Dr Charlotte Wiles of Chemtrix 'Continuous Primary Processing - From an R&D Concept to Implementatio

Continuous Primary Processing - From an R&D Concept to Implementation at an Industrial Scale Dr Charlotte Wiles (3rd October 2018)

Fundamentals of Flow Chemistry: Opportunities for Greater Process Control If the factors that influence a process or reaction are controlled – production becomes operator independent Variations in reactions stem from changes in; • Reaction time – reproduced by measuring & controlling pump flow rate • Temperature – reproduced using thermostat(s) • Feed composition – procedures for preparation &/or sourcing • Reactor vessel - flow reactors give the user repeatable control over heat & mass transfer Couple this with ‘Advanced Process Control (APC)’ strategies; • Able to perform corrective actions to mitigate disruptions 1. Design a manufacturing process to meet target(s) - Identify & control critical quality attributes - Understand impact of process parameter variability - Select hardware to ensure target condition are met 2. Monitor the process parameters to ensure consistent quality

Fundamentals of Flow Chemistry (2): How are Flow Reactions Performed?

Solutions (typically) of reagents are pumped into a reactor, where they are; •

Mixed

•

Heated or cooled

•

Reacted for specified period of time

•

Collected for analysis or product isolation

Conceptually, a basic flow reactor comprises of;

Pump A

Pump B

Collection

Key is to understand the requirements of your process & design the reaction set-up accordingly – This is in contrast to batch practices where you typically adapt the process to suit your available vessel(s)!

Fundamentals of Flow Chemistry (2): How are Flow Reactions Performed?

Solutions (typically) of reagents are pumped into a reactor, where they are; •

Mixed

•

Heated or cooled

•

Reacted for specified period of time

•

Collected for analysis or product isolation

Conceptually, a basic flow reactor comprises of;

Pump A

Pump B

Collection

Key is to understand the requirements of your process & design the reaction set-up accordingly – This is in contrast to batch practices where you typically adapt the process to suit your available vessel(s)!

Fundamentals of Flow Chemistry (2): How are Flow Reactions Performed?

Solutions (typically) of reagents are pumped into a reactor, where they are; •

Mixed

•

Heated or cooled

•

Reacted for specified period of time

•

Collected for analysis or product isolation

Conceptually, a basic flow reactor comprises of;

Pump A

Pump B

Collection

Key is to understand the requirements of your process & design the reaction set-up accordingly – This is in contrast to batch practices where you typically adapt the process to suit your available vessel(s)!

Fundamentals of Flow Chemistry (2): How are Flow Reactions Performed?

Solutions (typically) of reagents are pumped into a reactor, where they are; •

Mixed

•

Heated or cooled

•

Reacted for specified period of time

•

Collected for analysis or product isolation

Conceptually, a basic flow reactor comprises of;

Pump A

Pump B

Collection

Key is to understand the requirements of your process & design the reaction set-up accordingly – This is in contrast to batch practices where you typically adapt the process to suit your available vessel(s)!

Fundamentals of Flow Chemistry (2): How are Flow Reactions Performed?

Solutions (typically) of reagents are pumped into a reactor, where they are; •

Mixed

•

Heated or cooled

•

Reacted for specified period of time

•

Collected for analysis or product isolation

Conceptually, a basic flow reactor comprises of;

Pump A

Pump B

Collection

Key is to understand the requirements of your process & design the reaction set-up accordingly – This is in contrast to batch practices where you typically adapt the process to suit your available vessel(s)!

Fundamentals of Flow Chemistry (2): How are Flow Reactions Performed?

Solutions (typically) of reagents are pumped into a reactor, where they are; •

Mixed

•

Heated or cooled

•

Reacted for specified period of time

•

Collected for analysis or product isolation

Conceptually, a basic flow reactor comprises of;

Pump A

Pump B

Collection

Key is to understand the requirements of your process & design the reaction set-up accordingly – This is in contrast to batch practices where you typically adapt the process to suit your available vessel(s)!

Flow Technology: Drivers for Implementation Lab-scale: • Speed / flexibility • New reaction space • Reproducibility • Selectivity Process R&D: • Speed • Safety • Robustness

Outline your requirements; 1. What process / product?

2. What production volume & production rate are you targeting?

3. What are the heat & mass transfer requirements?

Production: • Speed • Safety • Robustness • Cost reduction

Flexibility & Standardisation: Modular, Future-proof, Customisable Standardisation: Reactors are often retro-fitted or connected to other unit operations, key is standard fittings (i.e. Swagelok, ANSI flanges) • On scale-up, key is to adhere to regulations such as PED Material of Construction: Due to long intended operation times, reactor materials must be carefully selected • Suitable for prolonged chemical exposure • General to suit future needs • Certified for use in food & drug applications Flexibility: This can refer to a range of requirements; • Chemicals • Process types • Production scales / regimes

Flexibility = Modular & Wide Ranging Chemical Compatibility!

Reaction Screening Labtrix®: High-throughput Suzuki-Miyaura Cross-Coupling

Advantages: • Low consumption of material (mg’s) • Fast data generation (100 samples/day) • Insight into key influences on product / by=product formation • Early indication of viability of manufacture

Reaction Conditions Not Accessible in Batch: Selective Acylation – No Protecting Group: PICATO® a Protein kinase C Activator for the treatment of actinic keratosis, synthesised via multi-step process. Flow conditions afforded a protecting group free route.

• • • •

>95 % purity, 40 % isolated yield Reduced diacylation No protecting group required Un-reacted sm easily recycled [1]. Org. Process Res. Dev. 2018, 22, 13−20.

Multi-step Reactions using KiloFlow®: Flow4API – Consortium led by TNO Telescoping: Optimised using 2 x Labtrix® systems and scaled in a custom KiloFlow®

Advantages: • • • •

mg consumption for process development Different temperatures for both steps No intermediate isolation required Reduced reactant excess & API intermediate in high yield (96.5 %)

Online Monitoring: Examples of Online Monitoring – FTIR

Online Monitoring: Examples of Online Monitoring – UPLC

Multi-point online analysis • Quantification of parameter effects on CQA Material attributes are measured & controlled, along with process parameters • Heading towards ‘Real-time Release’

Protrix® Flow Reactor: Customer Case – Dakin Oxidation Reasons for Flow: • Safety risk H2O2 at scale • Shorter synthetic route • Reduced reagent use • Increased throughput Protrix® for development: • Metal & glass-free reactor • Integrated thermal control → 30 s reaction cf. 6 h in batch → Quant. catechol (4.8 kg 8 h-1)

Continuous phase separation performed in the lab & batch extraction • Continuous extraction at scale using Zaiput extractor / separator set-up

Strategic Partner of

Plantrix® Industrial Flow Reactor: Buchem (BV) Buchem BV identified an opportunity to improve their productivity for an existing product - combining batch & flow Heart of the system was a 170 ml Plantrix® flow reactor containing SiC reactors, selected for chemical compatibility towards the challenging process & continuous mixing required, a 20 L Buchi rotavapor & a 50 L glass reactor followed Cooperation: Buchem, Flowid & Chemtrix Buchem – process & chemistry Flowid – system design & engineering Chemtrix – proof of concept & reactor design Advantages: • • • •

Higher productivity & robust process Smaller equipment Reduced material inventory Improved process control

Buchem CDMO Services: • R&D, pilot & production www.buchem.com

Plantrix® Industrial Flow Reactor: OmniChem CDMO – Commercial Scale Targeted a reduction in unit operations & increased productivity, OmniChem (Wetteren, BE) Customer process involved: • Three exothermic steps requiring slow addition (8 h) • Thermolabile intermediates & product • Two most exothermic (400 J/g) in Plantrix® • Potent product, OEB-5 (0.1-1 µg/m3) Developing a multi-stage continuous process gave; • Increased process safety due to thermal control • Minimised operator exposure • Higher productivity cf. batch (x2) Technical Advantages: • Small, mobile equipment tested in lab & moved to produce • Reduced material inventory • Process robustness enhanced via automation → Transforming 70 % of the process to continuous improved the use of existing batch capacity www.omnichem.com

PlantrixÂŽ Industrial Flow Reactor: APIs & Intermediates

Plantrix® Industrial Flow Reactor: Customer Application - Nitration

Solution - Plantrix®: • • • • •

Compact Robust Corrosion resistant Quality Solvent reduction

cGMP Continuous Tonne scale API production DSM uses Flow Reactors made of 3MTM (SiC) in a pharmaceutical production plant

Innovative Technology: Flow Reactor Benefits for Primary Processing 1. Safe Use of Extreme Reaction Conditions • Efficient mixing • Excellent thermal control • Process intensification of hazardous reactions 2. Reduced Development Time • Small hold-up volume • Rapid reaction optimisation • Minimal scale-up steps 3. Improved Process Control • High level of reaction control • Process reproducibility • Quality by Design (QbD) 4. Reduced Production Costs • Increased product quality • Reduced safety investments • Higher unit productivity

ü Efficiency ü Constant Quality ü Safety ü Sustainability

Closing Remarks: Flow Reactors – An Enabling Technology In order to successfully implement, there needs to be; 1.

• • •

Cultural Change Remove silos across business units Be open to different approaches Look to the process as a whole - not just ‘your part’

2. Management Support • Budget allocation to deliver on the goal(s) • Clear business drivers for change – Reduction in OPEX & CAPEX costs – Increase in process safety 3. Education • Training of the next generation is mandatory My personal view is that a Team is required to deliver the necessary change; • Chemists, Chemical Engineers, QA, Regulatory……..

• Cooperation with those that have experience (vendors, ‘competitors’, knowledge partners)

SiC Corrosion Resistant Flow Reactors: Pilot to Production Scale Reactor Volume -1) Flow Rate (ml min Owing to the excellent

example; Scale Ratio

Lab-scale

Production-scale

~1 to 12.5 ml

4000 ml

0.2 to 20 & thermal

+400 l/h corrosion resistance

1/340

1

Lithiations Product Name Protrix® Plantrix® MR555 Nitrations Oxidations Chlorinations / Brominations / Fluorinations Wolff-Kishner reductions Alkylations Controlled polymerisations (RAFT) Diels-Alder reactions Hofmann re-arrangements

of

3MTM

Examples include;

SiC, users employ Plantrix® in harsh environments, for • • • • • • • • • • •

Lithiations Nitrations Oxidations Chlorinations Brominations Fluorinations Wolff-Kishner reduction Alkylations Controlled polym. (RAFT) Diels-Alder reactions Hofmann re-arrang

* Patented bonding technique = braze-free reactor modules

Contact Details:

Dr Charlotte Wiles (CEO) Chemtrix BV – Headquarters Galvaniweg 8A 6101 XH Echt The Netherlands e-mail: c.wiles@chemtrix.com Tel: +31 (0) 467 022 600 +44 (0) 1482 466459

Please find details of our publications, application notes and white papers on our website www.chemtrix.com