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

Transcription

1 Ensuring An Effective Quality System M. 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. 2

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

4 GMPs in the 21 st Century Objective : Provide high quality, costeffective 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 costeffectiveness of agency oversight. 4

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 5

6 Inspection Guideline QSIT 1. Verify that a quality policy, management review and quality audit procedures, quality plan, and quality system procedures and instructions have been defined & documented. 2. Verify that a quality policy and objectives have been implemented. 3. Review the firm s established organizational structure to confirm that it includes provisions for responsibilities, authorities and necessary resources. 4. Confirm that a management representative has been appointed. Evaluate the purview of the management representative. 5. 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.

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

8 Drug Quality System for the 21 st 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 8 Know thy Process and Product

9 QS: Business Opportunity 9 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 Management Responsibilities Interested Parties Resource Management Measurement, Analysis and Improvement Satisfaction Requirements input Product Realization output 10

11 Quality Systems Process Transfer Material Controls Corrective & Preventive Actions Management Records, Documents, & Change Controls Production & Process Controls Equipment & Facility Controls 11

12 Global Standards Program Management Responsibilities Quality System Management Review Management Tools Corrective/ Preventive Action Facilities, Utilities & Equipment Production/ Process Controls Laboratory Controls Material Controls Documentation Management 1. Training 2. Performance/cGMP 3. Trend Analysis 4. Internal/External Audits 1. Adverse Events 2. Complaints 3. Deviations 4. Investigations 1. Facility Changes 2. Utilities 3. Maintenance 4. Reg. Submissions/Val. 1. Process Validation 2. Cleaning Validation 3. E M 4. Batch Records 5. Change Control 6. Regulatory Submissions 1. Handling of Raw Data 2. Assay Development 3. Stability Testing 1. Material Specifications 2. Accountability 1. Document Control 2. Annual Review of Docs 3. Electronic Doc. Mgmt. 12

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

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 14

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. 15

16 Pharmaceutical cgmps for the 21 st 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 16

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

18 Management Review Recurring/Non-recurring Deviations Recurring Non-Recurring Total Deviations Mar-05 Apr-05 May-05 Jun-05 Jul-05 Month 18

19 Management Review Open RARs Total RARs Open Total RARs Open > 30 Days Total RARs Open > 120 Days February March April May June July 19

20 Site Bulk Manufacturing Product Scorecard Bulk Metrics Q1 Actual Q2 Target Apr Actual May Actual Jun Actual Q2 Actual Delivery Index 100% 100% 100% 100% 100% 100% Throughput Index 104% 90% 124% 111% 85% 107% Average Yield Cost per Batch $,000 Cost per Gram $,000 Batches Failed Cost of Batches Lost $0 $0 $0 $0 $0 $0 Grams Produced Success Rate 100% 90% 100% 100% 100% 100% Grams Planned Thaw Rate NA Batches Completed Batches Planned

21 Bulk Quality General Scorecard 1 of 2 General Metrics Scorecard Q1 Actual Q2 Target Apr Actual May Actual Jun Actual Q2 Actual DEVIATIONS Number of Batches Thawed N/A N/A General Deviations per Batch < Average Cycle Time < Total Number of Deviations open >120 Days CAPAs Total Number of Open CAPAs N/A N/A Percent of Open Overdue CAPAs 0% 56% 53% 50% 53% OUT OF SPECIFICATION Number of OOS/AR generated < Average Cycle Time < Number of OOSs open >30 Days < Number of OOSs open >120 Days REMEDIAL ACTION REPORTS Total Number of instruments calibrated N/A ,748 Percent of Out of Tolerance TBD 1.2% 0.8% 1.1% 1.0% RAR Cycle Time Average 72 < Number of RARs open >30 Days < Number of RARs open >120 Days

22 Bulk Bulk Quality General Scorecard 2 of 2 General Metrics Scorecard Q1 Actual Q2 Target Apr Actual May Actual Jun Actual Q2 Actual CRITICAL WORK ORDERS Total Number of CWOs generated N/A Number of CWOs open >180 Days DOCUMENTATION METRICS Number of Change Requests initiated N/A Average Change Request Cycle Time < Number of Change Requests open >90 Days < ASSAY FAILURES Number of Assay Failures Chemistry 111 < Number of Assay Failures Bioanalytical 142 < ENVIRONMENTAL MONITORING Number of Action Alerts recorded 108 TBD Percent of open Alert Actions >30 Days old

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. 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 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 23

24 Guidance for Industry PAT 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 24

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

26 MVA can identify key sources of variation in the process and provide models for enhanced control Amevive 2K Titer Campaign and 2003 Campaign R R R R R R R R R R R R R R R R R R R R R 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 GrA280 Average UCL +3SD LCL -3SD Average

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

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

29 Investigations Process Flow Investigation Process Data General General (1) Event Occurs (6) Investigation Conducted Minimally include: 1. Problem statement 2. Data collection 3. Root cause analysis 4. Impact Statement 5. CAPA 6. Conclusion statement (2) Describe Event Type (3) Event communicated (7) Investigation Reviewed 1. Area manager assessment 2. Quality assessment (4) Decision to Investigate (8) Investigation Approved (5) Investigator Assigned 29

30 Investigation Approach 30 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 31

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. 32