1. FDA PROCESS ANALYTICAL TECHNOLOGY SUB COMMITTEE MEETING 25 TH FEBRUARY 2002 PERSPECTIVE ON PROCESS AND ANALYTICAL VALIDATION Robert S Chisholm

2. THE TRADITIONAL APPROACH Processes Validated at Life cycle commencement Operated/Controlled by Standard Operating Procedures (SOPs) Quality Assurance based on off-line testing of a sample of product at the end of each batch THE PAT BASED APPROACH On or at line Analysis for real time quality control of each unit operation process control throughout the batch Real time statistically based quality assurance throughout the batch Increased statistically based testing regimes provide the potential for release of product without further off-line testing

3. QUOTATION 1 THE NEED FOR STATISTICS Statistical thinking will one day be as necessary for efficient citizenship as the ability to read and write H G WELLS 1925

4. 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

5. Solid Dosage Facility FB Drier Milling Blender Press Coater Sieve Dispensary Wet granulationNIRNIR NIR NIR Direct Compression Figure 1

6. GENERALISED MODEL OF A PAT SYSTEM THE MODULES (Functionalities) Spectral (or other) data/model storage Analytical (or other) data storage Modelling Reporting (Batch and Validation Records and Storage) Statistical Process control (SPC) and Historic Trending THE MODES OF OPERATION Modelling Validation Manufacturing

7. GENERALISED MODEL OF A PAT SYSTEM Figure 2

8. CONSIDERATIONS FOR THE VALIDATION WG Regulatory status of Model source Data (Spectral analytical etc.) traceability and long term storage Traceability of spectral data, related, analytical data and model predictions for the model validation phase and its long term storage In manufacturing what form will the ‘PAT’ batch record and release data take, How can it be used by QA to release product and how would a regulatory body inspector find an audit path from it for verification The MES/SPC Activities provide process understanding and knowledge – What regulatory status if any is associated with them

9. FURTHER AREAS FOR DISCUSSION Registered processes (traditional) and statistically quality controlled processes Fundamental science and validation 21CFR11 and Computer validation complexity – Open and closed systems

10. QUOTATION FOR THE DAY THE IMPACT OF INNOVATION There is nothing:More difficult to plan :More doubtful of success :More dangerous to manage Than the creation of a new system For the initiator has The enmity of all who profit by preservation of the old institutions AND Merely lukewarm defenders in those who should gain by the new ones Machiavelli (1527)