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Manufacturing process control with PATSubstitution of off-line HPLC & GC by in-line IR spectroscopy

Christian Lautz, F. Hoffmann-La Roche Ltd, Basel, SwitzerlandIFPAC-2015, January 25-28, Arlington,USA

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Many thanks to the team that made it possible!

Project coordinationA. BeyelerC. Lautz

CSV & ITH. DupyW. FreiP. Hänle

QC/QAR. HauckH.-G. Tölle

PATM. BetschartA. FehrC. Lautz

ManufacturingH. GasserA. GebertM. HaffnerA. Heuscher

WorkshopsMachine ShopElectricians

Project Team M. Cordon-FederspielR. DiodoneU. HoffmannC. MössnerB. Ruff

EngineeringJ. BlindH. KäserD. ÜberschlagV. Roux

Special thanks toP. ChalusG. Thurau

Introduction

Feasibility study

Model development and validation

Manufacturing plant setup

Process qualification campaign

Model verification3

Introduction

Feasibility study




Model verification4

5

Manufacturing process: Flow-chart

Reaction

Quench on sulfuric acid

Extractions Aqueousphases

API dissolved in toluene

5% NaHCO3 solutionWater

Concentration(54 °C, 20-220 mbar)

Reflux(78 °C, dissolve crusts)

Cooling to 60 °C

Concentrationadjustment

Ethanol

Reflux(78 °C, dissolve crusts)

Cooling to 60 °C

API dissolved in ethanolConcentration: 18%(m/m)

API dissolved in ethanolConcentration: 17%(m/m)

Seeding(1%(m/m) Form A)API

Concentrationadjustment (opt.)

Cooling to 41 °C (within 90 minutes)

Aging(41 °C, 1 h)

DilutionEthanol

Solvent exchange(54 °C, 260-330 mbar)

Ethanol, toluene

Ethanol Cooling to -10 °C (within 7 h)

Polishing filtration(1.2 m filter)

RinsingEthanol

Aqueousphase IPC

Distiller Crystallizer Release analysis

Form B

6

Manufacturing process: CPP & CQA

• IPC sampling– The concentration of the API and residual toluene is determined via IPC

sample (concentration is a critical process parameter, CPP)

• Seeding and crystallization– Crystallization of the desired polymorphic form A can only be achieved by

seeding; from the supersaturated solution the undesired form B is formed upon spontaneous crystallization (polymorphic form is a critical quality attribute, CQA)

Form A

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IPC sampling issues

• Sampling of the warm supersaturated solution into a glass bottle has the risk of undesired precipitation of the API in the sampling system or the bottle

• Crystallization may occur upon cooling during transport to QC lab or during sample preparation

• Heating the sample to bring the API in solution again is an undesired intervention to re-create a representative sample

• Two methods from one sample, HPLC for API concentration and GC for residual solvent determination

• In short: Assay determination with a higher probability of failures

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It is obvious……

An in-line PAT method couldovercome the problems related to sampling

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Challenges for the PAT method

• Choice of an adequate technology to deliver desired accuracy for IPC samples, and apply same technology for both concentration determinations

• Follow the distillation to its end point in the first reactor, and / or determine the concentrations after filtration and dilution in the second reactor?

• Choice of probe technology for potential distillation (gas bubbles) and / or crystallization (encrustation on probe)

• For GMP sampling in manufacturing– Computer System Validation and (laboratory) instrument qualification– PAT method validation

Introduction

Feasibility study




Model verification10

11

Laboratory feasibility study

• IR was chosen as primary technology for a laboratory feasibility study due to the ruggedness of ATR probes to gas bubbles and (non-sticking) particles

• Transmission NIR spectroscopy was chosen as secondary technology, since it is more sensitive to gas bubbles (for probes with a horizontal slit)

• Quantitative chemometric models were developed for IR and NIR spectroscopy from the same set of calibration standards

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PAT method development

• Instrument– Mettler Toledo iC45m IR spectrometer equipped with HC22 ATR probe and

2 m AgX optical fiber; resolution 4 cm-1 with 256 scans per spectrum

• Sample preparation and measurement– Generic samples prepared from pure substances API, toluene and ethanol;

randomized amounts to avoid collinearity• API: 15.0–30.0%(m/m)• Toluene: 0-5.0%(m/m)

– 45 samples, measured at 55 °C in a thermostat (100 ml glass bottles with magnetic stirrer bar)

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IR method development results: API

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IR method development results: Toluene

0

5

10

15

20

25

30

140 200 260 320 380 440 500

Conc

entr

atio

n [ %

(m/m

) ]

Time [ min ]

API (IR)

API (HPLC)

Toluene (IR)

Toluene (GC)

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Technical scale-up: 50 L reactor

* Outside the calibrated model range

Time [ min ]

API (IR)[ %(m/m) ]

API (HPLC)[ %(m/m) ]

Toluene (IR)[ %(m/m) ]

Toluene (GC)[ %(m/m) ]

142 21.5 19.9 24.1* 30.3*

234 20.8 20.4 13.8* 15.8*

324 22.6 22.9 5.4 5.2

444 23.0 23.3 1.1 0.9

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Assessment of feasibility study results

• Quantitative IR models were successfully applied in technical scale-up for monitoring and in-line concentration determination

– “Real” production process (50 L scale) can be monitored with models derived from generic samples prepared from pure components

– Agreement between off-line analyses and in-line measurements– Successful preliminary test of validation based on a reduced number of

separate samples (robustness; linearity, accuracy, precision)

• Agreement to introduce an in-line spectroscopic concentration measure-ment in manufacturing for process qualification campaign

– Final chemometric models will also be based on generic samples from pure compounds since (only) this allows for necessary sample variability

– HPLC & GC analysis will not be used as basis for model development

17

Technical setup in manufacturingM

M

ATEX environment

Vertical slit NIR probe

ATEX NIRspectrometer

Non-ATEX environment

Bottom valve with ATR IR probe

ATEX IR spectrometer

Data visualisation for IR:Laptop in control room

Crystallizer

Distiller

Introduction

Feasibility study





19

IR method development and validation for GMP use

• Instrument– Mettler Toledo ReactIR 45P IR spectrometer, equipped with custom-made

ATR probe (90 cm length, 6.3 mm diameter) and 2.5 m AgX optical fiber – Instrument qualification and CSV successfully completed

• Concentration ranges– API: 10.9 – 25.4%(m/m)

• Specification: 15.3 – 18.7%(m/m); 17.0%(m/m) as target value– Toluene: 0 – 5.0%(m/m)

• Specification: max. 2.0%(m/m)– Cyclohexane: 0 – 1.3%(m/m) (denaturant in ethanol from solvent recovery)

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• Calibration samples / cross validation– 4 batches API, 2 qualities ethanol– 1 quality toluene and cyclohexane– 60 samples

• Robustness samples / external test-set validation– Mutual self-influence of analytes as well as influence of temperature, water,

cyclohexane and unidentified side products (from mother-liquor residue) tested

– 3 batches API, 3 qualities ethanol– 1 quality toluene, cyclohexane, water, mother liquor residue– 23 samples

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• Validation samples / external test-set validation– 1 batch API, 1 quality ethanol and toluene– Linarity, accuracy, precision and LOQ for toluene; no intermediate precision– 39 samples

• Samples measured at 54 – 66 °C in a thermostat (100 ml glass bottles with magnetic stirrer bar) with 256 scans per spectrum; resolution 4 cm-1

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IR method development results: Raw spectra

API Toluene

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IR method development results: APIP

redi

cted

- A

PI

Cross validation (model)Test-set validation

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IR method development results: API

• Cross validation results– Spectral range: 1100 – 1700 cm-1

– 1st derivative as data pretreatment– Principal components: 3– RMSECV: 0.07%(m/m)– Mahalanobis Distance: 1.66 ± 0.80

• Test-set validation results– RMSEP: 0.24%(m/m)– Acceptance criterion RMSEP: ≤0.8%(m/m)– Mahalanobis Distance: 1.58 ± 0.51– Mahalanobis Distance limit (MDL): 4.7

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Cross validation (model)Test-set validation

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• Cross validation results– Spectral range: 700 – 800 cm-1

– 1st derivative as data pretreatment– Principal components: 2– RMSECV: 0.08%(m/m)– Mahalanobis Distance: 1.31 ± 0.85


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First IR model application: Laboratory distillation

0

5

10

15

20

25

0 50 100 150 200 250 300 350

Conc

entr

atio

n [ %

(m/m

) ]

Time [ min ]

API (IR)

API (HPLC)

Toluene (IR)

Toluene (GC)

Time [ min ]

API (HPLC)[ %(m/m) ]

API (IR)[ %(m/m) ] MD Toluene (GC)

[ %(m/m) ]Toluene (IR)[ %(m/m) ] MD

284 17.5 17.4 1.57 0.38 0.35 2.33

326 16.6 16.2 1.61 0.38 0.38 2.28

Introduction

Feasibility study





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Setup of NIR spectrometer and probe in plant

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Setup of IR spectrometer and probe in plant

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Introduction

Feasibility study





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The spectroscopic limitations in manufacturing

• Background measurement with clean probe after installation– Empty reactor, dry and under nitrogen– Measurement possible only once before first batch due to (potential)

encrustation, thus valid/used throughout the whole campaign

• Stepwise control process established for IR spectrometer to ensure correct functionality of the spectroscopic GMP measurement

– Full set of functional tests before setup in plant– Slightly reduced set of functional tests after setup in plant, before first batch– SST before every plant batch– Full set of functional tests after removal from plant and return to laboratory

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The first manufacturing batch: Complete processDistiller (NIR) & Crystallizer (IR)

0

2

4

6

8

10

12

14

16

18

20

14

15

16

17

18

19

20

21

22

23

24

0 3 6 9 12 15 18

Tolu

ene

[ %(m

/m) ]

API [

%(m

/m) ]

Time [ h ]

Distillation & crystallization overview

Seeding at 41 °C

Start of ramp to -10 °C

Addition rate decreased

Vessel transfer (NIR → IR)

Stepwise dilution

Changes in stirrer speed

Specification for toluene can be reached without problems during solvent exchange

Every following batch showed crusts on probe after seeding

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The first manufacturing batch: IR data for APICrystallizer

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

18.0

18.5

19.0

19.5

20.0

0.0 0.5 1.0 1.5 2.0

Mah

alan

obis

Dis

tanc

e (M

D)

API [

%(m

/m) ]

Time [ h ]

Rinse with 200 kg ethanol

50 kg ethanol from spray ring

1.6

1.7

1.8

1.9

2.0

2.1

2.2

2.3

2.4

2.5

2.6

2.7

2.8

2.9

3.0

3.1

3.2

3.3

3.4

3.5

3.6

17.0

17.1

17.2

17.3

17.4

17.5

17.6

17.7

17.8

17.9

18.0

0 5 10 15 20 25 30 35 40 45 50 55 60

Mah

alan

obis

Dis

tanc

e (M

D)

API [

%(m

/m) ]

Time [ min ]

Sample at 60 °C:

API = 17.46% (m/m)MD = 1.81

Start cooling to 41 °C

50 kg ethanol from spray ring

38

The first manufacturing batch: GMP IR data for APICrystallizer

Sensitivity of the Mahalanobis Distance on temperature change becomes evident

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The results overview: Technical batches

Batch SampleGMP IR value

PolymorphYield

[ %(m/m) ] MD [ % ]

1Toluene <1.0 1.3

A 86.4API 17.5 1.8

2Toluene <1.0 1.3

A 86.1API 17.1 1.8

3Toluene 1.3 1.0

A 89.3API 17.2 1.6

4Toluene <1.0 1.1

A 89.3API 17.5 1.7

5Toluene 1.3 0.9

A 88.9API 17.3 1.6

All specifications and limits are met

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The results overview: Process qualification batches

Batch SampleGMP IR value

PolymorphYield

[ %(m/m) ] MD [ % ]

6Toluene 1.2 1.0

A 91.9API 18.0 1.7

7Toluene 1.1 1.0

A 91.9API 17.9 1.7

8Toluene 1.3 0.9

A 91.2API 17.5 1.6

All specifications and limits are met

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Assessment of PAT results from process qualification campaign

• No sampling necessary any more

• Direct in-line determination of two parameters from one IR spectrum– Residual toluene concentration after solvent exchange (off-line: GC)– API concentration prior to seeding (off-line: HPLC)

• Quantitative results in minutes, significantly reduced cycle time

• Control of API concentration within specification (CPP) to ensure precipitation of desired polymorph after seeding (CQA)

• 8 batches produced in Jan./Feb. 2014 with good results / reproducibility

• First validated spectroscopic PAT method for small molecule API manufacturing in Basel

Introduction

Feasibility study





43

IR method verification after the campaign

• Sample preparation and measurement– Verification samples / external test-set validation

• 1 batch API (campaign batch 2), 1 quality ethanol and toluene• 24 samples

– Samples measured at 60 °C in a thermostat (100 ml glass bottles with magnetic stirrer bar) with 256 scans per spectrum; resolution 4 cm-1

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12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26

Pred

icte

d AP

I [ %

(m/m

) ]

Actual API [ %(m/m) ] 44

IR method verification results: API

Cross validation (model)Test-set validationTest-set verification

45

IR method verification results: API


• Test-set verification results– RMSEP: 0.30%(m/m)– Mahalanobis Distance: 1.63 ± 0.54

-0.9

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400

Pred

icte

d -A

ctua

l API

[ %

(m/m

) ]

Sample number

Limit: RMSEP ≤ 0.8%(m/m)


46

IR method verification results: API predictions


0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400

Mah

alan

obis

Dis

tanc

e A

PI

Sample number

Limit: Mahalanobis Distance ≤ 4.7

47

IR method verification results: API MD


0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0

Pred

icte

d To

luen

e [ %

(m/m

) ]

Actual Toluene [ %(m/m) ] 48

IR method verification results: Toluene


49

IR method verification results: Toluene


• Test-set verification results– RMSEP: 0.12%(m/m)– Mahalanobis Distance: 1.25 ± 0.57

-0.55-0.50-0.45-0.40-0.35-0.30-0.25-0.20-0.15-0.10-0.050.000.050.100.150.200.250.300.350.400.450.500.55

0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400

Pred

icte

d -A

ctua

l Tol

uene

[ %

(m/m

) ]

Sample number



50

IR method verification results: Toluene predictions


0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400

Mah

alan

obis

Dist

ance

Tolu

ene

Sample number

Limit: Mahalanobis Distance ≤ 4.4

51

IR method verification results: Toluene MD


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The next (potential) steps

• PAT QC samples can now be handled by the production groups – Streamline efforts and procedures to simplify ease of use for shift workers– Intermediate reactor cleaning for longer campaigns

• Process automation in manufacturing – Control of distillation, transfer, dilution, IPC up to seeding point– NIR: Two probes on one spectrometer with multiplexer, long fibers possible– IR: One spectrometer and probe necessary per reactor, limited fiber length– Connection of spectrometer(s) to plant DCS (PAQ necessary)

• Method lifecycle– Introduce F-Ratio as secondary quality criterion with acceptance limits

derived from the process qualification campaign

Doing now what patients need next

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