Process Raman. Utilisation of Raman spectroscopy for primary and secondary pharmaceutical development. Allyson McIntyre Pharmaceutical Development

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1 Process Raman Utilisation of Raman spectroscopy for primary and secondary pharmaceutical development Allyson McIntyre Pharmaceutical Development IFPAC Annual Meeting, Arlington, VA (Washington DC) Jan 25 Jan 28, 2015

2 Process Raman at AZ Process Raman spectroscopy is regularly utilised at AZ. Explicit selectivity and quick measurement times. Routinely used in development laboratory settings. Employed at scale to provide further understanding of the processes. Routinely used in primary and secondary development settings. Case studies include, EOR determination, monitoring a continuous flow reaction and monitoring uniformity of dosage unit.

3 In situ monitoring of a heterogeneous etherification reaction using quantitative Raman spectroscopy References 1. R Hart, N Pedge, A Steven & K Sutcliffe, In situ monitoring of a heterogeneous etherification reaction using quantitative Raman spectroscopy, Org. Process Res. Dev., 2015, 19 (1), pp

4 Background In situ monitoring of etherification step Product team wanted to replace off-line HPLC used for inprocess control (IPC) with PAT method. Expected to be a high volume product. Could get time savings through use of PAT method to make real-time assessment of the progress of the reaction.

5 Further advantages of using PAT method Reaction mixture is heterogeneous, is off-line HPLC sample representative? In-line monitoring provided information on the levels of excess starting material chloropyrazine (3). Presence of chloropyrazine (3) downstream in the process at the crude API stage favoured crystallisation of undesired polymorph of the API. Therefore, designated a critical quality attribute (CQA) at this stage of the process so real-time monitoring was important.

6 Experimental A one-factor, three level series of experiments investigating the amount of solvent charged were performed to introduce robustness into the model. Solvent charge has large error in charging, giving a large contribution to spectral variation. In addition, two further lab scale user trials were completed at the set points. Different batches of input material were used to provide spectra with variable fluorescent background. PLS2 model chosen to simultaneously predict ether (1) and phenol (2).

7 Unprocessed Raman Spectra Variable nature of fluorescent background between experiments. Pre-processing was used to remove irregular fluorescent baselines.

8 Scale-up ~ 600 fold increase from lab to pilot plant. Special consideration for operating Raman spectroscopy in a hazardous area was required. For this work a dedicated bottom entry PAT port in the pilot plant reaction vessel was used.

9 Predicted Raman results for 1 st batch EOR based on % w/w of ether (1) Time min correspond to reagent addition phase, followed by a line wash, which resulted in a disturbance in the profile through dilution

10 EOR determination The in situ Raman data indicated reactions were complete before the time-point stipulated in the process description and batch sheet when an off-line sample would have been taken. Reaction progress faster at scale than the laboratory, providing knowledge about the effect of improved mixing efficiency of pilot plant scale vessels. End point for subsequent batches determined by Raman Spectroscopy alone.

11 Monitoring of a Strecker reaction in continuous flow manufacture using PAT in large scale lab

12 Background Non GMP campaign. Off-line analysis was not reliable. Required quick on/in-line analysis that could reliably determine the steady state of the reaction. Raman Spectroscopy selected to determine steady-state and the chemical composition of those steady-state conditions. Raman could be used across different continuous flow scales to monitor the reaction.

13 Off-line sampling of Strecker Chemistry Imine & Product labile to aqueous chromatographic conditions Product converts back to imine & amine Grab Sample N H 2 R O N R TMSCN, toluene HN CN R Grab Sample Imine converts back to amine Manual sampling over 83hrs of processing in the Large Scale Lab is not an option even if chromatography was capable of determining the true process state

14 Micro-scale chip reactor Coupled directly to MS (no chromatography)

15 Meso-scale coil reactor Non-contact Raman measurement

16 Scale-up Lab Plate reactor (Alfa Laval ART PR37) Immersion Optic Acquisition Parameters Kaiser Raman RXN 1 1 second exposure 10 accumulations No auto dark Cosmic Ray filter off 23 second measurement Sampled every 30s Spectral Pre-processing Normalise to Toluene band Integrate peak area No fluorescent background

17 Scale up Large scale lab Plate reactor Same set up conditions as lab plate reactor TMSCN Feed Raman Probe 2 Raman Probe 1 Amine Feed Methacrolein Feed

18 Reference Spectra Collected from batch reaction Only thing that cannot be detected is the amine starting material (observed by NIR) Imine Aldehyde TMSCN Product HCN

19 LSL campaign batch 1 Raman Instrument Imine Methacrolein Spectrum # (every 30s) Issue with reactor set-up detected real-time PAT assure that issue resolved and back running same day

20 Normalised Intensity LSL campaign batch 9 Raman Instrument Imine Methacrolein Time

21 Normalisd Intensity LSL campaign batch 9 Raman Instrument Imine Methacrolein HCN TMSCN Product Time

22 Normalised Intensity Instrument 2 Summary Raman Instrument Imine Methacrolein HCN TMSCN Product Manufacturing Time (minutes)

23 Continuous flow summary Raman spectroscopy successfully used across scales from meso scale LSL scale. In situ Raman spectroscopy was an integral part to the monitoring of this stage. The project will not proceed with manufacturing unless PAT is used they consider it as a part of the reactor.

24 Transmission Raman Spectroscopy to monitor uniformity of dosage unit in tablets during tablet manufacturing References 2. Macleod N A, C Eliasson & P Matousek, Hidden depths? New techniques for sub-surface spectroscopy. Spectrosc. Eur. 19(5), 7-10 (2007). 3. Johansson J, A Sparén, O Svensson, S Folestad & M Claybourn, Quantitative Transmission Raman Spectroscopy of Pharmaceutical Tablets and Capsules. Appl. Spectrosc., 61(11), (2007). 4. Eliasson C, N A Macleod, LC Jayes, F C Clarke, S V Hammond, M R Smith & P Matousek, Non-invasive quantitative assessment of the content of pharmaceutical capsules using transmission Raman spectroscopy. J. Pharm. Biomed. Anal., 47(2), (2008). 5. Macleod N A & P Matousek, Deep non-invasive Raman spectroscopy of turbid media, Appl. Spectrosc., 62(11), 291A-304A (2008). 6. Sparén A, J Johansson, O Svensson, S Folestad & M Claybourn, Quantitative Transmission Raman Spectroscopy of Pharmaceutical Tablets and Capsules. Am. Pharm. Rev., Jan/Feb (2009) 7. Fransson M, J Johansson, A Sparén & O Svensson, Comparison of multivariate methods for quantitative determination with transmission Raman spectroscopy in pharmaceutical formulations, J. Chemom. 24(11-12), (2010). 8. Townshend N, A Nordon, D Littlejohn, M Myrick, J Andrews & P Dallin, Comparison of the Determination of a Low-Concentration Active Ingredient in Pharmaceutical Tablets by Backscatter and Transmission Raman Spectrometry, Anal. Chem. 84, (2012).

25 Background Raman spectroscopy used as an alternative to near-infrared spectroscopy (NIR) for non-destructive quantitative analysis of solid pharmaceutical formulations. Compared with NIR spectra, Raman spectra have much better selectivity, which can facilitate calibration. For conventional backscatter Raman spectroscopy, sub-sampling has been an issue for quantitative analysis, but Raman spectroscopy in transmission mode has reduced this issue, since a large volume of an intact tablet is sampled during the measurement. Technique successfully applied in several drug development projects at AstraZeneca. Includes directly compressed formulations, it is essential to have good control of the variation of the content of drug substance in tablets. Case study -Transmission Raman spectroscopy to monitor the uniformity of dosage unit (UoDU) for whole tablets, during tablet manufacturing at the scaleup for a directly compressed formulation.

26 Quantitative Analysis of Solid Samples The major limitation of quantitative Raman analysis of bulk samples has been related to sub-sampling, due to backscatter mode measurements with a highly focused laser and detection optics. Focused No movement Focused Rotation & translation Wide area Transmission

27 Arbitrary scale Arbitrary scale Representative sampling of a tablet? Raman spectra of both sides of a two-layer tablet backscatter Raman shift (cm -1 ) transmission Raman shift (cm -1 ) Sparén et al, 2009: Am. Pharm. Rev. 12(1), 62, 66-71, 73

28 Experimental Between 100 and 200 uncoated tablets per batch were measured with transmission Raman spectroscopy. A small number of tablets (5-10 per batch) were selected for reference analysis, using liquid chromatography. Partial least squares regression (PLS) was used to build a calibration model between Raman spectra and LC reference values, with the aim of determining the concentration of drug substance in whole tablets. The dose of drug substance in each tablet (% label claim) was calculated by multiplying the concentration with the tablet weight.

29 Calibration model A typical calibration model to determine the concentration of drug substance in whole (left); prediction on an independent test set (right).

30 Label claim (%) Prediction of uniformity of dosage unit (%label claim) during tablet manufacturing of a batch, at the scale-up at Sweden Operations. Determination with Raman spectroscopy (blue circles), and liquid chromatography (red circles), respectively. The error bars indicate the variation of the three tablets measured at each sampling time point. 120 Raman Predictons LC reference 115 start tail container change container change end tail Charge (kg)

31 Summary Improved process understanding Can determine EOR during scale changes when mixing efficiency has altered Monitoring reactions real-time that otherwise would have been extremely challenging to monitor Useful for uniformity of dosage unit for directly compressed formulation tablet manufacturing Application of in-line Raman spectroscopy Examples of Raman spectroscopy across scales, including lab, LSL & Pilot plant Can be used for many applications in primary and secondary manufacturing Cost saving (life cycle management) Sampling burden minimised and EoR accurately determined

32 Acknowledgements Richard Hart Nick Pedge Anders Sparén Olof Svensson Magnus Fransson Confidentiality Notice This file is private and may contain confidential and proprietary information. If you have received this file in error, please notify us and remove it from your system and note that you must not copy, distribute or take any action in reliance on it. Any unauthorized use or disclosure of the contents of this file is not permitted and may be unlawful. AstraZeneca PLC, 2 Kingdom Street, London, W2 6BD, UK, T: +44(0) , F: +44 (0) ,