Lab to Plant Technologies to Accelerate Drug

Research Development and Scale-Up

Dom Hebrault

(Principal Technology Engineer)

Roche – Clarecastle

Ireland

Case Study

In-situ ReactIR as a PAT Tool for Manufacturing of a High Value Chemical

Brian Wittkamp, Ph.D.

Dom Hebrault, Ph.D.

Overview PAT- Manufacturing at Roche Clarecastle

Process Automation and Analytical Technologies

ReactIR 15

ParticleView_V19FBRM G400

Synthesis Workstation and calorimetersEasyMax, OptiMax

EasySampler

- Fundamental Vibrations- Sharp Features (good Qual)- Lattice, Inorganics, Heavy Atoms

Near, mid and far infrared

Near-IR(12,800-4000 cm-1)

Mid-IR(4000-200 cm-1)

Far-IR(200-10 cm-1)

Infrared Region

- Fundamental Vibrations- Sharp Features (good Qual)- High ε (good Quant)- Most organic functional groups

- Combination & Overtones of Fundamental Vibrations

- Broad Features (poor Qual)- Lower ε (good Quant)- O-H, N-H, S-H, C-H

Energy

Example : Lithiation of 3-Bromothiophene

+S

Br

S

Br

Li

THF

-40˚CN

Lii-Pr

i-Pr ..

Scale-up and Manufacturing

Ease-of-use Integrated temp RTD Fiber probes, flow cell

Full range of sampling technologiesQuick & easy

Multiplex fiber probes, flow cells Mirrored conduits* Full application range

(Pressure, temp, spectral range)

Reactions lab-to-plant Pilot / Plant batch or continuous Global rating (ATEX Zone 1,

C1, D1 Group B, T4)

ReactIR™ 15 – no purge ReactIR™ 45m ReactIR™ 45P

In-situ Mid-IR: From Research to Manufacturing

Sampling

John, O'Reilly; In-Line Mid-IR bridging the gap; Heidelberg, Oct 2013

The Chemistry:

Process Monitoring & Quality Control via PAT

Intermediate reduction step for anticancer drug Xeloda®

Quality, and safety risks (exotherm, hydrogen, salts)

John, O'Reilly; In-Line Mid-IR bridging the gap; Heidelberg, Oct 2013

What ReactIR™ monitors:

Process Monitoring & Quality Control via PAT

Tosylfuranoside(1600cm-1)

John, O'Reilly; In-Line Mid-IR bridging the gap; Heidelberg, Oct 2013

Offline Sampling Completion Checks

- Sampling during the exothermic reaction was considered unsafe

- Samples were only taken at the start & end point

- Each sample required 2 hours to complete analysis

- 25% of the reaction completion tests were deemed incomplete because of

high residual tosylfuranoside levels and required “aging” for an extra 10 hours

“Traditional” Process Flow

Batch aged - prompt to sample

Enter data in LIMS

Automation System

LIM System

Manufacturing Technician

QC Technician

IPC Instrument

Take sample

Enter data in LIMS

Bring sample to lab

Prepare sample

Run sample

Report sample

Report sample

Advance batch

=Potential delay point

Process Monitoring & Quality Control via PAT

John, O'Reilly; In-Line Mid-IR bridging the gap; Heidelberg, Oct 2013

ReactIR™ 45P

ATEX purgewith air cooled detector

Reactor (15,000L)

Sentinel™ probe with silicon window

Communication to PC and DCS via OPC UA or Modbus TCP/IP

Installation of ReactIR™ 45P in bottom outlet of process reactor

Process Monitoring & Quality Control via PAT

John, O'Reilly; In-Line Mid-IR bridging the gap; Heidelberg, Oct 2013

Real time ReactIR trends

Mid-IR trend data for output to the Process Control System (DCS) and the Process Information (PI) network

Process Monitoring & Quality Control via PAT

John, O'Reilly; In-Line Mid-IR bridging the gap; Heidelberg, Oct 2013

Reaction kinetics:• Formation of TEA-borohydride

complex• Reaction of tosylfuranoside

Chemical visualization:• Increase and depletion of

borohydride following each aliquot addition corresponds to 15kgs per aliquot

• Accumulation of unreacted borohydride (about 20% of charge)

“How do we know it’s working before we add the borohydride”The reduction is completed, confirmation that tosylfuranoside ≤ 0.2%

Process Monitoring & Quality Control via PAT

John, O'Reilly; In-Line Mid-IR bridging the gap; Heidelberg, Oct 2013

Understand how each critical reaction components relates to the process

Optimize the path of each critical component in each batch using in-situ ReactIR

Control the endpoint and eliminate "completion check sampling" by applying real-

time verification

Process Monitoring & Quality Control via PAT

John, O'Reilly; In-Line Mid-IR bridging the gap; Heidelberg, Oct 2013

Performance qualification: Inline instrument health check

- Replace physical sample extraction with in-situ ReactIR™ at starting point

- Insures validity of ReactIR™ data

- Insures consistent starting reactor composition

Process Monitoring & Quality Control via PAT

John, O'Reilly; In-Line Mid-IR bridging the gap; Heidelberg, Oct 2013

AccessAcquire

Analyze

ReactIR performance qualification & reactor composition - The Initial ReactIR™ spectrum is electronically transferred to QC-

PAT - QC-PAT evaluates the spectrum by comparing to a reference

spectrum and confirms the starting ratio of triethylamine to NMP is within specification- The spectra quality has proven consistent over 10 months with no

measurable loss in peak resolution, sensitivity or signal to noise

Process Monitoring & Quality Control via PAT

John, O'Reilly; In-Line Mid-IR bridging the gap; Heidelberg, Oct 2013

Conclusions

In-situ ReactIR™ Performance- "Issue-free" operation for over 18 months of

24/7 operation- Over 220 batches monitored and controlled- Yield increased from 68% to 77%- €3.8mEuros savings increased yield,

reduced batch time, elimination of offline analysis- No probe fouling or maintenance required - Reduced 8-person / 3 shift production

process to single shift 6-person process

John, O'Reilly; In-Line Mid-IR bridging the gap; Heidelberg, Oct 2013

Acknowledgements: Roche Clarecastle PAT team

John O’Reilly Process Analytical Technology

Frank Neville PAT Integration

Barry Reid IT

Martin Cronin Electrical & Instrument Engineering

Andy McInerny Mechanical Engineering

Maria Lennon QA

Brian Coffey Automation