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

Transcription

1 Manufacturing process control with PAT Substitution of off-line HPLC & GC by in-line IR spectroscopy Christian Lautz, F. Hoffmann-La Roche Ltd, Basel, Switzerland IFPAC-2015, January 25-28, Arlington,USA

2 Many thanks to the team that made it possible! Project coordination PAT Project Team A. Beyeler M. Betschart M. Cordon-Federspiel C. Lautz A. Fehr R. Diodone C. Lautz U. Hoffmann C. Mössner B. Ruff CSV & IT Manufacturing Engineering H. Dupy H. Gasser J. Blind W. Frei A. Gebert H. Käser P. Hänle M. Haffner D. Überschlag A. Heuscher V. Roux QC/QA Workshops Special thanks to R. Hauck Machine Shop P. Chalus H.-G. Tölle Electricians G. Thurau 2

3 Introduction Feasibility study Model development and validation Manufacturing plant setup Process qualification campaign Model verification 3

4 Introduction Feasibility study Model development and validation Manufacturing plant setup Process qualification campaign Model verification 4

5 Manufacturing process: Flow-chart Reaction Reflux (78 C, dissolve crusts) Cooling to 60 C Quench on sulfuric acid Aqueous phase Cooling to 60 C IPC API dissolved in ethanol Concentration: 17%(m/m) 5% NaHCO 3 solution Water Extractions Aqueous phases Ethanol Concentration adjustment Concentration adjustment (opt.) API dissolved in toluene API dissolved in ethanol Concentration: 18%(m/m) Cooling to 41 C (within 90 minutes) Concentration (54 C, mbar) Polishing filtration (1.2 m filter) API Seeding (1%(m/m) Form A) Ethanol Dilution Ethanol Rinsing Aging (41 C, 1 h) Ethanol Solvent exchange (54 C, mbar) Ethanol, toluene Reflux (78 C, dissolve crusts) Cooling to -10 C (within 7 h) Distiller Crystallizer Release analysis 5

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 Form B 6

7 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 7

8 It is obvious An in-line PAT method could overcome the problems related to sampling 8

9 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 9

10 Introduction Feasibility study Model development and validation Manufacturing plant setup Process qualification campaign Model verification 10

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 11

12 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: %(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) 12

13 IR method development results: API 13

14 IR method development results: Toluene 14

15 Technical scale-up: 50 L reactor Concentration [ %(m/m) ] Time [ min ] API (IR) [ %(m/m) ] API (HPLC) [ %(m/m) ] Toluene (IR) [ %(m/m) ] Toluene (GC) [ %(m/m) ] * 30.3* API (IR) API (HPLC) 13.8* 15.8* Toluene (IR) Toluene (GC) * Outside the calibrated model range Time [ min ] 15

16 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 measurement 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 16

17 Technical setup in manufacturing Non-ATEX environment ATEX environment M Distiller Data visualisation for IR: Laptop in control room Crystallizer M ATEX NIR spectrometer Vertical slit NIR probe ATEX IR spectrometer Bottom valve with ATR IR probe 17

18 Introduction Feasibility study Model development and validation Manufacturing plant setup Process qualification campaign Model verification 18

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: %(m/m) Specification: %(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) 19

20 IR method development and validation for GMP use 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 20

21 IR method development and validation for GMP use 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 C in a thermostat (100 ml glass bottles with magnetic stirrer bar) with 256 scans per spectrum; resolution 4 cm -1 21

22 IR method development results: Raw spectra API Toluene 22

23 IR method development results: API Predicted - API Cross validation (model) Test-set validation 23

24 IR method development results: API Cross validation results Spectral range: cm -1 1 st 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):

25 IR method development results: Toluene Cross validation (model) Test-set validation 25

26 IR method development results: Toluene Cross validation results Spectral range: cm -1 1 st derivative as data pretreatment Principal components: 2 RMSECV: 0.08%(m/m) Mahalanobis Distance: 1.31 ± 0.85 Test-set validation results RMSEP: 0.07%(m/m) Acceptance criterion RMSEP: 0.5%(m/m) Mahalanobis Distance: 1.23 ± 0.56 Mahalanobis Distance limit (MDL):

27 First IR model application: Laboratory distillation Concentration [ %(m/m) ] Time [ min ] API (HPLC) [ %(m/m) ] API (IR) [ %(m/m) ] API (IR) API (HPLC) MD Toluene (GC) [ %(m/m) ] Toluene (IR) [ %(m/m) ] Toluene (IR) Toluene (GC) MD Time [ min ] 27

28 Introduction Feasibility study Model development and validation Manufacturing plant setup Process qualification campaign Model verification 28

29 Setup of NIR spectrometer and probe in plant 29

30 Setup of IR spectrometer and probe in plant 30

31 Setup of IR spectrometer and probe in plant 31

32 Setup of IR spectrometer and probe in plant 32

33 Setup of IR spectrometer and probe in plant 33

34 Introduction Feasibility study Model development and validation Manufacturing plant setup Process qualification campaign Model verification 34

35 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 35

36 The first manufacturing batch: Complete process Distiller (NIR) & Crystallizer (IR) Changes in stirrer speed Vessel transfer (NIR IR) 14 API [ %(m/m) ] Addition rate decreased Seeding at 41 C Toluene [ %(m/m) ] Stepwise dilution Distillation & crystallization overview Time [ h ] 6 Every following batch Specification for toluene showed can be 4 crusts reached on without Start of ramp problems to -10 C during probe solvent after exchange seeding 2 36

37 The first manufacturing batch: IR data for API Crystallizer 20.0 Rinse with 200 kg ethanol API [ %(m/m) ] Mahalanobis Distance (MD) kg ethanol from spray ring Time [ h ] 37

38 The first manufacturing batch: GMP IR data for API Crystallizer API [ %(m/m) ] kg ethanol from spray ring Sample at 60 C: API = 17.46% (m/m) MD = 1.81 Start cooling to 41 C on temperature change becomes evident Time [ min ] Sensitivity of the Mahalanobis Distance Mahalanobis Distance (MD) 38

39 The results overview: Technical batches Batch Sample GMP IR value Yield Polymorph [ %(m/m) ] MD [ % ] 1 Toluene < API A Toluene < API A Toluene API A Toluene < API A Toluene API A 88.9 All specifications and limits are met 39

40 The results overview: Process qualification batches Batch Sample GMP IR value Yield Polymorph [ %(m/m) ] MD [ % ] 6 Toluene API A Toluene API A Toluene API A 91.2 All specifications and limits are met 40

41 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 with good results / reproducibility First validated spectroscopic PAT method for small molecule API manufacturing in Basel 41

42 Introduction Feasibility study Model development and validation Manufacturing plant setup Process qualification campaign Model verification 42

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 43

44 IR method verification results: API Predicted API [ %(m/m) ] Cross validation (model) Test-set validation Test-set verification Actual API [ %(m/m) ] 44

45 IR method verification results: API 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 Test-set verification results RMSEP: 0.30%(m/m) Mahalanobis Distance: 1.63 ±

46 IR method verification results: API predictions Predicted - Actual API [ %(m/m) ] Cross validation (model) Test-set validation Test-set verification Limit: RMSEP 0.8%(m/m) Sample number Limit: RMSEP 0.8%(m/m) 46

47 IR method verification results: API MD Cross validation (model) Test-set validation Test-set verification Limit: Mahalanobis Distance 4.7 Mahalanobis Distance API Sample number 47

48 IR method verification results: Toluene 5.0 Predicted Toluene [ %(m/m) ] Cross validation (model) Test-set validation Test-set verification Actual Toluene [ %(m/m) ] 48

49 IR method verification results: Toluene Test-set validation results RMSEP: 0.07%(m/m) Acceptance criterion RMSEP: 0.5%(m/m) Mahalanobis Distance: 1.23 ± 0.56 Mahalanobis Distance limit (MDL): 4.4 Test-set verification results RMSEP: 0.12%(m/m) Mahalanobis Distance: 1.25 ±

50 IR method verification results: Toluene predictions Predicted - Actual Toluene [ %(m/m) ] Cross validation (model) Test-set validation Test-set verification Sample number Limit: RMSEP 0.5%(m/m) Limit: RMSEP 0.5%(m/m) 50

51 IR method verification results: Toluene MD Mahalanobis Distance Toluene Cross validation (model) Test-set validation Test-set verification Limit: Mahalanobis Distance Sample number 51

52 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 52

53 Doing now what patients need next 53