Quality Management and Pharmaceutical Quality System

1. Basic Principles of GMP Quality Management and Pharmaceutical Quality System Section 1 and 2

2. Quality Management Objectives • To understand key issues in quality management, quality assurance, good manufacturing practices and quality control. • To understand specific requirements on quality management and quality assurance including: • Organization • Procedures, processes and resources. • To develop actions to resolve your current problems.

3. Quality Management Quality relationships Quality Management and PQS Quality Assurance GMP Production and Quality Control

4. PQS and Quality Management Comprehensive Pharmaceutical Quality System, GMP and Quality Risk management: • The manufacturer assumes responsibility. Ensures that products: • fit for their intended use • comply with marketing authorization • do not place patients at risk due to inadequate safety, quality or efficacy • Senior management and participation and commitment of staff, suppliers and the distributors 1.1. – 1.2.

5. PQS and Quality Management Pharmaceutical Quality System • Senior management - leadership and active participation in the PQS is essential. Ensure the support and commitment of all staff to the PQS. • Senior management has the ultimate responsibility to ensure: • effective PQS is in place • adequately resourced and that roles, responsibilities, and authorities are defined, communicated and implemented throughout the organization 1.1. – 1.2.

6. PQS and Quality Management • PQS should be defined and documented • Quality manual or equivalent documentation describing the quality management system including management responsibilities. • Periodic management review of the PQS • Continual improvement of PQS, products and processes 1.6. – 1.7.

7. PQS and Quality Management Pharmaceutical Quality System • Quality management is a wide-ranging concept • Totality of arrangements to ensure that products are of desired quality • It incorporates good manufacturing practices (GMP) and other factors such as product design and development 1.3.

8. PQS and Quality Management • GMP applies to the life-cycle stages • from the manufacture of investigational medicinal products, technology transfer, commercial manufacturing through to product discontinuation • PQS: can extend to the pharmaceutical development life-cycle stage • Should facilitate innovation and continual improvement • link between pharmaceutical development and manufacturing activities • Resourced and maintained (premises, personnel, equipment, facilities) 1.4.

9. PQS and Quality Management The PQS should ensure that: • product realization is achieved • designing, qualifying, planning, implementing, maintaining and continuously improving a system • product and process knowledge is managed • products are designed and developed (GMP, GLP,GCP) • SOPs for production and control operations • responsibilities are clearly specified in job descriptions 1.5.

10. PQS and Quality Management PQS should ensure that (2) • correct starting and packaging materials • controls on starting materials, intermediate products, and bulk products and other in-process controls, calibrations and validations are carried out • the finished product is correctly processed and checked • finished product release - certified that each production batch has been produced and controlled in accordance with the marketing authorization and regulations 1.5.

11. PQS and Quality Management PQS should ensure that (3) • management of outsourced activities • storage, distribution and subsequently handling • self-inspection and/or quality audit • investigation of deviations and preventive action • changes and their approval • regular reviews of the products (PQR) - need for improvement 1.5.

12. PQS and Quality Management PQS should ensure that (4) • monitoring and control systems for process performance and product quality • continual improvement • quality risk management (QRM) • suspected product defects and other problems are reported, investigated and recorded • corrective actions and/or preventive actions (CAPAs) (effectiveness should be monitored) 1.5.

13. PQS and Quality Management QA System should ensure that: • Products are designed and developed in accordance with GLP, GCP, and GMP • Production and control operations are clearly specified in SOPs • Managerial responsibilities are clearly specified in job descriptions • Systems ensure that the correct starting and packaging materials are used 1.5.

14. PQS and Quality Management QA System should ensure: • Starting materials, intermediate products, bulk products are controlled • In-process controls, calibrations, and validations are carried out • Finished products are correctly processed and checked • Products are not sold or supplied before release by authorized persons • Systems ensure that products are appropriately stored and distributed 1.5.

15. PQS and Quality Management QA System should ensure: • Self-inspection and/or quality audits are done regularly • Deviations are reported, investigated and recorded • Changes are controlled • Systems are followed to verify the consistency of processes and ensuring continuous improvement • Quality Risk Management is implemented 1.5.

16. PQS and Quality Management Quality Risk Management • Manufacturers should manage quality risks. Quality Risk Management (QRM) is a systematic process for: • assessment, control, communication and review of risks to the quality of the medicinal product. • QRM: • can be applied both proactively and retrospectively • Should be based on scientific knowledge and experience with the process • Should be linked to the protection of the patient 1.8. – 1.9.

17. Quality Risk Management (ICH Q9) Advanced training workshop for GMP inspectors Nairobi , 9-12 May, 2011

18. Quality Risk Management Quality Risk Management • Quality Risk Management follows a cycle of assessment, control, communication and review. • An appropriatetoolshouldbeused in riskassessment, such as: • Fault Tree Analysis (FTA) • Hazard and Operational Studies (HAZOP) • Failure Mode and Effect Analysis (FMEA) • Hazard Analysis and Criticality Analysis (HACCP) • Failure Mode, Effect, and Criticality Analysis (FMECA)

19. Quality Risk Management Failure Mode Effect Analysis • Breakdown in manageable steps • Process and product understanding needed • Evaluate failure mode and effect on outcome • Eliminate, contain, reduce, control • (Identify mode, cause, effect)

20. Product Quality Review Product quality review (PQR) • Regular, periodic or rolling quality reviews of all medicinal products • Normallyannually – canalsobe more frequently • Objective: • Verifying the consistency of the existing process • appropriateness of current specifications for both starting materials and finished product • highlight any trends • identify product and process improvements. 1.10.

21. Product Quality Review • PQR should include at least a review of: • starting materials and packaging materials (especially from new sources and review of supply chain) • critical in-process controls and finished product results • all batch failures and their investigation • deviations or non-conformances (and investigations and CAPAs) • all changes made to the processes or analytical methods • dossier variations submitted, granted or refused • results of the stability monitoring programme and any adverse trends 1.10.

22. Product Quality Review • PQR should include (cont).: • quality-related returns, complaints and recalls and the investigations • adequacy of previous corrective actions on product process or equipment • Post marketing commitments • qualification status of relevant equipment and utilities • technical agreements 1.10.

23. Product Quality Review Product quality review (PQR) • Results should be reviewed- assessment should be made whether CAPA or revalidation should be undertaken • CAPA completed in a timely and effective manner – verified • Product types can be grouped • Agreements in case of contracted parties • PQR in a timely manner and verified for accuracy 1.10.

24. Product Quality Review When inspecting PQR, also verify: • Correctness of data transferred • Trending of results • Calculations such as process capability index (CpK) - where appropriate • Accuracy in terms of APIs reflected, approved suppliers used, number of batches, variations, changes, complaints etc. • CAPAs and conclusion

25. PQS and Quality Management Good Manufacturing Practices (GMP) • That part of QA that ensures that products are consistently produced and controlled • Quality standards • Marketing authorization, clinical trial authorization and/or product specification • Aim: Diminishing risks that cannot be controlled by testing of product • Contamination and cross-contamination • Mix-ups (confusion) 2.1

26. PQS and Quality Management Basic Requirements for GMP – I • Manufacturing processes are clearly defined and systematically reviewed for risks – scientific knowledge and experience • Qualification and validation is performed • Appropriate resources are provided: • Qualified and trained personnel • Premises, space, equipment and services • Materials, containers, labels • Procedures, storage, transport • Laboratories and in-process control 2.1 a - c

27. PQS and Quality Management Basic Requirements for GMP – I • Clear, written instructions and procedures • Trained operators • Records of actions, deviations and investigations • Records for manufacture and distribution • Proper storage and distribution • Systems for complaints and recalls 2.1 d - j

28. PQS and Quality Management Group session – I • How many GMP deficiencies can you find in the photographs in the handout?

29. PQS and Quality Management Group session II • Imagine you are inspecting a pharmaceutical company for compliance with GMP • Consider the situations in the next slides which may have impact on a company’s quality management programme • Describe the action to be taken in each case

30. PQS and Quality Management Issues – I • Quality Management manual not established in writing • Limited human resources • Lack of qualified people • Processes not properly validated • Poor SOPs or standard batch documentation • More consideration to cost than quality • Family members in key positions of authority

31. PQS and Quality Management Issues – II • Substandard materials deliberately purchased • Technical staff not involved in purchasing • Inability to re-export substandard materials • Owner insists on selling rejects • Corruption • No commitment to training