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Paul Barton, Richard Braatz, Steve Buchwald, Klavs Jensen, Allan Myerson, and Bernhardt L. Trout
Raymond F. Baddour, ScD, (1949) Professor of Chemical Engineering, MIT
Director, Novartis-MIT Center for Continuous Manufacturing
New Technologies for Holistic Pharmaceutical Creation
2
Current State
3
Current State
4
Compare with the 1950’s
1950’s Today
6
Compare with Automotive industry
1950’s Today
7
Pharmaceutical Products
Discovery Development Manufacturing
Current approach
8
Product Development: Compare with the Electronics Industry
Need to develop product and process together!
9
Holistic Pharmaceutical Process Development
Discovery Development Manufacturing
Old approach
Discovery incl. Developability,
Manufacturability Development Manufacturing
New approach: break down the barriers
more up front loading of research new technologies
10
Aggregation Is a Major Quality Issue: Development
Often high concentrations are desired, 200 mg/ml+.
Desired shelf life 1-2 years.
11 11
Cell Culture Harvest
Low-pH Viral Inactivation
Viral Filtration
Protein A Capture
Polishing Step(s)
Formulation
Fill/Finish
0.5% to 25% of the product can be in the form of soluble/insoluble aggregates due
to high fermentation titer and elevated temperatures
Harsh elution and viral inactivation conditions can induce extensive
soluble/insoluble aggregation formation
Aggregates place an enormous burden on downstream purification steps due to clogging and separation difficulties
Formulation development is a costly and time consuming task, address aggregation
Product can have a relatively short shelf life if high concentrations are required
Gottschalk, U., ed. Process Scale Purification of Antibodies. 2009
Aggregation Is a Major Quality Issue: Manufacturing
12 12
Step Unit Operation Yield Total
Yield 1 Centrifugation 85% 85% 2 Depth Filtration 85% 72% 3 UF/DF 95% 69% 4 Protein A Chrom. 90% 62% 5 Virus Inactivation 98% 61%
6 Ion Exchange
Chrom. 95% 58% 7 Polishing Chrom. 95% 55% 8 Viral Filtration 98% 54% 9 UF/DF 98% 52%
10 Steril Filtration 98% 51%
Typical yields range from 40% to 75%
Most product loss occurs during cell culture harvest (Steps 1-3) • Yield can be improved if
product does not form insoluble aggregates
Downstream purification (Steps 6-7) yields and costs can be improved if aggregation is kept at a minimum during prior steps
Gottschalk, U., ed. Process Scale Purification of Antibodies. 2009
Aggregation Is a Major Quality Issue: Manufacturing
13
Development and Manufacturing Issues: Address During Discovery!
Protein aggregation is the most common and most problematic form of protein degradation
Aggregation Immunogenicity
High concentration monomeric
antibody solution, 200 mg/ml +
Manufacturing failure
Limitation on product delivery route
storage
Altered serum half-life
Reduction of functional activity
Hydrophobic-hydrophobic interactions drive aggregation
Develop methodology to detect and engineer out.
14
Hydrophobicity scale mapped onto antibody structure
• There are many hydrophobic residues that are exposed
Hydrophobic
Hydrophilic
Hydrophobicity scale
There are many exposed hydrophobic residues on the protein surface.
15
SAP identifies exposed hydrophobic patches
• RED regions are highly hydrophobic dynamically exposed patches
• BLUE regions are highly hydrophilic dynamically exposed patches
Hydrophobic
Hydrophilic
SAP scale SAP scale Hydrophobicity scale
SAP at
R=5Å
SAP at
R=10Å
+0.5
-0.5
+0.5
-0.5
RED regions are highly hydrophobic dynamically exposed patches. BLUE regions are highly hydrophilic dynamically exposed patches.
16
Mutation of SAP predicted aggregation prone regions
4 sites with high SAP values selected for mutations.
These sites are mutated to more hydrophilic residues.
variants generated
A1: L235K
A2: I253K
A3: L309K
A4: L235K L309K
A5:L234K L235K
SAP scale
+0.5
I253
L234
L309
L235 Mutational sites
engineered
-0.5
17
Validation of SAP Technology
Reduction in aggregation was measured by SEC-HPLC All mutants lead to decrease in aggregation
A1: L235K
A2: I253K
A3: L309K
A4: L235K L309K
A5: L234K L235K
Temperature = 58 °C Concentration = 150 mg/mL 20 mM His buffer
Chennamsetty, N. et al., PNAS 2009.
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Create “Biobetters” with Enhanced Stabilities
18
mAbs 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
Erbitux (Bristol-Myers Squibb)
2017 $0.7B Liquid 2 mg/mL
430 mg / week IV infusion
Rituxan, Avastin, Herceptin, and Erbitux have been selected as targets based on their current formulation, and delivery routes, their high SAP values, and their patent expiry date.
19
Application of SAP Technology to Rituxan®
19
Rituxan Fab region with aggregation hotspots in Red
Spatial Aggregation Propensity Study of Rituxan
L178H
A9L & I10L
Y101H*
V59L
Y101H*
L153L V3L
Front Back Probe Radius = 5 Å
*Located in the CDR-H3 Loop
Antigen Binding Region Hinge
region Hinge region
SAP scale
+0.5
-0.5
20
Aggregation propensity of Rituxan® Variants
N° 1 2 3 4 5 6 7
Chain L L L L L H H
Res. # 3 9 10 59 153 178 101
Residue Val Ala Ile Val Leu Leu Tyr
Mut. Gln Ser Ser Ser Asp Ser Ser
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Binding Affinity of Rituxan® Variants
• Binding to CD20: None of the mutations
outside of the function one in the CDR influence
antigen binding Mutation affecting
functionality Frac
tion
Antig
en b
ound
[Ab] (nM)
22
Viscosity ranking of mAbs using SCM
The above dataset includes IgG1, IgG2 and IgG4. Viscosities of 100 mg/ml mAb were measured under
heterogeneous conditions.
0
50
100
150
200
250
300
350
400
0 500 1000 1500 2000 2500
Visc
osity
[mPa
-s]
SCM Prediction
23
Holistic Pharmaceutical Process Development
Discovery Development Manufacturing
Old approach
Discovery incl. Developability,
Manufacturability Development Manufacturing
New approach: break down the barriers
more up front loading of research new technologies
25
Past Current > 2020
Disconnected process steps
Quality by Design
Process steps and their impact understood
Blue Sky Vision: Continuous Manufacturing
Seamlessly integrated and well characterized processes
Road Map for Pharmaceutical Manufacturing Paradigm shifts in manufacturing and quality envisioned
Traditional Manufacturing
26
Our Definition of “Continuous” (ultra QbD)
Flow
Integration (end to end)
Systems approach
Integrated control strategy
“Continuous” = Quality
27
DATA DERIVED FROM TRIAL-N-ERROR EXPERIMENTATION
DECISIONS BASED ON UNIVARIATE APPROACH
MVDA MODELS EMPIRICAL UNDERSTANDING
MECHANISTIC UNDERSTANDING
1st Principles
Process Understanding Pyramid: Understanding Quality
28
Comparing Design Space and Feedback Control (both consistent with Quality by Design) Braatz group
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
• Feedback methods: • Control strategy based on
feedback to a “parameter space”
• Easier to scale up • Design space does not need to
be exhaustively validated a priori
• Necessary for integrated manufacturing
By enabling the manufacturing of higher quality product, feedback control is preferable for real-time release
29
Integrated control implemented on continuous pilot plant
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
30
Integrated control implemented on continuous pilot plant from Richard Braatz and Paul Barton
D2
D1
R2
R1LC LC
M1 M2 S1
C1 C2
W1
LC LC
C3 C4
LC
LC LC
S3S4 W2
M3 M4
M5
S5 S6 E1 CS
CAT
A
B
S2
S1
S3
S1
PU1
PU2
PU4
PU3
S1
S1
S1
C
D
E
S1
EX1
EX2FP
LC
S1
FCsp
FT
FCsp
spsp
sp
FCsp
CC FT
CTFC
FCsp
TC
sp
spsp
FCsp
DCsp
sp
S1RC CC sp
DC
LC
sp
1CATA B I+ ←→
1 2 BPI C I P+ → +
2I E API+ →
First-principles dynamic models were built for each unit operation (UO) as they were developed
Models were validated and then placed into a plant-wide simulation
Plant simulation used to design UO & plantwide control strategy
31
Integrated control implemented on continuous pilot plant from Richard Braatz and Paul Barton
Met all purity specs in Summer 2012
Currently designing controls for a biologic drug manufacturing process (BioMAN)
D2
D1
R2
R1LC LC
M1 M2 S1
C1 C2
W1
LC LC
C3 C4
LC
LC LC
S3S4 W2
M3 M4
M5
S5 S6 E1 CS
CAT
A
B
S2
S1
S3
S1
PU1
PU2
PU4
PU3
S1
S1
S1
C
D
E
S1
EX1
EX2FP
LC
S1
FCsp
FT
FCsp
spsp
sp
FCsp
CC FT
CTFC
FCsp
TC
sp
spsp
FCsp
DCsp
sp
S1RC CC sp
DC
LC
sp
1CATA B I+ ←→
1 2 BPI C I P+ → +
2I E API+ →
33
Focus on New Technologies
Want leaps in improvement, not incremental steps.
Exploit new technological opportunities that come with “Continuous,” while also overcoming new challenges.
Open up mental frameworks for mindset change.
34
Examples of New Continuous Technologies Quality
Chemistry
Crystallization: API on Excipient
Direct Processing to Final Dosage Form
35
Examples of New Continuous Technologies Quality
Chemistry
Crystallization: API on Excipient
Direct Processing to Final Dosage Form
36
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
Pd-Catalyzed Cross-Coupling with Hydrazine in Continuous Flow: Functionalized Heterocycles: Steve Buchwald Group
DeAngelis, A.; Wang, D. H.; Buchwald, S. L. Angew. Chem. Int. Ed. 2013, 52, 3434
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
37
Examples of New Continuous Technologies Quality
Chemistry
Crystallization: API on Excipient
Direct Processing to Final Dosage Form
38
Goal and Challenges
•How can a given substrate be selected for a given API? •How can “secondary nucleation” and other bulk nucleation events be avoided?
39
Challenges
•How can “secondary nucleation” and other bulk nucleation events be avoided?
•Need more gentle stirring. •Need to control supersaturation more carefully.
40
Continuous Fluidized Bed Crystallizer (FBC)
Must set and control very carefully the supersaturation ratio.
41
4 Liter Vessel
3 peristaltic pumps
Nicolet 6700 FTIR
from Thermo Electron
Custom built glass
crystallization column from Ace Glass
ZnSe Dipper 210
Immersion Probe from
Axiom Analytical
• Gentle mixing
• Recycle
• Tight control of concentration
Continuous Fluidized Bed Crystallizer (FBC)
42
Operation of FBC: Quality Control via Model
44
Resulting Crystals
API : Acetaminophen Excipient: D-Mannitol
45
Concentration Profile + Loading Control
Run #1
Run #Ending Temperature
(°C)Starting Concentration
(mg ACE / g EtOH)Excipient Size
(m2/g)Steady State Concentration
(mg ACE / g EtOH)Steady State
SupersaturationDrug
Loading
1 15 196.4 0.0343 176.2 0.024 17.41 12 196.4 0.0343 166.6 0.028 23.5
2 15 196.5 0.0976 175.8 0.021 17.82 12 196.5 0.0976 169.8 0.047 21.7
46
Direct Compression and Friability Testing
• Direct Compression • Needed to add MCC and MgSt • Friability test accepted! (< 1%)
47
Dissolution
0
20
40
60
80
100
0 20 40 60 80
Wei
ght %
Dis
solv
ed
TIme (minutes)
Criteria: Not less than 80% of Acetaminophen is dissolved in 30 minutes: Passed!
48
Examples of New Continuous Technologies Quality
Chemistry
Crystallization: API on Excipient
Direct Processing to Final Dosage Form
49
Controlling API nucleation by tuning the nanopore shape in polymer excipients
No pore 15nm 40nm 120nm 300nm The scale bar is 200nm
Polymer surfaces with nanopores of various shapes and sizes were fabricated by Nanoparticle Imprint Lithography (NpIL), as well as Nanoimprint lithography (NIL)
50
Growth direction
100nm
Pores with crystals
(011
)
(100)
Empty pores
Control of Morphology and Polymorph + Processing
Scale bar is 100nm Why not (002) & (100)?
Crystal orientation verified by XRD
51
From Films to Tablets: Equipment with IMA
52
Electrospinning of Drug and Excipient
Dissolve drug and polymer in solvent
1) 2) Electrospin to produce fibers
3) Process mat into tablets
54
Nano-Crystallization in Emulsions in Hydrogel Particles (Prof. Pat Doyle)
Eral et. al. Crystal Growth & Design, 14, 2073 (2014)
Hydrated Particles Dried Particles Light Microscopy SEM of Nano-crystals
Direct Compression
CaCl2 recycle
56
Holistic Pharmaceutical Process Development
Discovery Development Manufacturing
Old approach
Discovery incl. Developability,
Manufacturability Development Manufacturing
New approach: break down the barriers
more up front loading of research new technologies
58
Automated screening and optimization with discrete variables : Klavs Jensen group
Brandon Reizman
Online HPLC Analysis
Reagent A Reagent B Reagent C Online
Reacted Slugs Mixing Zone Reactor
Real-time Feedback Algorithm
Inert Carrier Phase
Manipulation of Discrete and
Continuous Variables
Choose New Expts that Minimize
Uncertainty in Optimum x3
x2 x1
xk
xl
yp
f(x,y)
Construct Discrete Variable
Response Surfaces
x* Optimal
Experiment
Initialize with Standard Design of Expts
x3
x2
x1
59
Traditional optimization treats discrete and continuous variables separately: Klavs Jensen group
But this is problematic when discrete and continuous variables interact
With the one-variable-at-a-time approach, a screen at low T would miss identifying B as the better discrete variable With enumeration, we may waste many
experiments resolving the maximum for B
T
Yiel
d
A
B
Screen Here?
x1 x3
x2 One variable at a time…
y2
y1
Enumerate everything!
For continuous variables For discrete variables
60
Automated screening platform with feedback: Klavs Jensen group
Choose New Expts that Minimize
Uncertainty in Optimum x3
x2 x1
xk
x
yp
f(x,y)
Construct Discrete Variable
Response Surfaces
x* Optimal
Experiment
Initialize with Standard Design of Expts
x3
x2
x1
66
Suzuki-Miyaura cross-coupling optimization in presence of unstable boronic acid and product: Jensen group
+2 equiv DBU in THF
Palladacycle-Ligand?
T = 30oC-110oCtres = 1 min-10 min
1.5 equivN N
Loading = 0.5%-2.5%
5:1 THF:H2O
B(OH)2
BocN
Cl
BocN
Catalyst Max Yield* Optimal TON Symbol XPhos OMs 99% 88.7 SPhos OMs 95% 65.0 RuPhos OMs 90% 61.7 XPhos Cl 88% 42.2 XantPhos OMs 73% 29.0 PCy3 OMs 54% 31.7 PPh3 OMs 34% 18.7 PtBu3 OMs 27% 15.6
Optimum TON Conditions 1.0% XPhos OMs T = 97ºC tres = 4.7 min TON = 88.7 Yield* = 90%
0
200
400
600
0.51
1.52
2.53
40
60
80
100
120
tres (s)
Loading (mol%)
T (o C
)
0
20
40
60
80
100
120
TON *-Based on aryl halide conversion
Engaging the Broader Community
69
CM Meeting at MIT—May 20-21, 2014 Next meeting September, 2016
70
International Symposium on Continuous Manufacturing of Pharmaceuticals
~200 Attendees from Industry, Regulatory (FDA, EMA), Academia, Equipment Vendors
8 White Papers Presented—Audience/Panel Discussion
Published in J. Pharm. Sci, March, 2015
Keynote address: Janet Woodcock, Head of CDER, FDA
71
Drug Making Breaks Away From Its Old Ways ‘Continuous-Manufacturing’ Process Can Improve Quality Control, Speed Output
By Jonathan D. Rockoff Feb. 8, 2015 8:07 p.m. ET For decades, drug makers have used cutting-edge science to discover medicines but have manufactured them using techniques dating to the days of the steam engine….
72
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Acknowledgements
Novartis Pharmaceuticals, esp. Markus Krumme
MedImmune
Pfizer
Singapore-MIT Alliance
Colleagues at MIT, esp. Allan Myerson, and around the world
Students, Post-docs, and Researchers….
74
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