Anthony Newcombe PhD Principal Consultant, PAREXEL International

1. Quality Assurance & Systems Requirements Introduction to the development, implementation, and maintenance of compliant quality systems Anthony Newcombe PhDPrincipal Consultant, PAREXEL International Embassy of Denmark Invitation – FDA Seminar 2013 - April 23-24, 2013, Copenhagen, Denmark

2. Aims of the presentation To provide an introduction to the key Quality Systems required for GMP production of pharmaceuticals Highlight some of the key challenges for industry when implementing and maintaining Quality Systems Provide an overview of ICH Q10 (and associated guidance documents Q8, 9 and 11) and discuss the potential impact on Quality Systems

3. Deviation / Event management Corrective Action and Preventive Action (CAPA) System Change Management (Change Control) System Process Performance and Product Quality Monitoring System Pharmaceutical Quality System Review ICH guidelines and ‘enhanced’ pharmaceutical development ICH Q10 EudraLex - Volume 4 Good manufacturing practice (GMP) Guidelines, Chapter 1 ‘Quality Management’ Quality System challenges Presentation overview

4. Pharmaceutical development and scale-up may be challenging Source: Dr Gottschalk, Sartorius Stedim Biotech

5. Deviation / Event Management A Deviation is a departure from standard procedures or specifications resulting in non-conforming material and/or processes Or where there have been unusual or unexplained events which have the potential to impact on product quality, system integrity or personal safety A Deviation should be raised when there is a deviation from methods or controls specified in manufacturing documents, material control documents, standard operating procedure for products (usually using Trackwise) QA should evaluate the deviation and assess the potential impact to the product quality, validation and regulatory All completed deviation investigations should be approved by QA Manager or delegate

6. Deviation / Event Management: Quality System Challenges Deviations and events should be raised / QA assessed within a time specified within site procedures (for example within one business day) The deviation system often includes a target closure date of 30 days for all deviations Dates may be extended, but QA approval should escalated to prevent an unlimited number of extensions Quality metrics should track open and late deviations, but a ‘late’ deviation may be classified as one that is past the original 30 days, or was not extended before the current due date Use of the Quality System for planned deviations should be clearly defined within site procedures

7. Training and System Access Procedures often state that deviations should be raised ‘immediately’, for example during production Not all operators are trained to raise deviations and need to inform a supervisor to assess and enter details into Trackwise Does ‘immediately’ refer to: • The time that the operator notifies the supervisor? • The time that the supervisor enters the details into Trackwise? • Is a supervisor available within the production facility to enter the details into Trackwise? If not, what is the potential delay?

8. Deviations relating to training Training for GMP operations typically re-evaluated to align with SOP review every 2-3 years Even with electronic training systems, deviations due to overdue training are common, the tasks undertaken by the operator during this overdue period needs to be assessed and additional deviations may be required Typically two strategies employed for managing training: • A training co-ordinator manages training for a group or department, may be > 30 individuals • Individual responsibility for managing training and to ensure training activities are up to date • Both strategies may be required to ensure the required visibility and commitment to training activities…

9. Corrective Action and Preventive Action (CAPA) System A system for implementing Corrective actions resulting from the investigation of complaints, product rejections, non-conformances, recalls, deviations, audits, regulatory inspections and findings Preventive actions resulting from trends from process performance and product quality monitoring A structured approach to the investigation process should be used with the objective of determining the root cause CAPA methodology should result in product and process improvements and enhanced product and process understanding

10. Potential CAPA Challenges Root cause investigations should be undertaken using a structured approach utilising a cross functional team Tools including fishbone / Ishikawa diagrams are often used for root cause investigations The effectiveness of the actions should be evaluated for commercial manufacturing Some quality systems used permit deviations to be closed with actions open within the CAPA system, CAPA actions should be tracked and open actions evaluated on a regular basis by a site quality review team

11. Change Management (Change Control) System A change management system ensures continual improvement is undertaken in a timely and effective manner It should provide a high degree of assurance there are no unintended consequences of the change Oversight by the quality unit should provide assurance of appropriate science and risk based assessments Change Management should, as appropriate for the lifecycle stage: • Use Quality risk management (Q9) to evaluate proposed changes • Evaluate proposed changes relative to the marketing authorisation and need for a change to the regulatory filing • Evaluate proposed changes using expert teams • There should be an evaluation of the first batches produced or tested under the change to confirm the change objectives were achieved and that there was no deleterious impact on product quality

12. Change Management (Change Control): Challenges Delays may cause issues when the change control process proceeds faster than document review, for example BR review by QA QA review and approval process of executed documents should be timely and ensure completeness and accuracy Deviations may be raised by QA because current procedures were not followed BUT this is because procedures have been updated via the change control process between BR execution and review Un-necessary deviations and root cause investigations for issues with no product or GMP impact due to lengthy document review times

13. Process Performance and Product Quality Monitoring System Proposed changes should be evaluated relative to the marketing authorisation, including design space, where established, and/or current product and process understanding There should be an assessment to determine whether a change to the regulatory filing is required under regional requirements Proposed changes should be evaluated by expert teams contributing the appropriate expertise and knowledge from relevant areas (e.g., Pharmaceutical Development, Manufacturing, Quality, Regulatory Affairs and Medical), to ensure the change is technically justified. Prospective evaluation criteria for a proposed change should be set

14. Review of the Pharmaceutical Quality System Management Review of Process Performance and Product Quality Management reviews provide assurance that process performance and product quality are managed over the lifecycle Review should include a timely and effective communication and escalation process to raise appropriate quality issues to senior levels of management for review Results in appropriate actions, such as: • Improvements to manufacturing processes and products • Training and/or realignment of resources • Capture and dissemination of knowledge

15. Review of the Pharmaceutical Quality System, con’t Management should have a formal process for reviewing the pharmaceutical quality system on a periodic basis • Measurement of achievement of pharmaceutical quality system objectives • Complaint, deviation, CAPA and change management processes • Feedback on outsourced activities • Self-assessment processes including risk assessments, trending, and audits • External assessments such as regulatory inspections and findings and customer audits The Quality Management System should not be considered simply as a system to document events to ensure GMP compliance

16. Issued July 2008 as CHMP/ICH/214732/04 ‘Move from regulatory guidance to scientific guidance to harmonized pharmaceutical quality system applicable across the lifecycle of the product emphasizing an integrated approach to quality risk management and science’ Implementation of ICH Q10 throughout the product lifecycle should facilitate innovationand continual improvement and strengthen the link between pharmaceutical development and manufacturing activities ICH Q10, Pharmaceutical Quality System

17. ICH Q10 objectives Quality System Objectives (ICH Q10) • Deliver products with the quality attributes appropriate to meet the needs of patients • Establish effective monitoring and control systems for process performance and product quality • To identify and implement appropriate improvements, variability reduction, innovations and pharmaceutical quality system enhancements

18. ICH Q10 compliments ICH Q8, Q9 & Q11 ICH Q9 ICH Q8 (R2) Pharmaceutical Development ICH Q8 ICH Q9 Quality Risk Management • Guidance for 3.2.P.2 of CTD • ‘Enhanced’ Approaches • Design Space • Process Analytical Technology (PAT) • Control strategies • Critical attributes • Critical parameters • A-Mab & A-Vax case studies • Risk identification, analysis, evaluation • Control, reduction and acceptance • Use of risk tools: • FMEA, risk ranking, statistical tools ISO & ICH Q7 ICH Q10 ICH Q11 ICH Q10 Pharmaceutical Quality System ICH Q11 Development & Manufacture of Drug Substances • Product lifecycle • CAPA • Change Control • Process Performance Monitoring • Quality Systems Review • Guidance for Sections 3.2.S.2.2 – 3.2.S.2.6 of CTD • “traditional” and “enhanced” approaches • Quality Target Product Profile (QTPP) • Critical Quality Attributes (CQAs) • Control strategies

19. Regulatory guidance for pharmaceutical development continues to evolve

20. Regulatory guidance for process validation and pharmaceutical development Global Harmonisation Task Force, Process Validation Guidance GHTF/SG3/N99-10-04 (Ed 2) FDA guidance for Industry, Process Validation, General Principles & Practice, Nov 2008 (draft) EMEA Concept paper, Guideline on Process Validation, EMA/CHMP/CVMP/QWP/809114/2009 Consultation for Review EMEA Guidance for Process Validation EMEA/CVMP/598/99 Sep 2001 Process Validation of Protein Manufacturing, PDA TR 42, Sep/Oct 2005 2012 2003 2004 2004 2005 2001 1987 2008 2008 2009 2010 2011 EMEA Concept paper, Guideline on Process Validation FDA Guidance for Industry, Process Validation: General Principles & Practices May 1987 (draft) Practical GMPs for the 21st Century – A Risk based approach Sep 2004 ICH Q8R2, Pharmaceutical Development Aug 2009 EMEA Guidance for Process Validation EMEA/CVMP/598/99 Sep 2001 ICH Q11, Final Concept Paper, Development and manufacture of drug substances, Apr 2008 Final step ongoing

21. Enhanced approaches to pharmaceutical developmentAPIs, monoclonal antibodies and vaccines • A-Mab, 2009 (ISPE) • A-Vax, 2012 (PDA)

22. ICH Q10, conclusions ICH Q10 is not intended to create any new expectations beyond current regulatory requirements. Consequently, the content of ICH Q10 that is additional to current regional GMP requirements is optional The elements of ICH Q10 should be applied in a manner that is appropriate and proportionate to each of the product lifecycle stages, recognising the differences among, and the different goals of each stage

23. The new Quality Paradigms Science is no longer isolated; it is living across the lifecycle of the product/process within a Quality Management System Guidance describes the use of risk assessments (FMEA, risk ranking) to evaluate of critical Quality Attributes (CQAs), Critical Process Parameters (CPPs) and define control strategies throughout the product lifecycle Design Space / DoE studies may be used to transfer enhanced product and process knowledge from R&D to Manufacture to Regulatory Affairs Use of Quality Systems may need to be considered earlier in the development process to capture and document formal risk assessments and design space studies for enhanced pharmaceutical development

24. Thank You! Anthony Newcombe PhDPrincipal ConsultantPAREXEL Internationalanthony.newcombe@parexel.com