Download Process Redesign of Pharma Synthesis

School of Industrial and Information Engineering
Course 096125 (095857)
Introduction to Green and Sustainable Chemistry
A.A. 2015/2016
Process Redesign of Pharma
Synthesis
Prof. Attilio Citterio
Dipartimento CMIC “Giulio Natta”
http://ISCaMaP.chem.polimi.it/citterio/
Pharmaceutical Industry
• Major commercial sector in EU Region
 Italy is known to have long tradition as medicine chest
• Biotechnology and biochemical synthesis
 Genetic engineering/Fermentation
• Organic synthesis
 Chemical reaction/purification
•
API (Active Pharmaceutical Ingredient)
– The compound within the pill that treats the disease
•
2012, $325.8 Billion sales prescription drugs*
– $112 Billion sales for top 5 drugs classes
•
•
Energy usage is between 50-300 MJ/kg API***
Solvent usage is around 300 kg/kg API****
*Michael Bartholow, PharmD, CACP, 2012_U.S.Medicines_Report.pdf
Attilio Citterio
Top 20 Products of 2012 by Total Dollars
Rank
Product
Manufacturer
Sales ($)
Rank
Product
Manufacturer
Sales ($)
1
Nexium
AstraZeneca
$5,989,000,000
11
Singulair
Merck & Company
$3,300,000,000
2
Abilify
Otsuka America
$5,870,000,000
12
Rituxan
Genentech
$3,197,000,000
3
Crestor
AstraZeneca
$5,092,000,000
13
Plavix
Bristol-Myers
Squibb/sanofiaventis
$2,971,000,000
4
Advair
Diskus
GlaxoSmithKline $4,889,000,000
14
Atripla
Bristol-Myers Squibb
$2,899,000,000
Gilead
5
Cymbalta
Lilly
$4,720,000,000
15
Spiriva
Handihaler
Boehringer
Ingelheim
$2,833,000,000
6
Humira
Abbvie
$4,609,000,000
16
Oxycontin
Purdue Pharma
$2,808,000,000
7
Enbrel
Amgen
$4,337,000,000
17
Januvia
Merck & Company
$2,670,000,000
8
Remicade Centocor
$3,876,000,000
18
Avastin
Genentech
$2,661,000,000
9
Copaxone Teva CNS
$3,581,000,000
19
Lantus
sanofi-aventis
$2,327,000,000
10
Neulasta
$3,460,000,000
20
Truvada
Gilead Sciences
$2,305,000,000
Amgen
Michael Bartholow, PharmD, CACP, 2012_U.S.Medicines_Report.pdf
Attilio Citterio
The Best Selling
Drugs in the Word
2014 Sales in billions
http://qz.com/349929/best-sellingdrugs-in-the-world/
Attilio Citterio
Success Rate of a Pharmaceutical
Compound on Development Stage
Discovery
(2-10 Anni)
Success rate based on
development stage
5000-10.000
tested
Preclinical studies
(lab. test and animals)
Phase I
20-80 voluntary healthy used to
determine efficacy and dose
Phase II
100-300 voluntary patients used to
evaluate efficacy and side effects
Phase III
1000-5000 voluntary patients used to
monitor reactions for long term use
250
Preclinici
Studies
5
Interclinical
studies
Review FDA/
Approval
More
post-commercialization checks
Year
0
2
4
6
IND Filed
8
10
NDA Filed
Attilio Citterio
12
14
16
1
FDA approved
The Changing Landscape of
Development Compliance
Guidance: Using a
Draft Guidance:
Centralized IRB
Process in Multicenter Exception from Informed
Consent Requirements
Trials (3/06)
for Emergency Research
(9/06)
Guidance:
Immunotoxicity Studies
Guidance: ICH Q8 –
for Human
Pharmaceutical
Pharmaceuticals (4/06)
Development (5/06)
Draft Guidance:
Supervisory
Guidance:
Responsibilities of
Computerized Systems
Clinical Investigators (Out
Used in Clinical
for Comment – 5/07)
Investigations (5/07)
Attilio Citterio
Guidance: Establishment
and Operation of Clinical
Trial Data Monitoring
Committees (3/06)
Draft Guidance: Adverse
Event Reporting –
Improving Human Subject
Protection (Out for
Comment – 4/07)
Draft Guidance:
Approaches to
Complying with
CGMP During
Phase I (12/06)
Draft Guidance:
ICH Q10 –
Pharmaceutical
Quality System
(7/07)
The Changing Face of Drugs
Aspirin
Losec
Paracetamol
Active Price : $500/kg
Active price : $5/kg
Attilio Citterio
Breakdown of the World Pharmaceutical
Market (2012 sales)
In EU pharmaceutical trade
Surplus was estimated at
€ 80 BILLION
7,067
76,438
2012
2000
1990
2011
7,067
Attilio Citterio
80,000
The Global Pharmaceutical Market, 2012
Source: M. Buente, S. Danner, S. Weissbäcker, C. Rammé, Booz & Company, 2013.
Attilio Citterio
PORTFOLIO SHUFFLE
of Main Pharmaceutical Industries
Through swaps and divestitures, companies are rationalizing portfolios to focus on fewer
businesses. NOTE: Figures for 2015 are based on pro forma sales estimates, including deals
announced in 2014.
SOURCE: Ernst & Young
Attilio Citterio
Pharmaceutical Trend
 NEW PRODUCT DEVELOPMENT CYCLE EXTENDING
 NEW PRODUCT (NME) LAUNCHES DECREASING
 PATENT EXPIRY OF BLOCK BUSTERS PEAKING (2011-12)
 SHAREHOLDER EXPECTATIONS STILL HIGH
 MANUFACTURING COST INCREASING AND NOW
LARGER THAN RESEARCH & DEVELOPMENT
Attilio Citterio
Primary MFG Trends
 MORE COMPLEX MOLECULES
 PURITY & HYGIENE
 CROSS CONTAMINATION (FDA)
 ENVIRONMENTAL CONTROL (EA/HSE)
COST
ESCALATORS
 PRODUCT STEWARDSHIP (NGO’S)
Manufacturing Issues
•
Batch-based processes
•
Multi-step synthesis, transformations – intermediates
•
Isolations (purification)
•
Extensive use of multiple organic solvents and reagents –
varying degrees of toxicity
•
Limited health data on intermediates
Attilio Citterio
Manufacturing Issues
• Processes – solid/liquid – filtration, drying, etc
• Purity and yield
• 7-11 years between development and manufacture –
Regulatory steps (Phase I-III)
• 10% success rate for new drug development
• Outsourcing process steps
• Once process is approved by FDA,
any changes are hard to implement
Attilio Citterio
Drug Development Process: Clinical Phases
Following animal studies, compounds are tested in human
populations:
PHASE
I
DETAILS




Safety and tolerance of drug
Pharmacokinetics parameters
ADME: Adsorption, Distribution, Metabolism, & Excretion
Small population of healthy, paid volunteers
IIa
 Proof of concept
 Final decision on formulation
 Tens of patients
IIb
 Determination of active dose
 Double blind trials vs. comparators
 Hundreds of patients
IIIa
 Efficacy (1 dose) on limited number of indications vs. one comparator
 Thousands of patients (2,000 – 10,000)
IIIb
 Extension of indications (e.g., quality of life, comparison to other
marketed therapeutics)
IV
 Long-term safety and efficacy of launched product
Attilio Citterio
Drug Development Process: 5-7 Years
Between Project Start and Launch
48 months
*NCE
Approval
CLINICAL
PRE-CLINICAL
9 months
8 months
*FDA
Launch
submission
*IND filing
*NDA
8 months
9 months
23 months
15 months
Total
72 months
Phase I
Phase IIa
Phase IIb
Phase III
Phase III (continued)
FDA
pai
*PAI: Pre Approval Inspection
NDA
FILIMG
*IND: Investigational New Drug
*NCE: New Chemical Entity
Attilio Citterio
*FDA: Federal Drug Administration
*NDA: New Drug Application
Number of Trials and Development Time of
New Drugs
70
60
50
N° of 40
trials
30
20
10
0
Development time
(years)
1977-80
1981-84
1985-88
1989-92
1993-95
14.2
16
11.6
14
2,2
2,8
12
8.1
2,1
10
8
14.9
6,7
5,5
2,4
4,4
6
4
2
0
2,5
5,1
1960
1970
Preclinical phase
Attilio Citterio
6
5,9
3,2
1980
Clinical phase
1990-1996
Approval phase
Chemical Engineering: Adjustment





Significant shift from
traditional intensive capital
base chemicals
Stronger emphasis on
specialty materials at high
added value
Critical importance of a
development of more
sustainable chemical process
Growing of concepts of
engineered product
in the frame of chemical
engineering practice
Green Engineering
Attilio Citterio
Typical Biological (Antibody) Process
Attilio Citterio
Design in Chemical Engineering
Key role
Chemical process
design
Optimization of
process conditions
Yield of
chemical products
Critical
issues
SHE
Environment
Safety
Health
Attilio Citterio
Pharma Engineering
 EXOTIC MATERIALS
 SOPHISTICATED CONTROL
 AIR HANDLING & CONTAINMENT
 CONNECTIVITY & FLEXIBILITY
 MULTI - FUNCTIONALITY
Attilio Citterio
COST
ESCALATORS
Typical Flow Chart
H EAD ER
H EAT EXC H ANG ER
SOLVEN T
AZEO TRO PE
SOLIDS
VESSEL
W ET C AKE
FILTER
D RIER
W ET C AKE
R EC EIVER
R EC EIVER
R EC EIVER
PR O D UC T
FLO W SHEET
TYPIC AL BATC H R EAC TIO N / ISO LATION / DR YING
R EVISIO N D ETAILS SH O W N
O N SEPAR ATE R EV. SH EET
D R AW N BY
O R IG IN ATO R
Attilio Citterio
PR O JEC T N o.
SC ALE
D R G .N o.
SHT.N o.
R EV
D ATE
Batch Technology
OFF
GASES (OG)
REACTANTS (R)
PRODUCT (P)
REAGENTS/DILUENTS (RD)
P
RD + R
WASTE (W)
~ 1%
1.
OPTIMISE FOR TOTAL MASS BALANCE – NOT KEY REACTANT
2.
CHANGE IMPROVE REACTOR DESIGN – SELECTIVITY/RATE/YIELD
SEPARATION, ANALYSIS
I.E. SWEAT THE PROCESS
Attilio Citterio
Lead Times
ASSEMBLE
MAKE
MOVE
GOODS
INWARD
MOVE
MOVE
STORES
QUEUE
DELEY
MOVE
DELEY
DELAY
PACK
RIUNIUNIONE
PARZIALE
TOTAL ELAPSED TIME
VELOCITY RATIO = SPEED AT WHICH MATERIAL MOVES
VR =
SOM OF VALUE ADDS
TOTAL ELAPSED TIME
Attilio Citterio
~ 1%
SHIP
Potential Ways Forward
UNIT OPERATIONS APPROACH:
 REACTOR DESIGN - MUCH MORE INTENSIVE (Heat & Mass
Transfer Controlled)
 PRODUCTS DESIGN - Regio- and Stereo-specificity to
improve
- Manage morphology
 PURIFICATION
- Speed & precision
 SEPARATION
- Speed & precision
SYSTEM INTEGRATION:
 Synchronise Unit Operation System
 Optimise Process for Minimum Total Mass Balance, not
Maximise Yield of Key Reactant.
Attilio Citterio
How to Improve
PROCESS INTENSIFICATION/CATALYSTS
•
COST ENGINEERING
UNIT OP DRIVEN, NOT UNIT PROCESS
•
STANDARDISATION/PLUG IN – PLUG OUT
•
HIGHER VELOCITY
•
HIGHER PRODUCTIVITY
•
LOWER CAPEX INTENSITY
Sequence Selection
Route Selection
Recipe Development
Pilot Scale-up
Trail Production
Regulatory
Compliance
Site Evaluation
MULTI DISCIPLINARY COLLISIONS
Industrial Scale-up
and Tech Transfer
Industrial Production
Attilio Citterio
Clinical Phase
EHS Study
Post-Approval
•
Process Development
Preclinical Phase
•
Green Engineering Opportunities
• Investigate process early in development
• Solvent substitution – more benign solvents
• Solvent reduction
• Novel processes for material reuse/recovery
• Reduction in process steps
 “Telescoping” to eliminate intermediate isolations
 Challenge - maintain drug purity
and yield
Attilio Citterio
Green Engineering Needs
 Metrics to measure and
quantify – more than just
amount reduced
 Materials
 Mass intensity – amount
of raw material needed to
produce 1 kg of API
 Solvent intensity
 Waste intensity
 Water intensity




Emissions
Efficiency
Energy
Quantify broader
environmental impact
Attilio Citterio
250
Mass Intensity (kg/kg API)
quantify improvements
 What to measure, how to
200
150
100
50
0
Lab
Pilot
Production Scale
Full
Example: Redesign Sertraline Process
Sertraline: active component in Zoloft
Combined process:
•
•
•
•
Doubling up the yield
Substitution of CH2Cl2, THF, toluene and hexane with Ethanol
Eliminazione of 140 ton/year of TiCl4 use
Elimination of 150 ton/year of 35% HCl
NHMe
Cl
Pfizer
Cl
Attilio Citterio
Redesign Sertraline Process
HCl
EtOH
"imine"
isolated
MeNH2
EtOH
EtOAc
D-mandelic Ac.
Pd/C, H2
TiCl4/ MeNH2
Toluene/hexane
THF
- TiO2
- MeNH3Cl
+ H2O
EtOAc
D-mandelic Ac.
Pd/C/CaCO3,
HCl
EtOH
MeOH res
H2, EtOH
"imine"
not isolated
Sertraline
final product
isolated
Sertraline Mandelate
isolated
racemic mixture
not isolated
Attilio Citterio
Sertraline Mandelate
isolated
Sertraline
final product
isolated
Efficiency of “Carbon Frame” in the
Sertraline Synthesis
IX
O
O
3
Cl
Cl
+
O
O
IV
XI
X
O
OH
OH
CO2H
O
O
Benzene
O
O
Cl
Cl
Cl
Cl
Cl
Cl
T-S
Yield=33%
Cl
Cl
SOCl2/
AlCl3
Tetralone Yield=37%
VI
NCH3
O
VII
VIII
NCH3
NCH3
V
Separation
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Racemic mixture :
cis(+,-) e trans(+,-)
Total Yield =12.2%
T
Toluene
SMB
EtOH
THF
Attilio Citterio
S
Improvement of 10% in the Efficiency of
Carbon Use
•
Inside the Company (kg/kg Sertraline):
97
•
96
1 (most wastes are solvents)
In overall Pharma Complex (kg/kg Sertraline)
39,098
35,794
3,304
Impact more 3,000-times higher!
Attilio Citterio
Efficiency in the Use of Solvents (V → VI)
THF
Naphthalenone
Mixing
46
TiCl4
CH3NH2
0°C
Cooling.
1-5°C 47
Reaction,
Stir and
Cool <10°C
Adding
48
49
THF
Stirring
17 h, N2
50
THF
Filtration
aq/Washing
52
Naphthalenamine
51
TiO2 “panel"
THF
NCH3
O
+ Chemical Loss + Solvent
+ Reagents + Solvent
Cl
Cl
Vacuum
V
Cl
Cl
Attilio Citterio
VI
Improvement of 10% in the Use of Solvents
•
Inside the Company (kg.kg Sertraline)
97
•
89
8
Inside the Pharma Complex (kg/kg Sertraline)
39,098
38,493
605
The effect is higher inside the Society, but higher impact is out of
Society.
Attilio Citterio
Redesign of Sertraline Process
OH
O
CCl
Cl
Cl
+
+
Cl
Cl
AlCl3
O
C
Cl
Cl
CO2Et
t-BuOK
2 equiv. AlCl3
CO2Et
H2O
HBr/AcOH
H2C
CO2Et
CH
C
Cl
Cl
H2, Pd/C
EtO2C
H2
C
CH2
CH
(1) CH3NH2
O
Cl
Cl
SOCl2
(2) H2, Pd/C
Cl
Cl
Attilio Citterio
CH3
(3)-(5) sep. racemo HN
Cl
Cl
Alternative for TamifluTM (Oseltamivir
Phosphate)
• Synthesis of allyl amine without Azide
O
COOEt
O
COOEt
H2N
O
HN
• Diels-Alder Synthesis from Furan
O
COOEt
O +
EtO P
H
N
O
COOEt
EtO
AcHN
O
NH2 H3PO4
• Elaboration of Aromatic ring: meso approach
O
OH
HO
O
O
HO
COOEt
COOEt
COOH
Attilio Citterio
Redesign of a NCS Compund:
Benzodiazepine Synthesis
p-NO2-PhCHO
Z. rouxii, XAD-7 resin
HCl
H2NNHAc
 Improved synthesis
of an active drug for
nervous central
system.
air, NaOH, DMSO
MsCl, Et3N
1. NaOH, EtOH
2. KO2CH, Pd/C
For each 100 kg of product were eliminated:
• 300 kg of chromium wastes
• 34,000 liters of solvents
Attilio Citterio
 Interdisciplinar
approach, which
combine chemistry,
microbiology and
engineerig.
Eli Lilly and Company
Chemical & Biocatalytic Routes to QCA
Na2S2O4/H2O
Chemical Route
EtOH

di- N -oxide

aq. HCl
3 steps, 35% yield
Di-N-oxide: mutagenic
& high energy intermediate
35% H 2O 2
10% NaOH
QCA
Pseudomonas putida
whole cells
(COOH)2
Biocatalytic Route


1 step (3 enzyme reactions),
86% yield
Aqueous reaction at 28°C
2-Methylquinoxaline
Attilio Citterio
Quinoxaline
Chemical & Biocatalytic Process
Comparison
Raw materials for 1 kg QCA
Chemical Process
P. putida Process
0.97 kg
2.9 L
6.5 L
2-methylquinoxaline
benzyl alcohol
p -xylene
4N HCl
13.6 L
4N HCl
3.8 L
10% NaOH
11.7 L
10% NaOH
1.7 L
chloroform
142 L
inorganic salts
0.75 kg
N ,N -dimethylacetamide
ethanol
36 L
18 L
trace elements
H2O
0.005 kg
79 L


di-N -oxide
Na 2S2O4
3.9 kg
5.7 kg
35% H2O2
0.9 L
Biocatalytic route avoids hazardous di-N-oxide and uses 4x less starting
material
Reduced organic solvent consumption for biocatalytic route (3.8 L/kg
QCA) vs. chemical process (196 L/kg QCA). N.B.: CHCl3 induce cancer.
Attilio Citterio
Sildenafil Route Selection
O
O
HO
O2 N
O
EtO H N
Pr
Me
N
N
ClSO3H
Quench
O
SnCl 2 / HCl
Me
N
N
H 2N
H 2N
Pr
Pr
O
Me
N
EtO H N
N-methylpiperazine
N
N
Pr
N
N
O
ArCOCl
pyridine
Me
N
N
N
O2 S
O
Me
SOCl 2 / Toluene
N
H 2N
N
NH3
O2 N
Pr
NaOH /H2O2
EtO
H 2N
Me
N
N
CONH
EtOH
Pr
Me
Linear Synthesis (no convergency)
Poor from an environmental perspective
Late Stage Chlorosulphonation generates
a lot of aqueous waste, difficult to scale-up.
Tin Chloride Reduction Step
Usual Challenging Solvents (e.g. pyridine)
Pfizer
Attilio Citterio
Sildenafil Route Selection
clean
Four Steps
cyclisation
reaction
Potentially toxic
SILDENAFIL
Materials
M edicinal Chemistry Route: The clean reaction is in the middle of the synthesis
The potentially toxic materials are in the final step.
Four Steps
clean
cyclisation
Potentially toxic
SILDENAFIL
reaction
Materials
Commercial Route: The synthesis was redesigned to introduce convergency
The clean reaction is in the final step.
Attilio Citterio
Late Synthetic Stages
O
H 2N
O2 N
Me
N
N
H2 Pd/C
EtOAc
O
Pr
N
H 2N
EtO
N
CONH
Pr
OEt
EtOAc
96 %
CO2 H
O2 S
N
Base
N
N
Pr
EtOH
O2 S
N
N
N
Me
Me
CDI
EtOAc
N
N
Me
OEt H N
95 %
N
O2 S
O
Me
Me
Use of ethyl acetate in all three reactions, hydrogenation, activation, acylation leads
to an easy solvent recovery by distillation and clean environmental profile.
Final step is run very concentrated hence very little organic waste.
High yields late in the synthesis reduce the environmental impact of early steps
Attilio Citterio
Alternative in Friedel-Craft
Traditional reagents in Friedel-Crafts reactions:
Lewis Acid: aluminum chloride, tin(IV) chloride, boron trifluoride
Solvents: aromatic hydrocarbons, nitrobenzene, carbon disulfide,
methylene chloride
Lewis Acid
RCOCl
h, Sensit.
RCHO
• Photochemical acylation of benzoquinone with benzaldehyde
Attilio Citterio
Photochemical Alternative in Friedel-Crafts
O
N
N
Ph
O
Diazepam
Cl
OH
COOH
COR
hν
Ibuprofen
RCHO
O
OH
O
Doxepin
N
Attilio Citterio
Other Fotochemical Applications
CH3CHO
Ag2O
Ph2CHO
hν
CAN
Et3SiH
BF3
Kraus, Iowa State
Attilio Citterio
Applications in Farma Field
Traditional synthesis of Progesterone
 Great use of EDC, relevant volumes of acqueous and orgenic
wastes
Soja steroids
1. Oppenauer oxidation
15% used
2. Ozonolysis
stigmasterol
corticosteroids
bisnoraldehyde
progesteron
Pharmacia - Upjon
Attilio Citterio
Alternative Synthesis of Progesteron
• 89% less organic not recovered wastes,
• 79% less aqueous wastes
Soja steroids
4-idroxy-TEMPO
100% used
NaOCl, NaHCO3, KBr
bisnoralcohol
corticosteroids
bisnoraldehyde
progesteron
Attilio Citterio
Pharma Applications
Cytovene
 antiviral agent used in treatment of retinitis infections by
cytomegalovirus (CMV)
 Patients with Aids and with transplant of solid tissues
Improved synthesis:
 reduced chemical process stages from 6 to 2
 reduced the number of reagents and intermediates from 22 to 11
 eliminated 1.12 millions kg/year of liquid wastes
 eliminated 25,300 kg/year of solid wastes
 overall increase of yield: 25%
O
H
RHN
N
N
N
N
O
Ganciclovir
(Cytovene)
Attilio Citterio
OH OH
Pharma Applications
GTE Process – Cytovene Synthesis
1. HMDS, HOTf
2.
3. (EtCO)2, DMAP
4. MeOH, toluene
R = COEt
NH4OH
MeOH
Ganciclovir
(Cytovene)
Roche Colorado Corp.
Attilio Citterio
Pharma Applications
(+)-Citreoviridin Synthesis
 ATP synthase inhibitor
+ CO2
(3 atm)
dppp, (dba)3Pd2 CHCl3
THF, rt
Trost, Stanford University
Attilio Citterio
Pharma Applications
Trans-β-lactams synthesis through microwave induced
organic reactions (intermediate in the synthesis of Taxol/Taxotere)
irradiation with
microwave
high power
Bose, Stevens Institute of Technology
Attilio Citterio
Applications via Combined Methodologies
Tandem synthetic methods assistes by enzymes and electrochemistry
Conduritol C Synthesis:
1. E. Coli pDTG601
e-
2 Aceton
H2O
4 steps
eH2O/ H+
17 steps
(Hudlicky, University of Florida)
Attilio Citterio
Enzyme use for chiral compounds:
Synthesis of Pregabalin
Research-scale synthesis
1. LDA
2. BrCH2CO2R
Pregabalin
Final manufacture-scale synthesis
Lipase
Pregabalin
The savings come about because efficient syntheses that avoid exotic reagents, minimise
energy use and replace organic solvents with water are invariably cheaper to perform.
Attilio Citterio