1. Total Quality Management System (TQMS) AstraZeneca Solid Dosage Facility, Plankstadt, Germany Ali Afnan AstraZeneca Pharmaceuticals Engineering Group Alderley House, Alderley Park Macclesfield, UK ali.afnan@astrazeneca.com

2. Ali Afnan 2 Implementation of the TQM Strategy In-Process Control & Monitoring Key Process Operations Identification / specification of all incoming raw materials in the dispensaries (& the warehouse) Fluid Bed Drier end point control Continuous in-line monitoring of blending & end point control In-line monitoring of Tablet Quality parameters against registered specifications 21CFR11 compliant data management system Real-time continuous quality assurance The platform for parametric release

3. Ali Afnan 3 TQMS Benefits- I Enhanced product quality assurance Significant manufacturing cost reduction Reduction of product inventory The elimination of end-of-line off-line testing providing opportunity for a new way of working significant increase in supply chain velocity Reduces business risk Increases competitive advantage Allows “ remote ” regulatory inspection

4. Ali Afnan 4 TQMS- Dispensaries Systems approach NIR Analyser Brimrose AOTF Multiplexed Analyser Diffuse reflectance measurement (1100-2300 nm) CIP and WIP probes Performs the analyses at every dispensing operation Allows control of recipe management Release of incoming materials by the plant Utilising Bespoke 21CFR11 compliant software Local panel PC’s Barcode readers

5. Ali Afnan 5 TQMS- Dispensary Operation Operator scans material barcode (Article No. & Batch No.) Analyser enabled for operation Operator prompted through dispensing process Trigger actuated by operator Spectra collected with probe in-situ I.D. reported & confirmed Qualitative/ qualitative results reported & stored

6. Ali Afnan 6 TQMS- FBD Probe permanently installed FBD CIP and WIP probe designed to minimise fouling Operator scans product barcode (Article No. & Batch No.) Analyser enabled for operation Predicted moisture values sent to FBD Control System for drying end point.

7. Ali Afnan 7 The Blending Process Process of changing the constituent matrices Mixing (re-distribution) of particles of differing: physical characteristics / chemical properties Process of attrition & agglomeration A complex process Currently under scientific scrutiny Driving a “holistic” re-assessment of blend process understanding and means of monitoring.

8. Ali Afnan 8 TQMS- The Blending Process Objectives are: To monitor the “whole” powder mix in the blending vessel Non-invasively & non-intrusively To determine completion of the blending process During every blending operation To deliver consistent quality Applicable to a range of blender types

9. Ali Afnan 9 TQMS NIR Blend Monitoring System IBC with Sapphire window Brimrose AOTF NIR “Free-Space” Analyser Portable Sample (Beam) size: 9 mm x 5 mm Diffuse reflectance (1100-2300 nm) Battery & mains operation CIP and WIP analyser All solid state hardware Provides process reproducibility 21CFR11 compliant package

10. Ali Afnan 10 Analyser Interface Eliminates the need for optical coupling

11. Ali Afnan 11 Blending System in Position

12. Ali Afnan 12 Blending & Monitoring at 10 rpm

13. Ali Afnan 13 TQMS Blender Operation Real-time blend monitoring for “end-point” control &/or other parameters (active or excipient) Stop signal transmitted to blender control unit on reaching ”end point” On returning the analyser to Docking Station, data is down-loaded to data storage system Batteries get recharged Analyser is in stand-by until next batch

14. Ali Afnan 14 TQMS- Operator Interface I

15. Ali Afnan 15 TQMS- Operator Interface II

16. Ali Afnan 16 TQMS- Operator Interface VII

17. Ali Afnan 17 TQMS- Operator Interface IIX

18. Ali Afnan 18 TQMS Tablet Analyser Unique, novel, purpose-built Brimrose AOTF analyser Transmission (800-1300 nm) and, Diffuse reflectance (1100-2300 nm) Non-destructive, real-time tablets analysis of tablets ex press prior to check weighing system IP65 instrument CIP and WIP analyser Vibration resistant Up to 30 tablets per minute, different tablet size and shapes

19. Ali Afnan 19 Analyser in-situ

20. Ali Afnan 20 Tablet Analyser- Off-line

21. Ali Afnan 21 TQMS Tablet Analyses For monitoring: Moisture I.D. of active (& excipient) Concentration of active (& excipient) Dissolution Disintegration Hardness Density

22. Ali Afnan 22 Manufacturing Operations responsible for Quality Assurance  Quality Control @ time of manufacture  Compliance @ point of use @ every manufacturing process  Statistical process control @ Lower cost than existing practices Extensive testing & Analyses per manufacturing process TQM System

23. Ali Afnan 23 Acknowledgements Dr Johann Mueller- Plant Manager, PTF, Plankstadt Dr Hubert Gotta- QA Manager, Plankstadt Dr Christina Gerhaeusser- QA, Plankstadt Dr Thorsten Herkert- QA, Plankstadt Mr Peter Marshall- Process Engineer, Tech. Dev. Section, PEG Mr Peter Jewitt- PTF Project Manager, PEG Mr Daniel Frick, Development IS, Molndal Mr Bengt Boissier, Development IS, Molndal The NIR Team Mr Robert Chisholm, Tech. Dev. Section Manager, PEG Mr Simon Blackett, Tech. Dev. Section, PEG Mr Ray Bolton, Tech. Dev. Section, PEG