Ensuring An Effective Quality System M. Kowolenko, Ph.D. SVP, Biopharmaceutical Operations & Technology

1. Ensuring An Effective Quality SystemM. Kowolenko, Ph.D.SVP, Biopharmaceutical Operations & Technology

2. Role of the Quality Unit • Compliance with all relevant regulations and commitments made in license applications or supplements • Systems that assure control over the manufacturing and timely disposition process, regardless of location • Assure that products meet all safety claims, have the identity and strength and meet all the quality and purity characteristics stated • Provide leadership in the Continuous Improvement Process leading to risk* reduction and improved customer satisfaction *Probability and severity of harm.

3. Requirements Internal • Meet business objectives • Produce product with all specified attributes • “Right the first time” • Efficient • Value-added • MAINTAIN CONTROL – BE COMPLIANT

4. GMPs in the 21st Century – Objective : Provide high quality, cost-effective oversight of industry manufacturing, processing and distribution to reduce risk. Apply the most current scientific knowledge about risk management and quality assurance to the FDA's requirements, including Current Good Manufacturing Practice (CGMP) inspection, compliance, and enforcement activities. • Develop new inspection approaches to more effectively utilize new and existing resources. Implement an efficient, risk-based system to promote the wide availability of safe FDA-regulated imports by increasing the standards and improving the practices of source countries and at points of entry into U.S. commerce, improving detection of noncompliant products, and developing standards and procedures to maximize the cost- effectiveness of agency oversight. https://www.fda.gov/oc/mcclellan/strategic_risk.html

5. Agency Expectations • Systems that demonstrate Business in appropriate Control • Management Oversight • Proper delegation and administration • Effective communication • Audit, Monitor, Report • Uniform enforcement, corrective actions • Continuous improvement

6. Inspection Guideline – QSIT • Verify that a quality policy, management review and quality audit procedures, quality plan, and quality system procedures and instructions have been defined & documented. • Verify that a quality policy and objectives have been implemented. • Review the firm’s established organizational structure to confirm that it includes provisions for responsibilities, authorities and necessary resources. • Confirm that a management representative has been appointed. Evaluate the purview of the management representative. • Verify that management reviews, including a review of the suitability and effectiveness of the quality system are being conducted. • Verify that quality audits, including re-audits of deficient matters, of the quality system are being conducted.http://www.fda.gov/ora/inspect_ref/igs/qsit/qsitguide.htm • http://www.fda.gov/cder/dmpq/7356_002M.pdf

7. Form – 483 What’s Hot: 2004 2005 Quality Unit Investigations Investigations Validation Analytical Methods Record keeping (QU) Validation Equipment and Facilities Equipment and Facilities Analytical Methods

8. Drug Quality System for the 21st Century • Science – based Manufacturing Program • – Role of PAT • Clear understanding of HACCP as it relates to process • – Risk based approach • - Q9 Quality Risk Management • Quality by design • – fitness for use • – “life-cycle” of specifications • - Design Space • “Know thy Process and Product”

9. QS: Business Opportunity • Do Current Business Systems & Practices meet worldwide requirements? • Are the program documents too procedurally specific, inadequate, or absent to allow communication of requirements within a given system? • Issues: • ownership avoidance • dilute compliance • stalemate issue resolution • foster untimely response to changes • lack of management oversight

10. Quality Systems ISO 9004 Quality Management System Interested Parties Interested Parties Management Responsibilities Resource Management Measurement, Analysis and Improvement Satisfaction input output Product Realization Requirements

11. Quality Systems Corrective & Preventive Actions Process Transfer Production & Process Controls Management Equipment & Facility Controls MaterialControls Records, Documents, & Change Controls http://www.fda.gov/ora/inspect_ref/igs/qsit/qsitguide.htm

12. Global Standards Program

13. Global Standards Program Hierarchy Approves program approach, responsibility, resources Core Stakeholders Quality Manual Lead Team/Steering Committee Defines “must have” Global Standards SOP Work/Job Instructions Answers “how to” Working Groups Provides Records Working Groups Other Supporting Documentation

14. How do we make Quality everyone's concern? • Enhance metrics related to operational performance and add programs that incorporate increased “awareness”. • operational performance metrics • evolution of original supply chain “cost of quality” program • increased interdepartmental involvement • clear timelines, responsibility and accountability • success measured as delivering on commitments

15. How do we gauge performance in a global organization? Management Review • Objective is to assure we are operating in control and highlight issues before they become a crisis. • Supplement daily and weekly meetings regarding production. • Provide Sr. Management with a common tool for assessing global operations, determining resource allocations, and assuring operational activities are aligned. • Meet compliance requirements of Quality Systems.

16. Pharmaceutical cGMPs for the 21st Century A Risk-Based Approach (Final Report Fall 2004) • Under a quality system, the review should consider at least the following: • The results of audits and other assessments • Customer feedback, including complaints • The analysis of data trending results • The status of actions to prevent a potential problem or a recurrence • Any follow-up actions from previous management reviews • Any changes in business practices or environment that may affect the quality system (such as the volume or type of operations) • Product characteristics meet the customer’s needs

17. Surveillance Leads to Proactive Management of Operations Rejected/Discrepant material Statistical Analysis of Process Performance Laboratory Testing Trend Reports Maintenance Records Industry Surveillance/ Compliance Updates Vendor Performance OOS Investigations Internal Audits Customer Complaints Product Rework/Reprocessing EM Reports BPDRs/Withdrawals/Recalls Annual Product review Issues Management Review

18. Management Review

19. Management Review

20. Site Bulk ManufacturingProduct Scorecard

21. Bulk QualityGeneral Scorecard 1 of 2

22. Bulk Bulk QualityGeneral Scorecard 2 of 2

23. Management Review Action Item Responsible Due Date Provide “Product Quality Overview” presentation to RTP-MR attendee list. Prior to Next Meeting Investigate/Evaluate configuration capability within TRACKWISE for sending notifications to TRN owners (or others as applicable) prior to the current 30-days notification. Next Meeting Include identification of corrective actions when presenting observable OOS/AR trends. Also to include: # related to OOSs, # related to ARs, # related to release testing for product mfg at RTP,# related to release testing for product mfg at other locations, # related to in-process testing, # related to stability testing, others as applicable. Next Meeting Understand the mechanism/process by which a given RAR could be left open for >120 days. What is the cause of the 21 RARs reported as open >120 days for the July-05 metrics. Next Meeting Further define scorecard metric definitions (e.g. CAPA, CWO, Validation) September Meeting Obtain assessment from CMC regarding the appropriate follow-up to the proposal of discontinuing the IMDM use testing. September Meeting

24. Guidance for IndustryPAT – A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance • Design and optimization of drug formulations and manufacturing processes within the PAT framework can include the following steps (the sequence of steps can vary): • Identify and measure critical material and process attributes relating to product quality • Design a process measurement system to allow real-time or near real-time (e.g. on-, in- or at-line) monitoring of all critical attributes • Design process controls that provide adjustments to ensure control of all critical attributes • Develop mathematical relationships between product quality attributes and measurements of critical material and process attributes

25. Process Monitoring Compare batch profile to average +/- 3 standard deviations

26. MVA can identify key sources of variation in the process and provide models for enhanced control Batch 1 Batch 14 Batch 28 Batch 42 Batch 56 Batch 70 Batch 84 Batch 98 Batch 112 Batch 126 Batch 140 The end result is more consistent processes with lower failure rates

27. On-line Batch Monitoring Combines and compares all the critical process parameters to the average batch Identifies process problems before they cause failures

28. Process Improvement and Problem Solving Process Improvement and Problem Solving • Provide T/O with tools to do the appropriate root-cause analysis • Identify the difference between Process Improvement and Problem Solving • Is fundamental to how we approach Exceptions and CAPA • MVA • ASQ training

29. Investigations Process Flow

30. Investigation Approach • QC Assay - investigation • Methods & Process • Cell culture • Downstream, including SLRs • PVRs • Deviations and CCRs • Materials • Cell banks • Serum and Basal medium powder • Resins • Machines & Equipment • Equipment & Facilities work orders (CWO) • Bioreactor trains, columns, skids, storage areas, etc • New equipment • Organization & Systems • SOPs & training • Decision-making (ie., column repacking) • Organization

31. Investigation Techniques • DataMining • Statistical Tools • Pattern-recognition & analysis • “Gap Analysis” • Site current vs. historical • Site vs. Site • Analytical Testing Methods to diagnose/isolate by unit operation • Experimental Design (scaled-down process), if needed

32. Opportunities in Compliance and cGMP Compliance makes good business sense: • The intent of the regulatory agencies is to assure consistency in the product produced – an understanding of the risk/benefit and design space of your process. • Manufacturing organizations want consistency and predictability to maximize facility utilization. • Both parties benefit from constant surveillance and feedback of the quality system process.