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New Technologies for Holistic Pharmaceutical

Creation

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

Current State

Current State

Compare with the 1950s

1950s
4

Today

Compare with Automotive industry

1950s

Today

Pharmaceutical Products
Current approach
Discovery

Development

Manufacturing

Product Development: Compare with the


Electronics Industry

Need to develop product and process together!

Holistic Pharmaceutical Process Development


Old approach
Discovery

Development

Manufacturing

New approach: break down the barriers


Discovery incl.
Developability,
Manufacturability

Development

Manufacturing

more up front loading of research new technologies


9

Aggregation Is a Major Quality Issue:


Development
Often high

concentrations are
desired, 200 mg/ml+.

Desired shelf life 1-2


years.

10

Aggregation Is a Major Quality Issue:


Manufacturing
Cell Culture Harvest
Protein A Capture
Low-pH Viral Inactivation
Polishing Step(s)
Viral Filtration

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

Formulation development is a costly and


time consuming task, address aggregation

Fill/Finish

Product can have a relatively short shelf


life if high concentrations are required

Gottschalk, U., ed. Process Scale Purification of Antibodies. 2009


11

11

Aggregation Is a Major Quality Issue:


Manufacturing
Step

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%

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
9
UF/DF
98%
52%
aggregation is kept at a
10
Steril Filtration
98%
51%
minimum during prior steps
Gottschalk, U., ed. Process Scale Purification of Antibodies. 2009
8

12

Viral Filtration

98%

54%

12

Development and Manufacturing Issues: Address


During Discovery!
Protein aggregation is the most common and most
problematic form of protein degradation
storage

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

Hydrophobic-hydrophobic interactions drive aggregation

Develop methodology to detect and engineer out.


13

Hydrophobicity scale mapped onto antibody structure


There are many hydrophobic residues that are exposed

Hydrophobicity scale
Hydrophobic
Hydrophilic

There are many exposed hydrophobic residues on the protein surface.


14

SAP identifies exposed hydrophobic patches


RED regions are highly hydrophobic dynamically exposed patches
BLUE regions are highly hydrophilic dynamically exposed patches
SAP
at
R=10

SAP
at
R=5
Hydrophobicity scale

SAP scale

SAP scale

Hydrophobic

+0.5

+0.5

Hydrophilic

-0.5

-0.5

RED regions are highly hydrophobic dynamically exposed patches.


BLUE regions are highly hydrophilic dynamically exposed patches.

15

Mutation of SAP predicted aggregation prone regions


variants generated
A1: L235K
A2: I253K
A3: L309K
Mutational
sites
engineered

L234
L235
L309
I253

SAP
scale
+0.5

A4: L235K L309K


A5:L234K L235K

-0.5

4 sites with high SAP values selected for mutations.


These sites are mutated to more hydrophilic residues.
16

Validation of SAP Technology


Reduction in aggregation was measured by SEC-HPLC
All mutants lead to decrease in aggregation
Temperature = 58 C
Concentration = 150
mg/mL
20 mM His buffer

A1: L235K
A2: I253K
A3: L309K
A4: L235K L309K
A5: L234K L235K
Chennamsetty, N. et al., PNAS 2009.
17

Create Biobetters with Enhanced Stabilities


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 (BristolMyers 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.
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18

Application of SAP Technology to Rituxan


Spatial Aggregation Propensity Study of Rituxan

Rituxan Fab region with aggregation hotspots in Red


Front

Back
Y101H*

Probe Radius = 5
*Located in the CDR-H3 Loop

L178H

Y101H*
Antigen
Binding
Region

Hinge
region

V59L

SAP scale

Hinge
region

V3L

A9L & I10L

+0.5

L153L

-0.5

19

19

Aggregation propensity of Rituxan Variants

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 Affinity of Rituxan Variants

Fraction Antigen bound

Binding to CD20:

Mutation
affecting
functionality

[Ab] (nM)

21

None of the mutations


outside of the function one
in the CDR influence
antigen binding

Viscosity ranking of mAbs using SCM


400
350

Viscosity [mPa-s]

300
250
200
150
100
50
0

500

1000

1500

2000

2500

SCM Prediction

The above dataset includes IgG1, IgG2 and IgG4.


Viscosities of 100 mg/ml mAb were measured under
heterogeneous conditions.

22

Holistic Pharmaceutical Process Development


Old approach
Discovery

Development

Manufacturing

New approach: break down the barriers


Discovery incl.
Developability,
Manufacturability

Development

Manufacturing

more up front loading of research new technologies


23

Road Map for Pharmaceutical Manufacturing


Paradigm shifts in manufacturing and quality envisioned

Blue Sky Vision:


Continuous Manufacturing
Quality by Design
Traditional
Manufacturing

Disconnected process steps

Past
25

Process steps and their


impact understood

Current

Seamlessly integrated and


well characterized
processes

> 2020

Our Definition of Continuous (ultra QbD)


Flow
Integration (end to end)
Systems approach
Integrated control strategy
Continuous = Quality
26

Process Understanding Pyramid:


Understanding Quality
1st
Principles

MECHANISTIC
UNDERSTANDING
MVDA MODELS
EMPIRICAL UNDERSTANDING

DECISIONS BASED ON
UNIVARIATE APPROACH
DATA DERIVED FROM
TRIAL-N-ERROR EXPERIMENTATION
27

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
28

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
By enabling the manufacturing of Necessary
higher quality
product,
for integrated
manufacturing
feedback control is preferable for
real-time release

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
29

Integrated control implemented on continuous pilot


plant from Richard Braatz and Paul Barton
CAT
sp

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

validated and then


placed into a plantwide simulation

Plant simulation

used to design UO &


plantwide control
strategy

Integrated control implemented on continuous pilot


plant from Richard Braatz and Paul Barton
CAT
sp

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

Met all purity specs

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)

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.


33

Examples of New Continuous Technologies


Quality
Chemistry
Crystallization: API on Excipient
Direct Processing to Final Dosage Form

34

Examples of New Continuous Technologies


Quality
Chemistry
Crystallization: API on Excipient
Direct Processing to Final Dosage Form

35

Pd-Catalyzed Cross-Coupling with Hydrazine in Continuous


Flow: Functionalized Heterocycles: Steve Buchwald Group

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

Examples of New Continuous Technologies


Quality
Chemistry
Crystallization: API on Excipient
Direct Processing to Final Dosage Form

37

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?
38

Challenges
How can secondary
nucleation and other bulk
nucleation events be avoided?

Need more gentle


stirring.
Need to control
supersaturation more
carefully.
39

Continuous Fluidized Bed Crystallizer (FBC)

Must set and control very carefully the supersaturation ratio.


40

Continuous Fluidized Bed Crystallizer (FBC)


Custom built
glass
crystallization
column from
Ace Glass
ZnSe Dipper
210
Immersion
Probe from
Axiom
Analytical
Nicolet
6700 FTIR
from
Thermo
Electron
41

3 peristaltic
pumps

4 Liter
Vessel

Gentle mixing
Recycle
Tight control of
concentration

Operation of FBC: Quality Control via Model

42

Resulting Crystals
API : Acetaminophen
Excipient: D-Mannitol

44

Concentration Profile + Loading Control


Run #

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 and Friability Testing

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

Criteria: Not less than 80% of Acetaminophen is


dissolved in 30 minutes: Passed!
47

Examples of New Continuous Technologies


Quality
Chemistry
Crystallization: API on Excipient
Direct Processing to Final Dosage Form

48

Controlling API nucleation by tuning the nanopore


shape in polymer excipients

No pore
The scale bar is 200nm

120nm

15nm

Polymer surfaces with nanopores


of various shapes and sizes were
fabricated by Nanoparticle Imprint
Lithography (NpIL), as well as
Nanoimprint lithography (NIL)

49

300nm

40nm

Control of Morphology and Polymorph + Processing

(011)

Crystal orientation verified by XRD

(100)

Growth
direction

Empty pores

Pores with crystals

100nm

Why not (002) & (100)?


50

Scale bar is 100nm

From Films to Tablets: Equipment with IMA

51

Electrospinning of Drug and Excipient


1)

2)

Dissolve drug and


polymer in solvent

3)

52

Process mat into tablets

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)

Holistic Pharmaceutical Process Development


Old approach
Discovery

Development

Manufacturing

New approach: break down the barriers


Discovery incl.
Developability,
Manufacturability

Development

Manufacturing

more up front loading of research new technologies


56

Automated screening and optimization with


discrete variables : Klavs Jensen group
Reagent A

Reagent B Reagent C
Online

Manipulation of
Discrete and
Continuous Variables

Inert Carrier
Phase

Real-time Feedback
Algorithm

Online HPLC
Analysis
Mixing Zone

Initialize with Standard


Design of Expts

Reactor

Reacted Slugs

Construct
Discrete Variable
Response Surfaces
xk

x3

Choose New Expts


that Minimize
Uncertainty in Optimum
x3

f(x,y)

x*
x2
x1 58

xl

yp

x1

Optimal
Experiment

x2
Brandon Reizman

Traditional optimization treats discrete and


continuous variables separately: Klavs Jensen group
For continuous variables
x2

One
variable at
a time

x1

x3

For discrete variables


y2

Enumerate
everything!

y1

But this is problematic when discrete and continuous


variables
Screen interact
Yield

Here?

59

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

Automated screening platform with feedback:


Klavs Jensen group

Initialize with Standard


Design of Expts

Construct
Discrete Variable
Response Surfaces
xk

x3

Choose New Expts


that Minimize
Uncertainty in Optimum
x3

f(x,y)

x*
60

x2

yp

x1

Optimal
Experiment

x2

Suzuki-Miyaura cross-coupling optimization in presence


of unstable boronic acid and product: Jensen group
N

Cl

Boc
N
B(OH)2
1.5 equiv

2 equiv DBU in THF


5:1 THF:H2O
T = 30oC-110oC
tres = 1 min-10 min

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

*-Based on aryl halide conversion

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

Engaging the Broader Community

CM Meeting at MITMay 20-21, 2014


Next meeting September, 2016

69

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

70

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.

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72

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.


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