1. | Slide 1 of 57 October 2007 Dr A J van Zyl Technical Officer HTP/PSM/QSM World Health Organization (WHO) Geneva, Switzerland vanzyla@who.int Training Workshop on Pharmaceutical Development with a focus on Paediatric Formulations 15 October 2007 Tallinn, Estonia 1 Good Manufacturing Practices (GMP) and Inspections

2. | Slide 2 of 57 October 2007 Good Manufacturing Practices (GMP) and Inspections Outline and Objectives of presentation Introduce WHO GMP texts –Main principles –Supplements –Others In the context of Prequalification Current and future approaches Inspections in prequalification

3. | Slide 3 of 57 October 2007 Good Manufacturing Practices (GMP) and Inspections WHO GMP text: Main principles WHO Technical Report Series, No. 908, 2003 –Annex 4 Regularly reviewed and updated Divided into "chapters" or "quality systems" Quality assurance,

4. | Slide 4 of 57 October 2007 Good Manufacturing Practices (GMP) and Inspections 1. Quality assurance 2. Good manufacturing practices for pharmaceutical products (GMP) 3. Sanitation and hygiene 4. Qualification and validation 5. Complaints 6. Product recalls 7. Contract production and analysis 8. Self-inspection and quality audits

5. | Slide 5 of 57 October 2007 Good Manufacturing Practices (GMP) and Inspections 9. Personnel 10. Training 11. Personal hygiene 12. Premises 13. Equipment 14. Materials 15. Documentation 16. Good practices in production 17. Good practices in quality control

6. | Slide 6 of 57 October 2007 Good Manufacturing Practices (GMP) and Inspections Other texts: Sterile products Herbal medicines Radiopharmaceuticals HVAC Water systems Sampling etc

7. | Slide 7 of 57 October 2007 Good Manufacturing Practices (GMP) and Inspections Also to consider when necessary: PIC/S guidelines ISO guidelines –Sampling –Risk management –Clean rooms ICH guidelines –ICH Q9 USA FDA –Guidelines and guidance

8. | Slide 8 of 57 October 2007 Good Manufacturing Practices (GMP) and Inspections Context in Prequalification Product specific (dosage form) inspections SOPs followed: –Planning, preparation, conduct, report –Inspection team Appropriate guidelines used Report with references to text, and rating –Critical, major, minor

9. | Slide 9 of 57 October 2007 Good Manufacturing Practices (GMP) and Inspections A critical deficiency was defined as a deficiency which had produced, or led to a significant risk of producing, either a product which was harmful to the human patient or a product which could result in a harmful residue in a food producing animal. A major deficiency was defined as a non-critical deficiency, which had produced or might produce a product which did not comply with its marketing authorisation. A minor deficiency was defined as a deficiency where an observation made could improve the quality system and quality assurance approach of the manufacturer, but which did not have a major impact on the quality of the product.

10. | Slide 10 of 57 October 2007 Good Manufacturing Practices (GMP) and Inspections Inspection approach Normally a "routine type" of GMP inspection Opening meeting, follow the flow, closing meeting On site inspection (production and quality control) and documentation review Quality systems approach Modern challenges including risk assessment

11. | Slide 11 of 57 October 2007 Good Manufacturing Practices (GMP) and Inspections Guiding principles: Risk based orientation Science based policies and standards Integrated quality systems International standards Public interest

12. | Slide 12 of 57 October 2007 Good Manufacturing Practices (GMP) and Inspections Product quality and performance ensured through –design (manufacturing processes) Product and process specifications –Understanding of affect of formulation and process factors on product quality and performance Quality by design (build quality into the product) Interaction between review, compliance and inspection

13. | Slide 13 of 57 October 2007 Good Manufacturing Practices (GMP) and Inspections Where to start?

14. | Slide 14 of 57 October 2007 12.1 Premises Principle Important aspects to be kept in mind to ensure the suitability of the operations to be carried out for different dosage forms and product range: lLocation Design Construction Adaptation Maintenance

15. | Slide 15 of 57 October 2007 12.4 Premises Principle Premises must be located to minimize risks of cross- contamination, e.g. not located next to a malting factory with high airborne levels of yeast

16. | Slide 16 of 57 October 2007 12.2 Premises General The layout and design should aim to: Minimize risks of errors Permit effective cleaning Permit effective maintenance Avoid cross-contamination, build-up of dirt and dust Avoid any adverse effect on the quality of products

17. | Slide 17 of 57 October 2007 Premises Design Principles Keep in mind: Material flow People flow Process flow Ensure logical flow 12.10

18. | Slide 18 of 57 October 2007 Premises Example of Materials and People Flow Arrival of goods Entrance for visitors Entrance for Workers Shipment of goods Material Flow People Flow Zone: Clean Zone: Packaging Zone: Controlled

19. | Slide 19 of 57 October 2007 12.8, 12.32 Premises Construction Suitable materials Electrical supply Suitable lighting (especially for visual on-line checks) Temperature and relative humidity control Appropriate and effective ventilation These may affect products during manufacture or storage as well as functioning of equipment

20. | Slide 20 of 57 October 2007 Premises The temperature and relative humidity should be controlled, monitored in accordance with an SOP, and the results recorded. The limits should be appropriate according to the materials stored and product processed

21. | Slide 21 of 57 October 2007 Premises

22. | Slide 22 of 57 October 2007 12.11 – 12.36 Premises Specific areas Review some recommendations for specific areas in the following slides (Part 2): Ancillary areas Storage areas Weighing areas Production areas Quality control areas

23. | Slide 23 of 57 October 2007 Premises

24. | Slide 24 of 57 October 2007 Premises

25. | Slide 25 of 57 October 2007 Premises Separate receiving and dispatch bays äMaterials and products protected from weather Area to clean incoming materials provided

26. | Slide 26 of 57 October 2007 Premises

27. | Slide 27 of 57 October 2007 Premises

28. | Slide 28 of 57 October 2007 Premises

29. | Slide 29 of 57 October 2007 12.16, 12.17 Premises Storage areas - 2 Appropriate temperature and relative humidity conditions within defined limits äProvided, controlled, monitored and recorded Good storage conditions: clean, dry and appropriate lights

30. | Slide 30 of 57 October 2007 12.21 Premises Storage areas – 4 Printed packaging materials Critical to ensure compliance with correct labelling of products Special attention to sampling Special attention to safe and secure storage Ensure compliance with specifications, prevent mix-ups

31. | Slide 31 of 57 October 2007 12.23 Premises Weighing areas Weighing operations – in separated areas Appropriate design (see also training material on HVAC) Provision for dust control Smooth, impervious, durable, easy-to-clean finishes Cleaning procedures and records Documentation, e.g. SOPs, logs and records

32. | Slide 32 of 57 October 2007 Premises Design of areas for weighing of materials Proper air supply Dust control measures (including extraction of dust and air) Easily cleanable surfaces No areas for dust accumulation Protection of material, product and operator

33. | Slide 33 of 57 October 2007 Premises

34. | Slide 34 of 57 October 2007 12.24 Premises Production areas - 1 Minimize risk of cross-contamination: Dedicated and self-contained facilities for some products such as highly sensitizing materials (e.g. penicillins) or biological preparations (e.g. live microorganisms) Separate facilities for other products such as some antibiotics, hormones, cytotoxic substances Non-pharmaceuticals normally not in the same facility, e.g. pesticides, herbicides

35. | Slide 35 of 57 October 2007 Premises Finishing of floors, walls and ceilings Much better

36. | Slide 36 of 57 October 2007 Equipment All aspects including Design, installation, operation, performance, specifications, logs, maintenance, use, cleaning, qualification, calibration etc…

37. | Slide 37 of 57 October 2007 Equipment Contents and direction of flow indicated e.g. water lines, equipment components, air-handling systems

38. | Slide 38 of 57 October 2007 14.7 – 14.10 Materials Starting Materials – I Purchasing – important operation From approved suppliers – if possible, direct from the manufacturer Specifications for materials Consignment checks äIntegrity of package äSeal intact äCorresponds with the purchase order äDelivery note äSupplier’s labels Cleaned and labelled with information

39. | Slide 39 of 57 October 2007 Materials

40. | Slide 40 of 57 October 2007 Documentation

41. | Slide 41 of 57 October 2007 Validation Scope WHO guideline focuses mainly on the overall concept of validation It serves as general guidance only Principles may be useful: –in production and control of active pharmaceutical ingredients (APIs) and finished pharmaceutical products Validation of specific processes and products (e.g. sterile product manufacture) requires much more consideration and a detailed approach beyond the scope of the guideline 2.1

42. | Slide 42 of 57 October 2007 Validation Scope Many factors affecting the different types of validation Manufacturers should plan validation to ensure –regulatory compliance and –product quality, safety and consistency The general text in the guideline (part 1 of presentation) may be applied to validation and qualification of: –premises, equipment, utilities and systems –processes and procedures More specific principles addressed in the appendices (parts 2 to 7) Semi-automatic or fully automatic clean-in-place (CIP) systems and other special cases should be treated separately. 2.2 – 2.4

43. | Slide 43 of 57 October 2007 Qualification and Validation

44. | Slide 44 of 57 October 2007 Good Manufacturing Practices (GMP) and Inspections Utilities HVAC Water Compressed air Steam...

45. | Slide 45 of 57 October 2007 Prefilter Air flow patterns AHU Main filter Uni-directional Turbulent 1 23 HVAC

46. | Slide 46 of 57 October 2007 + Production Room Exhaust air treatment Central air handling unit Terminal air treatment at production room level Fresh air treatment (make-up air) HVAC Main subsystems

47. | Slide 47 of 57 October 2007 Qualification – examples of aspects to consider in qualification (OQ, PQ) Test Differential pressure on filters Turbulent / mixed airflow Description Uni-directional airflow / LAF Room differential pressure Airflow velocity / uniformity Airflow volume / rate Parallelism Air flow pattern 22 N/A2, 3 Optional 22 2N/A 23 1 := As built (ideally used to perform IQ) 2 = At rest (ideally used to perform OQ) 3 = Operational (ideally used to perform PQ) HVAC

48. | Slide 48 of 57 October 2007 Water for Pharmaceutical Use

49. | Slide 49 of 57 October 2007 Separate guideline in addition to basic GMP Part 1: Management and organization Part 2: Materials, equipment, instruments and devices Part 3: Working procedures and documents, and safety in the laboratory Part 4: Inspecting the laboratory Quality Control

50. | Slide 50 of 57 October 2007 Good Manufacturing Practices (GMP) and Inspections Quality control (also micro, water, environment…) Sampling and testing Reference Standards Specifications Stability testing Source/raw data Qualification and validation

51. | Slide 51 of 57 October 2007 Good Manufacturing Practices (GMP) and Inspections Other aspects to look at include: Validation (process, cleaning etc) CAPA, failure investigation Change control Deviations Complaints Product quality review

52. | Slide 52 of 57 October 2007 Good Manufacturing Practices (GMP) and Inspections Unlimited resources ? Inspectors ? Days ? Guidelines ?

53. | Slide 53 of 57 October 2007 Quality Risk Management Process

54. | Slide 54 of 57 October 2007 Good Manufacturing Practices (GMP) and Inspections Planning and conduct of inspection Type of product(s) Type of material(s) Premises Changes (deviations, additional products, cleaning procedure, campaigns etc) Utilities and applications

55. | Slide 55 of 57 October 2007 Good Manufacturing Practices (GMP) and Inspections Summary GMP remains important component of ensuring QA and quality New approaches in quality (including risk management, CAPA, PAT) Impact on total approach including –Product design, product development, pilot batches, production batches Quality systems and quality assurance

56. | Slide 56 of 57 October 2007 Good Manufacturing Practices (GMP) and Inspections Acknowledgements WHO Training modules –Basic and supplementary ICH Q9 S Galson and LX Yu

57. | Slide 57 of 57 October 2007 Good Manufacturing Practices (GMP) and Inspections Thank you