Académique Documents
Professionnel Documents
Culture Documents
Creation
Current State
Current State
1950s
4
Today
1950s
Today
Pharmaceutical Products
Current approach
Discovery
Development
Manufacturing
Development
Manufacturing
Development
Manufacturing
concentrations are
desired, 200 mg/ml+.
10
Formulation
Fill/Finish
11
Unit Operation
Yield
Total
Yield
Centrifugation
85%
85%
Depth Filtration
85%
72%
UF/DF
95%
69%
Protein A Chrom.
90%
62%
Virus Inactivation
98%
61%
Ion Exchange
Chrom.
95%
58%
Polishing Chrom.
95%
55%
Downstream purification
12
Viral Filtration
98%
54%
12
Manufacturing
failure
Limitation on product
delivery route
Immunogenicity
Aggregation
High concentration
monomeric
antibody solution,
200 mg/ml +
Altered serum
half-life
Reduction of
functional activity
Hydrophobicity scale
Hydrophobic
Hydrophilic
SAP
at
R=5
Hydrophobicity scale
SAP scale
SAP scale
Hydrophobic
+0.5
+0.5
Hydrophilic
-0.5
-0.5
15
L234
L235
L309
I253
SAP
scale
+0.5
-0.5
A1: L235K
A2: I253K
A3: L309K
A4: L235K L309K
A5: L234K L235K
Chennamsetty, N. et al., PNAS 2009.
17
Patent
Expiry
US
sales
Formulation
Dosage
Delivery
Rituxan
(Genentech)
2015
$2.6B
Liquid
10 mg/mL
650 mg / week
IV
infusion
Herceptin
(Genentech)
2015
$1.4B
Solid
21 mg/mL
140-420 mg /
1-3 weeks
IV
infusion
Avastin
(Genentech)
2017
$3.0B
Liquid
25 mg/mL
700 mg / 2
weeks
IV
infusion
2017
$0.7B
Liquid
2 mg/mL
430 mg / week
IV
infusion
18
Back
Y101H*
Probe Radius = 5
*Located in the CDR-H3 Loop
L178H
Y101H*
Antigen
Binding
Region
Hinge
region
V59L
SAP scale
Hinge
region
V3L
+0.5
L153L
-0.5
19
19
20
Chain
Res. #
10
59
153
178
101
Residue
Val
Ala
Ile
Val
Leu
Leu
Tyr
Mut.
Gln
Ser
Ser
Ser
Asp
Ser
Ser
Binding to CD20:
Mutation
affecting
functionality
[Ab] (nM)
21
Viscosity [mPa-s]
300
250
200
150
100
50
0
500
1000
1500
2000
2500
SCM Prediction
22
Development
Manufacturing
Development
Manufacturing
Past
25
Current
> 2020
MECHANISTIC
UNDERSTANDING
MVDA MODELS
EMPIRICAL UNDERSTANDING
DECISIONS BASED ON
UNIVARIATE APPROACH
DATA DERIVED FROM
TRIAL-N-ERROR EXPERIMENTATION
27
Design-space methods:
Strategy based on operation
within a fixed parameter space
Applicable to each continuous
process unit operation
Complicated to apply to an entire
integrated pharmaceutical
manufacturing plant
28
Feedback methods:
S. Mascia, P.L. Heider, H. Zhang, R. Lakerveld, B. Benyahia, P.I. Barton, R.D. Braatz, C.L. Cooney, J.M.B. Evans, T.F.
Jamison, K.F. Jensen, A.S. Myerson, and B.L. Trout. End-to-end continuous manufacturing of pharmaceuticals:
Integrated synthesis, purification, and final dosage formation. Angewandte Chemie, 52(47), 12359-12363, 2013
29
CAT
A + B
I1
FC
PU2
C1
R1
A
B
sp
LC
M1
M2
S1
C2
sp
LC
PU1
sp
W1
FT
D1
FC
sp
S2
sp
S1
LC
sp
DC
FC
S3
S1
S1
M3
sp
FC
M4
R2
I1 + C I 2 + PBP
CC
RC
sp
C3
LC
S3
LC
S4
LC
sp CC
FT
FC
CT
sp
C4
LC
W2
LC
sp
PU4
sp
D2
I 2 + E API
LC
sp
DC
E
S1
S1
PU3
S1
S1
M5
sp
30
EX2
dynamic models
were built for each
unit operation (UO)
as they were
developed
Models were
S1
EX1
First-principles
FC
S5
S6
TC
E1
CS
FP
Plant simulation
CAT
A + B
I1
FC
PU2
C1
R1
A
B
sp
LC
M1
M2
S1
C2
sp
LC
PU1
sp
D1
sp
sp
S1
in Summer 2012
W1
FT
FC
S2
LC
sp
DC
FC
S3
S1
S1
S1
M3
sp
FC
M4
R2
I1 + C I 2 + PBP
sp
C3
LC
S3
LC
S4
LC
sp CC
CC
RC
FT
FC
CT
sp
C4
LC
W2
LC
sp
PU4
sp
D2
I 2 + E API
LC
sp
Currently designing
DC
E
S1
S1
PU3
S1
S1
M5
sp
EX1
31
EX2
FC
S5
S6
TC
E1
CS
FP
controls for
a biologic drug
manufacturing
process (BioMAN)
34
35
Safety:
Hydrazine-transition metal or
hydrazine-oxidant combinations
present a significant explosion
hazard
Hydrazine is highly toxic
Flow Advantages:
By utilizing continuous flow
technology, the safety issues are decreased
Minimize isolation and handling of sensitive aryl hydrazine intermediates
Tandem multistep process decreases synthetic manipulation necessary
Low catalyst loadings and mild reaction conditions
Methodology used in CHAD (WSJ) as an alternative route for an unstable ArNHNH2
intermediate
36
DeAngelis, A.; Wang, D. H.; Buchwald, S. L. Angew. Chem. Int. Ed. 2013, 52, 3434
37
Challenges
How can secondary
nucleation and other bulk
nucleation events be avoided?
3 peristaltic
pumps
4 Liter
Vessel
Gentle mixing
Recycle
Tight control of
concentration
42
Resulting Crystals
API : Acetaminophen
Excipient: D-Mannitol
44
Ending Temperature Starting Concentration Excipient Size Steady State Concentration Steady State Drug
(C)
(mg ACE / g EtOH)
(mg ACE / g EtOH)
Supersaturation Loading
(m2/g)
1
1
15
12
196.4
196.4
0.0343
0.0343
176.2
166.6
0.024
0.028
17.4
23.5
2
2
15
12
196.5
196.5
0.0976
0.0976
175.8
169.8
0.021
0.047
17.8
21.7
Run #1
45
Direct Compression
Needed to add MCC and MgSt
Friability test accepted! (< 1%)
46
Dissolution
Weight % Dissolved
100
80
60
40
20
0
20
40
TIme (minutes)
60
80
48
No pore
The scale bar is 200nm
120nm
15nm
49
300nm
40nm
(011)
(100)
Growth
direction
Empty pores
100nm
51
2)
3)
52
Electrospin to produce
fibers
Nano-Crystallization in Emulsions in
Hydrogel Particles (Prof. Pat Doyle)
Hydrated Particles
Dried Particles
Light Microscopy
Direct Compression
SEM of
Nano-crystals
CaCl2 recycle
54
Eral et. al. Crystal Growth & Design, 14, 2073 (2014)
Development
Manufacturing
Development
Manufacturing
Reagent B Reagent C
Online
Manipulation of
Discrete and
Continuous Variables
Inert Carrier
Phase
Real-time Feedback
Algorithm
Online HPLC
Analysis
Mixing Zone
Reactor
Reacted Slugs
Construct
Discrete Variable
Response Surfaces
xk
x3
f(x,y)
x*
x2
x1 58
xl
yp
x1
Optimal
Experiment
x2
Brandon Reizman
One
variable at
a time
x1
x3
Enumerate
everything!
y1
Here?
59
Construct
Discrete Variable
Response Surfaces
xk
x3
f(x,y)
x*
60
x2
yp
x1
Optimal
Experiment
x2
Cl
Boc
N
B(OH)2
1.5 equiv
Optimum TON
Conditions
1.0% XPhos OMs
T = 97C
tres = 4.7 min
Boc
N
TON = 88.7
Yield* = 90%
Max Yield*
Optimal TON
XPhos OMs
99%
88.7
SPhos OMs
95%
65.0
RuPhos OMs
90%
61.7
120
XPhos Cl
88%
42.2
100
XantPhos OMs
73%
29.0
PCy3 OMs
54%
31.7
PPh3 OMs
34%
18.7
PtBu3 OMs
27%
15.6
66
Symbol
120
T ( oC)
Catalyst
Palladacycle-Ligand?
Loading = 0.5%-2.5%
100
80
80
60
60
40
40
2.5
2
600
1.5
Loading (mol%)
20
400
200
1
0.5
tres (s)
TON
69
70
71
72
Acknowledgements
Novartis Pharmaceuticals, esp. Markus Krumme
MedImmune
Pfizer
Singapore-MIT Alliance
Colleagues at MIT, esp. Allan Myerson, and
around the world
74