What are Biotechnology Products?

What are Biotechnology Products?
Southern African Regional and International
Regulatory
Biotechnology Workshop 2007
Pretoria August 16 2007
Prof. dr. Daan J.A. Crommelin
Chair board of Pharmaceutical Sciences of F.I.P.
Dept. Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences,
UIPS
Scientific Director of the Dutch Top Institute Pharma, Leiden
Co-founder of OctoPlus, Leiden
UIPS
Utrecht Institute for
Pharmaceutical Sciences
International Journal of Pharmaceutics
2003, November, 266, 3-16
How biopharmaceuticals differ
from
low molecular weight drugs
•
•
•
Molecular weight
Complexity of structure
Characterization
Structure and physico-chemical properties
Protein purity
Biological activity
• Stability
• Immunogenicity
• Needle focused
Crommelin DJA, et al. Int J Pharm 2003;266:3-16.
With the highest growth rates within the
entire pharma market, biopharmaceuticals
will reach > US$ 92 billion revenues in 2011
Most biopharmaceutical
proteins have small
markets, but high value
< 10 kg/yr, > US$10,000/g
Biopharmaceuticals will outperform the total pharmaceutical market
With over 1/3 of ALL pipeline products the market forecast is
US$ 92 billion in 2011
Knaeplein, 2007
…Biopharma in Perspective
• The first biotech therapy to earn FDA approval was recombinant
human insulin (Genentech & Eli Lilly) in 1982.
√ζχεαδα
• Since then, as of Oct 2006, more than 250 drugs & vaccines for
nearly 400 indications developed by biotech companies have
been approved by FDA (inc. small-molecules and tissueengineered products).
http://bio.org/speeches/pubs/er/approveddrugs.asp
• More than 400 biotech drugs & vaccines are currently in clinical
trials targeting more than 200 diseases
Courtesy Özceada
The Rise of Biopharma…
The number of Biotech approvals surpassed the small molecule
approvals in 2002 (US)
Source: BioGeneriX
Technology Evolution in Pharma
Industry
Market & Technology
Maturity
Chemistrybased
compounds
Extraction-based
biological compounds
Therapeutic
recombinan
t proteins
Gene
Therapy
Immature
Vaccinal
recombinan
t proteins
Vaccine
cell
Cell
therapy therapy
Emerging
Growing
Mature
Decreasing
• Common
• Fully
• Mastering
• Non validated • Validated
technologies technologies technologies mastered and technologies
opmized
• Ongoing
• First products • More
technologies • Manufacturing
alternatives required
optimization
entering
products in
• Many
development development
• Decreasing number
• Many
products in
phases
• Few products products in
development of products in
development and,
• No products
in the market development and in the
eventually, in the
and in the
in market
market
market
market
Source: Paulo
Barbanti
Biogenerics Opportunity
Biologics with $16.4 bn sales value
came off patent in EU in the last 3 years
Drug
Indication
EU Patent
Expiry
Insulin
DM
2003
3.0
Interferon beta
MS
2003
3.8
Anemia
2005
6.1
Neutropenia
2006
3.5
EPO
G-CSF
2006 Sales (USD
bn)
16.4
Regulatory Aspects For Biotech
Approvals
• Original products:
EU: EMEA
USA: FDA (BLA)
• Biosimilars:
EU: General guidelines + product specific guidelines via EMEA
• 2 approvals (Omnitrope by Sandoz & Valtropin by BiogeneriX)
• 1 rejection (interferon alpha)
• 7 in process (2 EPO’s); Dne
USA: No standard biosimilar approval route via BLA
• Few approvals (hGH, insulin etc.) through FDA, section
505(b)(2)
• Small sales because of no product substitutability
Dynepo….. Epoetin delta
Binocrit, Epoetin alfa Hexal and Abseamed
Biopharmaceuticals = pharmaceutical
biotech products
• Medical aspects:
indications for serious diseases; meeting
unmet medical needs
• Economical aspects
relatively small, but fast growing
• Pharmaceutical aspects:
delicate complex molecules
potent molecules (?)
delivery issues
Protein Conformations
Lactate
Dehydrogenase
Mixed α/β
Immunoglobulin
Fold: β
Hemoglobin B
Chain: α
Description in Compendial Standards
Monoclonal antibody: Mw 150,000
Acetominophen = Paracetamol Mw 150
Five expression technologies for protein
production
Bacteria
Yeast
Transgenic Animals
Sheep, goat,
cow
Mammalian Cells
Saccharom
yces
CHO
Transgenic Plants
Tobacco,
moss
Escherichia
coli
Downstream processing
The Problem of Formulating Proteins
• Very large and unstable molecules
• Structure is held together by weak, noncovalent forces
• Easily destroyed even under relatively mild
storage/handling conditions
Interactions in Proteins
Wang [ref. 5]
The conformational state of a protein
Stability issues
Chemical
instability
• Disulfide
Exchange
• Deamidation
• Oxidation
• Proteolysis
Physical instability
•
•
•
•
Denaturation
Aggregation
Precipitation
Adsorption
Epo: isoform distribution (IEF) of epo products
Isoform distribution
B
A
Cathode
E
IA
IB IIA
IIB
IIIA IIIB
IV
V
VII
VIII
E
E
VI
Anode
Sample
Isoform patterns: deviations displayed by 9 of the 11 samples
(including additional basic and acidic isoforms, and increased
bar intensity) compared with the EPREX® standard (E)
Bottom line: complete characterization: mission impossible
International Journal
of Pharmaceutics
Th
e
qu
in
the ali
t
p r y is
oc
es
s
2003, November,
266, 3-16
Edited by
Jiskoot and Crommelin
AAPS press 2005
UIPS
Utrecht Institute for
Pharmaceutical Sciences
Immunogenicity of
Biopharmaceuticals
Huub Schellekens, Utrecht University
UIPS
Utrecht Institute for
Pharmaceutical Sciences
Sequence variation
A
L
C
N
A
T
human
F K
K
T
K
A
L
S
N
A
I
Glycosylation
non-human
F K
K
F
K
Immunogenicity
Contaminants &
Formulation
impurities
Length of
treatment
Assay technology
Application
route
Patient features
Dose
Unknown
factors
February
(from: Schellekens, Nature Reviews Drug Discovery, June 2002)
Delivery of Proteins
Welcome to the kingdom of the needle
• Are we stuck to the needle?
The Problem…for (Biotech) Drugs
? ?
?
+
++ +
Protein/DNA
The
problem
The problem
1. Cell selection/access
2. Entry cytoplasm
3. (Entry nucleus)
nucleus
cytoplasm
Target cell
Why Other Routes of Administration than
the Parenteral Route: ...
Get Away from the Needle…?
• Patient compliance/patient
friendliness
(Non)-parenteral Delivery
Routes of Pharmaceutical
Proteins
Lo
• Oral ….. t
s
• Rectal ….. o
f
• Nasal …...
wo
• Transdermal / Intradermal …...
r
k!
• Buccal …...
!!
• Pulmonary …...
Gas-driven intradermal
injection
Bioavailability of Pulmonary Delivered Peptides and
Proteins in Animals
Molecule
Molecular mass
No. of amino acids
Absolute Bioav.
(%)
__________________________________________________________________________
Growth hormone
22 125
191
9
G-CSF
18 000
175
62
α-Interferon
19 271
165
>56
PTH-84
9418
84
>20
PTH-34
4278
34
40
Insulin
5786
51
57
Human calcitonin
3416
32
17
Salmon calcitonin
3430
32
17
Glucagon
4381
29
<1
Somatostatin
3146
28
<1
LHRH
1182
9
95
__________________________________________________________________________
J.S. Patton / Advanced Drug Delivery Reviews 42 (2000) 239-248
Insulin Uptake via the
Pulmonary Route
• Bioavailability around 10 %
loss in device
loss through disposition in non-lung
tissue
absorption loss
Patton, J.S., Adv. Drug Delivery Research 35, 1999,
235-247
exubera
Microneedles
Subcutaneous injection of proteins:
their fate
Crommelin and Sindelar, 2002
Crommelin and Sindelar, 2002
PEG IL-2 Plasma
Conc. ng/mL
1000
Blood Lymphocytes
3
Cells/mm x 10exp3
50
40
0
30
100
20
Δ
10
10
0
0
3
6
9
12
15
Days After SC Administration
PEG IL-2 pharmacokinetics and pharmacodynamics (changes in blood lymphocyte count) after subcutaneous administration of 10 MIU/kg in rats, modeled
according to the PK/PD model depicted in Figure 13.
Braeckman, 2003