Second entry biologicals
Subsequent entry biologicals
Off-patent biotech products
Multisource products
Follow-up biologics
Biosimilars
Similar biological medicinal products
24 Jan. 2010
Modern College of Pharmacy, Pune
92
Pioneer Company
Genentech
Abbott
Products
Indication(s)
US Patent/
Market
Exclusivity
Expires
EU Patent/
Market
Exclusivity
Expires
NutropinTM (somatropin)
AbbokinaseTM (eudurase
urokinase)
HumulinTM (recombinant insulin)
Ceredase TM (algucerase):
Cerezyme TM (imiglucerase)
Streptase TM (streptokinase)
Intron ATM (IFN-alfa-2b)
Serotim TM (somatropin)
Humatrope TM (somatropin)
Growth disorders
Ischemic events
Expired
Expired
Expired
Expired
Diabetes
Gaucher disease
Expired
Expired
Expired
Expired
Ischemic events
Hepatitis B and C
AIDSwasting
Growth disorders
Expired
Expired
NA
NA
Anemia
Roche
Genetech
InterMune
EpogenTM, Procrit TM, EpresTM
(erythropoietin)
NeoRecormonTM (erythropoietin)
TNKaseTM (tenecteplase TNK-tPA)
ActimmuneTM (IFN-gamma-Ib)
Expired
Expired
Expired
Expired
ODE
2013
Genentech
Activase TM, Alteplase TM (tPA)
Anemia
Acute myocardial infarction
Chronic granulomatous
Disease (CGD), malignant
obsteopetrosis
Acute myocardial infaretion
Chiron
ProleukinTM (IL-2)
HIV
Eli Lilly
Genzyme
AstraZeneca
Biogen/Roche
Serono
Eli Lilly
Amgen
Amgen
NeupogenTM (filgrastim G-CSF)
Anemia, leukemia, neutropenia
24 Jan. 2010
Modern College of Pharmacy, Pune
Expired
NA
Expired
Expired
Expired
Expired
Expired
Expired
Expired
2012
Expired
Expired
2010
Expired,
Expired
2012
Expired,
Expired
2012, 2015 93
Main elements CHMP guidelines
concerning biosimilars
• The concept of similar biological products
is applicable to any biological medicinal
product. But it is more likely applied to
highly purified products, which can be
thoroughly characterized
• In order to support pharmacovigilance
monitoring, the specific product given to the
patient should be clearly identified
24 Jan. 2010
Modern College of Pharmacy, Pune
94
Main elements CHMP guidelines
concerning biosimilars
• The active substance of the biosimilar product
must be similar in molecular and biological terms
to the active substance of the reference medicinal
product e. IFN alpha 2a is not similar to IFN alpha
2b
• The same reference product throughout the
comparability program
• The pharmaceutical form, dose and route of
administration of the biosimilar and the reference
product should be the same
24 Jan. 2010
Modern College of Pharmacy, Pune
95
Main elements CHMP guidelines
concerning biosimilars
• If the reference product has more than one
indication, the safety and eficacy for all
indications have to be justified or demonstrated
for each indication separately
• The clinical safety must be monitored on an
ungoing basis after marketing approval
• The issue of immunogenicity should always be
addressed, and its long-term monitoring is
necessary
24 Jan. 2010
Modern College of Pharmacy, Pune
96
Thank You
24 Jan. 2010
Modern College of Pharmacy, Pune
97