1.  Siemens Nederland N.V. 2001 FDA13April2004 1 Presented by Troy Logan at the Advisory Committee for Pharmaceutical Science meeting on April 13, 2004

2.  Siemens Nederland N.V. 2001 FDA13April2004 2 for internal use only Siemens – PAT solution in pharmaceutical industry

3.  Siemens Nederland N.V. 2001 FDA13April2004 3 Reducing production cycle times Right first time quality (RFT) Preventing rejects, scrap, re-processing Managing variability (improving energy and material use and increasing capacity) Facilitating continuous processing (improve efficiency) Increasing automation to improve operator safety and reduce human errors Real time release PAT opportunities (FDA’s PAT Draft Guidance)

4.  Siemens Nederland N.V. 2001 FDA13April2004 4 Ultimate step – Real Time Product Release Production and release of pharmaceuticals, without final tests Quality is based only on review of process characteristics

5.  Siemens Nederland N.V. 2001 FDA13April2004 5 Standardized over the complete unit BioreactorHarvest & separation PurificationBuffer + Medium FormulationFinishingPackaging

6.  Siemens Nederland N.V. 2001 FDA13April2004 6 Multidisciplinary approach Process Analytics Chemometrics / MVDA Process under- standing (advanced) Controls Process development Modelling MES regulatory

7.  Siemens Nederland N.V. 2001 FDA13April2004 7 PROCESS Control Process Monitoring PAT concept IT / MES INFRASTRUCTURE 1101001001 1001000100 100101111 1001110101 Process Analytics process Specif. verification real-time product release monitoring iterative learning control (process) knowledge optimization control modules electronic batch record equipment modules pharma modules batch

8.  Siemens Nederland N.V. 2001 FDA13April2004 8 Real Time Product Release Process output Temperature, pH, pO2 pressure Close loop control (physical / chemical parameters only) parameters only) Process feed Off lineOn line Required Process information PAT Iterative Learning Control QualitativeQuantitativeFingerprint Transform to quality data Product M Bio- reactor Monitoring Temperature, pH, pO2, pressure Lab based review of product quality holdrelease

9.  Siemens Nederland N.V. 2001 FDA13April2004 9 Infection detection with PAT B. subtilis, C. albicans, S. aureus, E. coli, Ps. Aeruginosa, A. niger and L. Brevis Infected (10 2 CFU / ml )Non infected on yeast based fermentation and substrate samples: Biological contamination

10.  Siemens Nederland N.V. 2001 FDA13April2004 10 Bioreactor process monitoring In-situ NIR Probe

11.  Siemens Nederland N.V. 2001 FDA13April2004 11 Use of PAT as qualitative tool Example vaccine production Process track monitoring and early detection of disturbances Scores plot for the two main principal components on collected spectra during the batch process Process pattern : process fingerprint / signature (multidimensional profile) Comparing “fingerprints” of different batches Change in process status Disturbance Start End

12.  Siemens Nederland N.V. 2001 FDA13April2004 12 Process Path definition Data analysis PAT implementation Road Map Product Q assessment Process assessment analyzer assessement Risk assessment 1. Measure (Monitoring + Process understanding) Process control definition (ideal process runs) Process control for process corrections Knowledge + Change management Continuous optimization & improvement 2. Control 3. Optimization Time Validation Plan People & organizatio- nal Managm.