Biotech Products PDF
Biotech Products PDF
Biotech Products PDF
(biopharmaceuticals):
Other sources of variability?
Definitions
Low-molecular-weight drug
Generic drug
Biopharmaceutical
Biosimilar, or similar
biological medicinal
product
1. EMEA definition.
Biopharmaceuticals
Introduced in the beginning of the 1980s
More than 150 products marketed around
the world
Over 370 products in development for a
wide range of serious conditions
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$10,000/g
With over 1/3 of ALL pipeline products the market forecast is US$ 92 billion in
2011
Knaeplein, 2007
Technology Evolution in
Pharma Industry
Chemistrybased
compounds
Extraction-based
biological compounds
Therapeutic
recombinant
proteins
Vaccinal
recombinant
proteins
Gene
Therapy
Immature
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
Yeast
Transgenic Animals
Mammalian Cells
Saccharomyces
CHO
Transgenic Plants
Tobacco, moss
Escherichia coli
knaeplein
Th
e
qu
in
the ali
t
p r y is
oc
es
s
2003, November,
266, 3-16
Generic
name
Hu IFN
alpha-2a
Roferon
Lys
No
Hu IFN
alpha-2b
Intron
Arg
Yes
PEGylated proteins
PEG-Interferon alfa
PEG-G-CSF
.
http://www.roche.com/pages/facets/10/pegasyse.htm
Schmidt CA, et al. Arq Bras Endocrinol Metab. 2003;47:183-9; Schellekens H. Eur J Hosp Pharm. 2004;3:43-7.
Isoform distribution
B
Cathode
IA
IB IIA
IIB
IIIA IIIB
IV
VII
VIII
VI
Anode
Sample
Schellekens
Enhancement of efficacy
Growth hormone
Neutralization of
endogenous protein
Megakaryocyte-derived growth
factor (MDGF)
Epoetin
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
12
10
8
Assay validation!
6
4
2
0
400
200
100
50
25
12,5
Serum Dilution
Hanover
Uppsala
Rijswijk
Rome
Basel
Copenhagen
6,25
3,1
Interferon alfa
1996
Response
14
12
10
8
6
4
2
0
Negative
< 2000
> 2000
Generic
name
Hu IFN
alpha-2a
Roferon
Lys
No
Hu IFN
alpha-2b
Intron
Arg
Yes
Type of
interferon
% Antibodies
r-IFN alpha 2a
20
r- IFN alpha 2b
1800
A (n = 190)
1600
1400
1200
1000
800
B (n = 86)
600
400
C (n = 110)
200
D (n = 81)
E (n = 74)
0
0
1999 2000
2001
2002 2003
Year
Eprex
(post 1998)
NeoRecormon
(1990 launch)
HSA
Polysorbate 80
Polysorbate 20
Glycine
Glycine
HSA
Complex of
5 other
amino acids
Calcium chloride
Urea
26
27
30
Avonex
NAb (% of patients)
25
BG9015
20
15
10
5
0
6
12
18
Treatment (months)
24
months
Two mechanisms:
Reaction to neo-antigens
(classical immune response)
Breaking of self-tolerance
Type of product
Human homologues
(recombinant human proteins)
Immune
response
(antibody
production)
Cause
Monomeric proteins
non-immunogenic
Aggregated proteins
immunogenic
5-10 nm
Not
immunogenic
Immunogenic
~60 nm
Not
immunogenic
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
Product
Indication(s)
Genentech
Nutropin (somatropin)
Abbott
EU patent/market
exclusivity expires
US patent/market
exclusivity expires
Growth disorders
Expired
Expired
Abbokinase (eudurase
urokinase)
Humulin (recombinant insulin)
Ischaemic events
Expired
Expired
Diabetes
Expired
Expired
Ceredase (alglucerase);
Cerezyme (imiglucerase)
Gaucher disease
Expired
Expired
Ischaemic events
Expired
Expired
Expired (France)
2007 (Italy)
Expired
Eli Lilly
Genzyme
Biogen/
Roche
Intron A (interferon-alpha-2b)
Hepatitis B and C
Serono
Serostim (somatotropin)
AIDS wasting
NA
Expired
Eli Lilly
Humatrope (somatropin)
Growth disorders
NA
Expired
Amgen
Anaemia
Expired
2013
Roche
NeoRecormon (epoetin)
Anaemia
Expired
NA
Genentech
Expired
Expired
InterMune
Actimmune
(interferon-gamma-Ib)
Expired
2006/2012
Genentech
Expired
Expired/2010
Chiron
Proleukin (interleukin-2)
HIV
Expired
2006/2012
Amgen
2006
2015
Biosimilars guidelines
(EMEA concept papers)
Biosimilars
Product-class-specific annexes
(concept papers)
Somatotropins
Epoetins
Insulins
G-CSF
Others?
Innovators..
Eprex, Procrit, Janssen-Cilag
Epogen, Amgen
NeoRecormon, Roche
Interchangeability..
United States (U.S. FDA Considerations on
Possible INN Policies for Biosimilars)
U.S. FDA believes that the only way to
establish pharmacologic interchangeability
is through scientific data
Europe (Thomas Lonngren media interview)
It is not possible we would guarantee a
biosimilar is interchangeable (with its
originator) the decision is based on
clinical experience that you could switch
Wim Jiskoot