FDA Pqri 5 Oct 2015-Trout

8/16/2019 FDA Pqri 5 Oct 2015-Trout

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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 ChemicalEngineering, MIT

Director, Novartis-MIT Center for Continuous Manufacturing

New Technologies for Holistic PharmaceuticalCreation


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Current State


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Current State

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://www.nordmark-pharma.de/en/company/milestones.html&ei=yEvqVJiAM4yZgwTzsICwAQ&psig=AFQjCNG8pFCGApR6Azf_vOZgHLmB63ziTw&ust=1424727321057335


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Compare with the 1950’s

1950’s Today

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://www.nordmark-pharma.de/en/company/milestones.html&ei=yEvqVJiAM4yZgwTzsICwAQ&psig=AFQjCNG8pFCGApR6Azf_vOZgHLmB63ziTw&ust=1424727321057335http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://www.nordmark-pharma.de/en/company/milestones.html&ei=yEvqVJiAM4yZgwTzsICwAQ&psig=AFQjCNG8pFCGApR6Azf_vOZgHLmB63ziTw&ust=1424727321057335


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Compare with Automotive industry

1950’s Today


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Pharmaceutical Products

Discovery Development Manufacturing

Current approach


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Product Development: Compare with theElectronics Industry

Need to develop product and process together!


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Holistic Pharmaceutical Process Development


Old approach

Discovery incl.Developability,

ManufacturabilityDevelopment Manufacturing

New approach: break down the barriers

more up front loading of research new technologies


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Aggregation Is a Major Quality Issue:Development

Often highconcentrations aredesired, 200 mg/ml+.

Desired shelf life 1-2years.


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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 dueto high fermentation titer and elevated

temperatures

Harsh elution and viral inactivationconditions can induce extensive

soluble/insoluble aggregation formation

Aggregates place an enormous burden ondownstream purification steps due toclogging and separation difficulties

Formulation development is a costly andtime consuming task, address aggregation

Product can have a relatively short shelflife if high concentrations are required

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

Aggregation Is a Major Quality Issue:Manufacturing


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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 from40% to 75%

Most product loss occursduring cell culture harvest

(Steps 1-3)• Yield can be improved if

product does not form insolubleaggregates

Downstream purification(Steps 6-7) yields andcosts can be improved ifaggregation is kept at aminimum during prior steps

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

Aggregation Is a Major Quality Issue:Manufacturing


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Development and Manufacturing Issues: AddressDuring Discovery!

Protein aggregation is the most common and mostproblematic 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.


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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.


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SAP identifies exposed hydrophobic patches

•

RED regions are highly hydrophobic dynamically exposed patches• BLUE regions are highly hydrophilic dynamically exposed patches

Hydrophobic

Hydrophilic

SAP scaleSAP scaleHydrophobicity scale

SAPat

R=5Å

SAPat

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.


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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

L235Mutational

sites

engineered

-0.5


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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 °CConcentration = 150mg/mL20 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 Liquid10 mg/mL

650 mg / week IVinfusion

Herceptin(Genentech)

2015 $1.4B Solid21 mg/mL

140-420 mg /1-3 weeks

IVinfusion

Avastin(Genentech)


700 mg / 2weeks

IVinfusion

Erbitux (Bristol-Myers Squibb)


430 mg / week IVinfusion

Rituxan, Avastin, Herceptin, and Erbitux have been selected astargets based on their current formulation, and delivery routes,their high SAP values, and their patent expiry date.


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Application of SAP Technology to Rituxan®

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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 Hingeregion

Hinge

region

SAP scale

+0.5

-0.5


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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 mutationsoutside of the function one

in the CDR influence

antigen bindingMutationaffecting

functionality F r a c t i o n A n t i g e n b o u n d

[Ab] (nM)


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Viscosity ranking of mAbs using SCM

The above dataset includes IgG1, IgG2 and IgG4.

Viscosities of 100 mg/ml mAb were measured underheterogeneous conditions.

0

50

100

150

200

250

300

350

400

0 500 1000 1500 2000 2500

V i s c o s i t y [ m P a - s ]

SCM Prediction


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Old approach

Discovery incl.

Developability,Manufacturability

Development Manufacturing




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Past Current > 2020

Disconnected process steps

Quality by Design

Process steps and theirimpact understood

Blue Sky Vision:Continuous Manufacturing

Seamlessly integrated andwell characterizedprocesses

Road Map for Pharmaceutical ManufacturingParadigm shifts in manufacturing and quality envisioned

Traditional

Manufacturing


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Our Definition of “Continuous” (ultra QbD)

Flow

Integration (end to end)

Systems approach

Integrated control strategy

“Continuous” = Quality


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DATA DERIVED FROMTRIAL-N-ERROR EXPERIMENTATION

DECISIONS BASED ON

UNIVARIATE APPROACH

MVDA MODELSEMPIRICAL UNDERSTANDING

MECHANISTICUNDERSTANDING

1stPrinciples

Process Understanding Pyramid:Understanding Quality

C S C


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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 pharmaceuticalmanufacturing plant

• Feedback methods:• Control strategy based on

feedback to a “parameterspace”

• Easier to scale up

• Design space does not need tobe exhaustively validated apriori

•

Necessary for integratedmanufacturingBy enabling the manufacturing of higher quality product,

feedback control is preferable for real-time release


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Integrated control implemented on continuous pilotplant

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

I d l i l d i il


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Integrated control implemented on continuous pilotplant from Richard Braatz and Paul Barton

D2

D1

R2

R1LC LC

M1 M2 S1

C1 C2

W1

LC LC

C3 C4

LC

LCLC

S3

S4 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

EX2

FP

LC

S1

FCsp

FT

FCsp

spsp

sp

FCsp

CCFT

CTFC

FCsp

TC

sp

spsp

FCsp

DCsp

sp

S1RC CC

sp

DC

LC

sp

1

CAT A B I + ←→

1 2 BP I C I P + → +

2 I E API + →

First-principles

dynamic modelswere built for eachunit operation (UO)as they weredeveloped

Models werevalidated and thenplaced into a plant-wide simulation

Plant simulationused to design UO &

plantwide controlstrategy

I t t d t l i l t d ti il t


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Integrated control implemented on continuous pilotplant from Richard Braatz and Paul Barton

Met all purity specs

in Summer 2012

Currently designing

controls fora biologic drugmanufacturingprocess (BioMAN)

D2

D1

R2

R1LC LC

M1 M2 S1

C1 C2

W1

LC LC

C3 C4

LC

LCLC

S3

S4 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

EX2

FP

LC

S1

FCsp

FT

FCsp

spsp

sp

FCsp

CCFT

CTFC

FCsp

TC

sp

spsp

FCsp

DCsp

sp

S1RC CC

sp

DC

LC

sp

1

CAT A B I + ←→

1 2 BP I C I P + → +

2 I E API + →


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Focus on New Technologies

Want leaps in improvement, not incremental steps.

Exploit new technological opportunities that comewith “Continuous,” while also overcoming newchallenges.

Open up mental frameworks for mindset change.

Examples of New Continuous Technologies


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Examples of New Continuous Technologies Quality

Chemistry

Crystallization: API on Excipient

Direct Processing to Final Dosage Form



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Chemistry



Pd Catalyzed Cross Coupling with Hydrazine in Continuous


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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 ContinuousFlow: Functionalized Heterocycles: Steve Buchwald Group

DeAngelis, A.; Wang, D. H.; Buchwald, S. L. Angew. Chem. Int. Ed. 2013, 52 , 3434

Safety:

Hydrazine-transition metal orhydrazine-oxidant combinationspresent a significant explosionhazard

Hydrazine is highly toxic

Flow Advantages:

By utilizing continuous flowtechnology, the safety issues are decreased



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Chemistry




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Goal and Challenges

• How can a given substrate be selected for a given API?

• How can “secondary nucleation” and other bulknucleation events be avoided?


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Challenges

• How can “secondarynucleation” and other bulknucleation events be avoided?

•Need more gentlestirring.

•Need to controlsupersaturation morecarefully.


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Continuous Fluidized Bed Crystallizer (FBC)

Must set and control very carefully the supersaturation ratio.


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4 LiterVessel3 peristalticpumps

Nicolet6700 FTIRfrom

ThermoElectron

Custom builtglass

crystallizationcolumn from Ace Glass

ZnSe Dipper210ImmersionProbe from

Axiom Analytical

• Gentle mixing

• Recycle

• Tight control ofconcentration

Continuous Fluidized Bed Crystallizer (FBC)


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Resulting Crystals

API : AcetaminophenExcipient: D-Mannitol


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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 StateSupersaturation

DrugLoading

1 15 196.4 0.0343 176.2 0.024 17.4

1 12 196.4 0.0343 166.6 0.028 23.5

2 15 196.5 0.0976 175.8 0.021 17.8

2 12 196.5 0.0976 169.8 0.047 21.7


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Direct Compression and Friability Testing

• Direct Compression

• Needed to add MCC and MgSt

• Friability test accepted! (< 1%)


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Dissolution

0

20

40

60

80

100

0 20 40 60 80

W e i g h t %

D i s s o l v e d

TIme (minutes)

Criteria: Not less than 80% of Acetaminophen isdissolved in 30 minutes: Passed!



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Chemistry



C t lli API l ti b t i th


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Controlling API nucleation by tuning the nanoporeshape in polymer excipients

No pore 15nm 40nm120nm 300nmThe scale bar is 200nm

Polymer surfaces with nanoporesof various shapes and sizes were

fabricated by Nanoparticle ImprintLithography (NpIL), as well asNanoimprint lithography (NIL)


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From Films to Tablets: Equipment with IMA


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Electrospinning of Drug and Excipient

Dissolve drug andpolymer in solvent

1) 2)Electrospin to producefibers

3)Process mat into tablets

Nano-Crystallization in Emulsions in


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Nano-Crystallization in Emulsions inHydrogel Particles (Prof. Pat Doyle)

Eral et. al. Crystal Growth & Design, 14, 2073 (2014)

Hydrated Particles Dried Particles Light Microscopy SEM ofNano-crystals

Direct Compression

CaCl2 recycle


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Old approach

Discovery incl.

Developability,Manufacturability

Development Manufacturing



Automated screening and optimization with


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Automated screening and optimization withdiscrete variables : Klavs Jensen group

Brandon Reizman

Online HPLC Analysis

Reagent A Reagent B Reagent COnline

Reacted SlugsMixing Zone Reactor

Real-time Feedback

Algorithm

Inert CarrierPhase

Manipulation ofDiscrete andContinuous Variables

Choose New Exptsthat Minimize

Uncertainty in Optimum

x 3

x 2

x 1

xk

xl yp

f(x,y)

ConstructDiscrete Variable

Response Surfaces

x*Optimal

Experiment

Initialize with StandardDesign of Expts

x 3

x 2

x 1

Traditional optimization treats discrete and


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Traditional optimization treats discrete andcontinuous variables separately: Klavs Jensen group

But this is problematic when discrete and continuousvariables interact

With the one-variable-at-a-time approach,a screen at low T would miss identifyingB as the better discrete variable

With enumeration, we may waste manyexperiments resolving the maximum for B

T

Y i e l d

A

B

ScreenHere?

x1x3

x2 Onevariable at

a time…

y2

y1

Enumerate

everything!

For continuous variables For discrete variables


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Suzuki-Miyaura cross-coupling optimization in presence


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Suzuki Miyaura cross coupling optimization in presenceof unstable boronic acid and product: Jensen group

+2 equiv DBU in THF

Palladacycle-Ligand?

T = 30oC-110oC

tres = 1 min-10 min

1.5 equiv

N NLoading = 0.5%-2.5%

5:1 THF:H2O

B(OH)2

BocN

ClBocN

Catalyst Max Yield* Optimal TON SymbolXPhos 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

Pt Bu3 OMs 27% 15.6

Optimum TON

Conditions1.0% XPhos OMsT = 97ºCtres = 4.7 min

TON = 88.7

Yield* = 90%

0

200

400

600

0.5

1

1.5

2

2.5

3

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


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Engaging the Broader Community

CM Meeting at MIT—May 20-21, 2014


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g y , Next meeting September, 2016

International Symposium on Continuous


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International Symposium on ContinuousManufacturing of Pharmaceuticals

~200 Attendees fromIndustry, Regulatory (FDA,EMA), Academia, EquipmentVendors

8 White Papers Presented— Audience/Panel Discussion

Published in J. Pharm. Sci ,March, 2015

Keynote address: JanetWoodcock, Head of CDER,FDA


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Drug Making Breaks Away From Its Old Ways‘Continuous-Manufacturing’ Process Can Improve

Quality Control, Speed Output

By Jonathan D. RockoffFeb. 8, 2015 8:07 p.m. ET

For decades, drug makers have used cutting-edge science to discovermedicines but have manufactured them using techniques dating to the daysof the steam engine….


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Acknowledgements

Novartis Pharmaceuticals, esp. Markus KrummeMedImmune

Pfizer

Singapore-MIT Alliance

Colleagues at MIT, esp. Allan Myerson, and

around the world

Students, Post-docs, and Researchers….


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FDA Pqri 5 Oct 2015-Trout

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