Ozonolysis@LONZA - Business Review Webinars

Continuous Flow Technology in Industrial Applications
From lab to ton scale production featuring ozonolysis
Business Review Webinar
Dr. Dominique M. Roberge / November 9, 2011 / Webinar from Visp, Switzerland

Our extensive know-how and offering have
evolved to meet customer needs
Financially Stable / Global Footprint
• CHF 2.7 billion (2010 sales)
• 45 facilities; 11,000+ employees
Focused on Life Sciences
ces
• Bioresearch
• Pharma & Biotech
• Nutrition
• Personal Care
Global leader in custom manufacturing
• Chemical and biological APIs, cell therapy
• Lead optimization through market supply
10-Nov-11
slide 2

•Our Visp, Switzerland site is home to
numerous cutting-edge technologies
Location
• 150km east of Geneva
• Footprint: t 90 hectares
Fine Chemistry in Visp
• Cracker for C2 supply
• Continuously operating
production (e.g. Niacin)
• R&D, process development,
small-scale production, and
fine chemical complex FCC
for pharma production
• Large fermentation units
Some key technologies
• Large-Scale (10 m 3 ; total over 400 m 3 ),
cGMP
• cGMP phosgene plant
• cGMP Continuous Ozonolysis
10-Nov-11
slide 3

Lonza Niacin
• Continuous process from feed
preparation to packaging
• Manufactured under
cGMP conditions
• One dedicated facility in Visp,
Switzerland
• Thousand of tons per year
O
HNO 3
OH
N
MEP
N
Niacin
10-Nov-11
slide 4

Pharma Production Campaign
Production Duration Productivity Yield Unit operations Unit operations
[t/a] [t/d] [%] reaction workup
44 4-8 weeks 1.5 77 2.1 2.7
Batch processes are:
• Versatile (can deal with various phases: solid-liquid-gas; liquid and
downstream operations: distillation, extraction…).
• Flexible (can accommodate various reaction kinetics);
Continuous processes are:
• Efficient (bulk chemical industry).
You need a combination of both Toolbox concept
10-Nov-11
slide 5

The Toolbox Concept: Modular Approach
This a fundamental change in production strategy for the pharma
and fine chemical industries.
The toolbox concept enables to adapt a production unit to a
chemical system.
The ‘toolbox’ concept must be based on physical-chemical
characteristics of the reaction such as:
‣ Take into account the various kinetics and residence times.
‣ The reaction phases (liquid–solid–gas).
‣ Integration of mixing and heat exchange capabilities.
‣ Avoiding dead volumes cGMP.
10-Nov-11
slide 6

Microreactors are at the heart of a
dramatic shift in API production
It enables continuous processes based on plug flow reactors with minimal volume
of reagents, rapid dynamic responses and robustness, good temperature
control, efficient mixing, etc.
•outlet cooling
•inlet i l t cooling
•delay
•loop
•outlet product
•inlet fluid 1
•inlet fluid 2
•outlet cooling
•inlet cooling
10-Nov-11
•11 – 600 mL/min
slide 7

All Lonza FlowPlate MicroReactors
Development Reactor
• View the chemistry
• Reaction at tiny flow rates
• Test different
Production Reactor
• Flexibility / versatility via different
plates for unit operations
• Design as key ingredient to
scale-up
• Multi-purpose
•FlowPlate TM Lab
•Plate Size: A6
•Plate Size: A5
•Channel structure
•Sandmeyer Prize 2010
10-Nov-11
slide 8

Plate Design for Gas -
Liquid Reactions
Please refer to the webinar recording to view the video at:
www.business-review-webinars.com/Lonza-Webinar
i bi bi
10-Nov-11
slide 9

Lonza MicroReactor
as Universal Modules
Equipment Features
• Modular, robust, over 100 bar
• Hastelloy plates: process fluid
• Aluminum plates: thermal fluid
• Compactness, easy to adapt
• Each plate = one specific
design
•1
•22
• 1 Plate for multi-injection
• 2 Reactor system with 6
plates
• 3 A6 and A5 reactor systems
•3
10-Nov-11
slide 10

Scale-up Concept with Lonza
FlowPlate MicroReactors
•FlowPlate
•A++
•Portable skid mounted
units anywhere
• Visp FCC
• Nansha, China
• Our customers
•A6 •A5 •A4
Laboratory System
Flow labs fully integrated
with kg-Labs
Continuous SSP (MRT)
Lonza pilot Unit
Commercial Manufacturing
Modular, flexible on skid mounted
units
1-150150 g/min
150-600 g/min
06 0.6- 5kg/min
Few g to tens of kg
0.1–5 tons campaigns
5–80 tons campaigns
- Your green and - Plugging issues solved
- Fully automated
sustainable process of - Accelerated development at
tomorrow
lower costs
-Fit for any scale
- Streamlined and simplified processes
- Drastic reduction in costs of goods
10-Nov-11
slide 11

Handling Unstable Reaction Intermediates:
From lab to ton scale production featuring ozonolysis
Dr. Markus Nobis / November 9, 2011 / Webinar from Visp, Switzerland

Structure
• About Lonza
• Ozone – some facts and requirements
• Ozonolysis @ Lab scale
• Development of an Ozonolysis / Risk assessment
• Ozonolysis @ Production scale /example
• Future concept
10-Nov-11
slide 13

Ozone –
some facts
• Ozone
• Gaseous Oxidant, characteristic smell
• Bp.: -112°C (liquid: deep intense blue)
• Not storable - has to be generated on site
• How to generate
• Ozone generation is carried out via silent electric
discharge in the presence of dried oxygen or air
10-Nov-11
slide 14

Ozonolysis -
Important Facts
• Ozone: Toxic due to the oxidative potential.
• Ozonides/Alkoxyhydroperoxides: Sometimes less stable
intermediates in the liquid phase.
• Aerosoles: Possibility of explosive mixtures of substrate droplets,
Oxygen and Ozone in the headspace over the reaction solution
slide 15

Ozonolysis on technical scale -
Why use Ozone as an Oxidant?
• One of the best reagents to obtain carbonyl compounds directly
from unsaturated compounds
• High atom efficiency
• Equal number of unit operations
• Lower reagent and waste treatment costs
• Comparable development costs to other chemical transformations
10-Nov-11
slide 16

Ozonolysis -
Chemical Platform
R
N
COOH
COOH
US Appl. 20030216577
R
N
COR'
COOH
R
COOR
n
Unsaturated Esters
Aromatic
Carboxylic Acids
O
X
Oxides
WO / 2009 / 014431
R
n
O
O
O
Isolable Ozonides
R
X
N
X=PR, NR, S
R
R
O
Nef-Reaction
R'
Ozone
NO 2
n
R
R'
n
R
R''
OH
R'' R'
R
n CH 2 OH
Alcohols
O
Aldehydes, Ketones
US Appl. 20060224019
US Appl. 20080319232
R
R
n
R
R
n
CHO
Unsaturated Aldehydes
R
HO
R
O
n
O
COOR
Carboxylic Ester
R
n
Aldehyde
CHO
OH
Carbon acids
R EP 2 060 556 A1
Schreiber et al.
slide 17

Ozonolysis in industrial applications -
Laboratory requirements for scale up activities
• Reaction parameters: High flexibility of the setup required to allow the
fast adoptions to new process conditions (Ozonolysis and Downstream
Processing)
• Reaction volume: Capability to handle different product volumes; ideally
with the same flow device.
• Materials: Compatibility to process conditions
• Data: Fast and reliable access to necessary information for safety assessment
directly out of the process development Short time to launch
►Solution: Flow technology and microreactor
technology (MRT)
10-Nov-11
slide 18

Ozonolysis in industrial applications -
Requirements on technical scale
• Risk assessment: Periodical risk assessment of the
production train in addition to the project related risk
assessment
• Ozone Injection: Minimization of the potential risk regarding
aerosoles by the applied system for the Ozone injection
• Chemistry / Process: Optimization of the reaction conditions
to minimize the Ozone content in the vented Offgas
• Ozonides: Clear understanding about the technical handling
and chemical behaviour of the unstable intermediates
• Staff: Extensive training (periodically and project related)
slide 19

Ozonolysis at Lab scale

Ozonolysis -
Approach the process in 4 steps with novel flow concepts
Requirement
Perfect control of the process on technical scale
•Feasibility Access the molecule
•Development Define the essential parameters
•Tech transfer Implement the process on technical scale
•Production Applicaton of the process
Feasibility Development Tech transfer Production
10-Nov-11
slide 21

Feasibility Development Tech transfer Production
Ozonolysis –
Flow concept for the fast initial testing - requirements
• Reaction / Chemistry
• Selectivity Idea about the requirements
• Downstream processing Initial idea about the targeted
Molecule, limiting factors
• Knowledge about safety critical points e.g. Aerosoles
• System/Equipment
• Flexible set-up to allow fast change over to other reaction
conditions (e.g. small scale flow/MRT)
• Capability of the set-up to generate fast and reliable data
regarding g important parameters of the reaction
• First scale up capabilities screening of DSP
• Possibility for the fast implementation of different work-up
conditions
10-Nov-11
slide 22

Feasibility Development
TechTransfer Production
Ozonolysis in flow –
Concept for fast initial testing and fast development
• Four key components
• Fast change over
Offgas
• Flexible work up design:
Flow / MRT / Batch
• Flexible operation:
batch vs. conti mode
• Scale-up: mimicing production
scale- up to multigram scale
Reaction
Ozone
Balancing
Dedicated Laboratory for
Ozonolysis development
Ga as
sepa arator
Pump
Ozo one
Injec ction
O3-
Generator
Air/Oxygen
3O 2 →2O 3
Feed
10-Nov-11
Downstream
Reaction
M.Nobis, D.Roberge, Chemistry Today, vol.29 n.1 January/February 2011
upstream
slide 23

Development of an Ozonolysis:
Fast R&D and transfer to production scale

Feasibility Development Techtransfer Production
A concept for fast development and implementation
• Aim 1: Identification of essential parameters
• Safety Critical parameters
• Quality determining parameters
• Aim 2: Implementation of improvement potential
• Ozone efficiency Minimum target: >95%
• Temperature regime Target: avoidance of cryogenic conditions
• Ozone concentration Target: 80-90% of the possible range
• Substrate concentration high/low
• Change of the process operation mode: Discontinuous/continuous
Capability to apply the tailored solution
• Possibilities for the application of different scales
(1-5 gram 100grams scale) with the same device!
• Mimicing i i of production system in R+D (!)
10-Nov-11
slide 25

Development of an Ozonolysis:
Risk Assessment

Feasibility Development Techtransfer Production
Ozonolysis Risk Assessment
• Safety studies: Proof of
• Stability of the intermediates
• Robustness of the down stream
processing procedure
• Integrated part in R&D activities
@Lonza:
Generation of the process safety
data package:
• DSC / RC-1/ Miniautoclave
• Thermal decomposition of
intermediary stages and products
Definition of technical Measurements for
the safe handling of the Ozonolysis
process
Re-assessment in case of a change of
the reaction conditions!
10-Nov-11
slide 27

Feasibility Development Techtransfer Production
Ozonolysis Risk Assessment
• Chemistry
• Solvents
• Reduction/oxidation agent
• Accumulation of reaction potential during
work-up
• Autocatalytic ability in case of Ozonide
degradation
• Process
• Concentration of the Ozonide in solution:
Risk of dry-out/precipitation (mech. stress!)
• Consideration of potential thermal stress on
the ozonation process on scale (hot spots
during oxidation/reduction)
• Quench as safety fall back option?
• Compatibility of materials
• Materials in contact with Ozone and
ozonation products
• Compatibility of sealing and gasket materials
10-Nov-11
slide 28

Feasibility Development Techtransfer Production
Ozonolysis Risk assessment – waste treatment
• Handling of Ozone containing gas streams
• Risk assessment regarding destruction of
Ozone content:
• Catalytical destruction
• Thermal destruction
• Scrubbing
Measurements in case of technical failure
• Handling of waste streams from downstream
processing
• Aqueous waste streams: biological vs.
thermal treatment (e.g. scrubber solutions)
• Judgement about harzards ards deriving ing from
mixing waste streams with other waste
streams (Reactivity)
• Organic waste streams (distillates / side
streams)
10-Nov-11
slide 29

Feasibility Development Techtransfer Production
Ozonolysis @ Production scale:
The technical implementation using flow chemistry

Feasibility Development Techtransfer Production
Ozonolysis@LONZA
Ozonolysis Production train
• Dedicated production train for conversions
with Ozone
• Ozonolysis can be carried out under
temperature conditions down to -80°C
• Capacity: 8.5 Kg Ozone/hour
• Ozonolysis is carried out in a contained
loop-reaction system (Reactor Volume
450L)
• Kg to mT-scale possible due to operability
under discontinuous to continuous process
conditions
• Trained team for the ozonolysis
slide 31

Feasibility Development Techtransfer Production
Ozonolysis@LONZA
Production capabilities – technical environment
• Ozonolysis @ Lonza is fully embedded d in the technical and regulatory
environment of an multipurpose facility
• broad range of up- and downstream processing methodologies!
• Flexible concept of the facility
• allows to switch the down stream processing from discontinuous
to continuous mode
Disconti / batch
Conti
slide 32

Feasibility Development Techtransfer Production
Ozonolysis at Production Scale:
Example

Feasibility Development Techtransfer Production
Ozonolysis@Lonza
Ozonolysis of Chrysanthemic acid methylester
RO
O
Ozone
Reduction
RO
O
O
Feasibility Development Techtransfer Production
10-Nov-11
slide 34

Feasibility Development Techtransfer Production
Ozonolysis at LONZA
Future concepts

Feasibility Development Techtransfer Production
Ozonolysis@Lonza:
Downstream processing - MRT and Continuous Flow
• New Concepts:
• Focus on the downstream processing:
• Application of catalysis and environmentally friendly
methodologies
Ozonid
Ozonid/
H 2
Cat
Product
Ozonid
H 2
NaBH 4 (aq)
10-Nov-11
• Tunable Specifity:
• Change of the selectivity due to the change of the process
conditions
• Processing of the primary ozonation products:
• Flow and micro / meso structured devices for the efficient
mass and heat transfer
slide 36

Feasibility Development Techtransfer Production
Ozonolysis@Lonza
Downstream processing - MRT /Continuous Flow (II)
• Innovation: optimization of the Downstream processing (DSP)
• Include more eco-friendly conversions in the DSP
• Capability based on the MRT/microstructured devices:
Oxidation with Oxygen under pressurized conditions
• Homogeneous oxidation of Ozonides via MRT to carbon
acids
Ozonide
Ozonide/
H 2 O2
Carbon
Ozonide
H 2 O 2
acid
NaOH(Aq)
O 2
slide 37
10-Nov-11

Feasibility Development TT Production
Summary
• Ozone can be advantageously applied for the clean Oxidation of different
unsaturated starting materials
• Development of the Ozonolysis process requires the same or less number of
unit operations compared to other oxidation protocols
• Ozonloysis can be handled safe, even on large scale – risk assessment has
to be carried out to define the required measurements
• Flow chemistry and MRT allows the fast and flexible development and scaleup
to productions scale
• Ozonolysis@Lonza: dedicated train for the ozonolysis production; high
flexibility of the plant set-up allows us to switch operation mode (semi
batch/conti) t if required
ed
slide 38

Thank you for your attention

Back-up slides

Toxicity of Ozone
slide 41

Chemistry – Involvement of Solvents into the Ozonide
• Criegee Mechanism
slide 42