How the adoption of the PIC/S GMP code by the Australian Therapeutic Goods Administration (TGA) will impact pharmaceutical companies who use contract manufacturers. Presentation discusses the regulatory obligations and how quality risk management should be used.

1. Impact and Influence of Regulatory Changes to the Contract Manufacturing Market

2. An Australian case study Late January, 2003 serious adverse reactions were reported to the TGA by consumers of ‘Travacalm’ Contract manufacturer was Pan Pharmaceuticals The product contained 200 micrograms of Hyoscine Hydrobromide (AI)

3. An Australian case study 87 adverse reactions Hallucinations 19 people hospitalised Product sponsor was Key Pharmaceuticals who contracted Pan Pharmaceuticals to manufacture five batches, for the first time

4. An Australian case study TGA testing revealed that the content of AI varied from 0% to 700% of all five batches involved The subsequent urgent audit of Pan Pharmaceuticals revealed that; The wet granulation method of manufacture (as specified in Marketing Authorisation) had not been used Very poor mixing validation studies The particle size of the Hyoscine Hydrobromideactive ingredient used by Pan was too large to be mixed uniformly throughout the batch

5. An Australian case study Series of other citations Elimination of out of specification results Manipulation of HPLC data and records Subsequent recall of 1800 products License suspension of Pan Pharmaceuticals

6. An Australian case study Contract manufacturing issues (contract acceptor) Pan had deviated from the Marketing Authorisation requirements during manufacture Pan did not communicate this or other out of specification results to contract giver No ‘authorised person’ checks that batches complied with the Marketing Authorisation

7. An Australian case study Contract manufacturing issues (contract giver) Key had not audited Pan Key had not checked the quality of the final product A ‘GMP agreement’ was in place

8. Impact and Influence of Regulatory Changes to the Contract Manufacturing Market Open your mind Figure 6 It’s too simplistic to just speak in reference to the PIC/S GMP Chapter 7 The Pharmaceutical industry demands more than this

9. Impact and Influence of Regulatory Changes to the Contract Manufacturing Market Contract manufacture and analysis incorporated into a Quality Systems approach Nothing is ‘stand alone’ Validation Quality Control Quality Risk Management

10. Impact and Influence of Regulatory Changes to the Contract Manufacturing Market Build quality in Cannot test quality into a product Management responsibilities Resources Manufacturing operations Evaluation activities

11. Impact and Influence of Regulatory Changes to the Contract Manufacturing Market Key concepts Quality Quality by Design, product development Quality risk management CAPA Change management Quality unit Inspection

12. Impact and Influence of Regulatory Changes to the Contract Manufacturing Market Management responsibilities Provide leadership Structure organisation Build a Quality System to meet requirements Establish policies, objectives and plans Review the system

13. Impact and Influence of Regulatory Changes to the Contract Manufacturing Market Resources General arrangements Personnel development Facilities and equipment Control outsourced operations

14. Impact and Influence of Regulatory Changes to the Contract Manufacturing Market Manufacturing Design, develop, document product and processes Examine inputs Perform and monitor operations Address non conformities

15. Impact and Influence of Regulatory Changes to the Contract Manufacturing Market Evaluation activities Analyse data for trends Conduct internal audits Quality risk management CAPA Promote improvement Guidance for Industry – Quality Systems Approach to Pharmaceutical CGMP Regulations, U.S. Dept of Health and Human Services, FDA, September 2006

16. The new frontier – Quality Risk Management ICH Q9 Annex II, Potential Applications for Quality Risk Management Quality Risk Management as Part of Integrated Quality Management

17. The new frontier – Quality Risk Management Quality Risk Management as Part of Integrated Quality Management Regulatory operations Inspections and assessment Development Facilities, equipment and utilities

18. The new frontier – Quality Risk Management Quality Risk Management as Part of Integrated Quality Management Materials management Production Lab control and stability studies Packaging and labelling

19. Contract Manufacture and Analysis The system of Quality Assurance appropriate for the manufacturer of medicinal products should ensure that: Medicinal products are not sold or supplied before an Authorised Person has certified that each production batch has been produced and controlled in accordance with the requirements of the Marketing Authorisation and any other regulations relevant to the production, control and release of medicinal products

20. Contract Manufacture and Analysis Avoid misunderstandings Primary intentis that no product or work of unsatisfactory quality is manufactured Defined Agreed Controlled

21. Contract Manufacture and Analysis Written contract (details commercial, contractual status) Duties and responsibilities Qualified person responsible for batch release has specific duties to fulfill

22. Contract Manufacture and Analysis Marketing Authorisation Change management

23. Contract Manufacture and Analysis

24. Contract Manufacture and Analysis

25. Contract giver Assess the competence of the contract acceptor Maintain GMP compliance, Marketing Authorisation requirements and technical requirements by means of the contract “...successfully”

26. Contract giver Full disclosure Problems known that may pose hazards All information necessary Business benefits Get it done right, the first time, every time

27. Contract Acceptor Adequacy Premises Equipment Knowledge and expertise Personnel competence

28. Contract Acceptor Contract acceptors must hold their own Marketing Authorisation 3rd party agreements are prohibited without prior consent, evaluation and approval No adverse impact on product quality

29. The contract Specifies respective responsibilities Technical aspects Pharmaceutical technology Analysis of data GMP Marketing Authorisation requirements

30. The contract or a ‘GMP agreement’ Can be acceptable to have a less formal ‘GMP agreement’ in the place of a contract A commercial contract and a linked and cross referenced GMP agreement Cost disclosure

31. The contract or a ‘GMP agreement’ Legally binding commercial contract Price Indemnity Confidentiality clause requiring non disclosure of the contract to any third party Using this methodology, only the GMP agreement would be shown to an auditor

32. Materials flow Materials Received materials are fit for their intended purpose Meet their assigned acceptance criteria Are released by a Qualified Person Contract giver must ensure that each batch received complies with specifications or has been released by an authorised person

33. Materials flow Qualified Persons responsibilities Purchasing Testing and release of materials Production Quality controls Sampling and analysis

34. GxP critical documentation Records Manufacturing Analytical Distribution Reference and retention sampling and documentation

35. Auditing The contract giver can visit and audit the contract acceptor’s facilities The contract acceptor may be subjected to regulatory audits

36. GMP requirements Counterfeiting Ongoing stability program Monitoring stability post marketing Extending stability to the end of the product shelf life

37. What’s not covered in PIC/S GMP code chapter 7? Complaints and recalls Stability testing Reprocessing Methodology of change control Retention periods for GxP records and retention samples Include these in your contracts or GMP agreements

38. ICH Q8 – Pharmaceutical Development ICH Q8 Pharmaceutical Development Quality by Design The aim of Pharmaceutical Development is to design a quality product and its manufacturing process, to consistently deliver the intended performance of the product

39. ICH Q8 This concept relies on a ‘lifecycle’ approach where knowledge evolves as experience with the product is realised ICH Q8 Pharmaceutical Development ICH Q9 Quality Risk Management ICH Q10 Pharmaceutical Quality System

41. Knowledge from clinical phase studies

42. Quality Risk Management

44. ICH Q8, Q9 and Q10 Utilise Q8, Q9 and Q10 to; Reduce the risk exposure to the company posed by a lack of information Reduce the risk exposure to the customer posed by a lack of information

45. ICH Q8 Operating within a design space Hidden sources of variability exist within any process Assessment of these variables and their impact on product quality

46. ICH Q8 Critical Quality Attribute (CQA) the characteristics that define product quality and feed directly in to Quality by Design

47. ICH Q8 Critical Quality Attribute (CQA) Quality attributes that must be controlled within pre defined limits Assurance that product meets its intended safety, efficacy, stability and performance

48. ICH Q8 Critical Process Parameter (CPP) a process parameter that must be controlled within pre defined limits Assurance the product meets its pre defined quality attributes

49. Continual improvement New technologies Communication Implementation using a lifecycle approach

50. Example of a GMP Agreement for contract manufacturing (Page 1)

51. Example of a GMP Agreement for contract manufacturing (Page 2)

52. Example of a GMP Agreement for contract manufacturing (Page 3)

53. Example of a GMP Agreement for contract manufacturing (Page 4)

54. Example of a GMP Agreement for contract manufacturing (Page 5)