Good Manufacturing Practices – Part II 3 Specific GMP topics: Premises, Documentation and Validation

2. Good Manufacturing Practices – Part II 3 Specific GMP topics: Premises, Documentation and Validation WHO EMRO 1st Workshop on the WHO Prequalification Programme: Priority Essential Medicines, Cairo, Egypt, 6 and 7 June, 2007 Anton Norder, MSc Technical Officer 20 Avenue Appia CH-1211 Geneva 27 Switzerland E-mail: nordera@who.int 2

3. Guidelines and references • Booklet:Quality Assurance of pharmaceuticals. A compendium of guidelines and related materials. Volume 2, second updated edition. Good manufacturing practices and inspection. World Health Organization, Geneva, 2007. • Good Manufacturing Practices for pharmaceutical products: main principles. WHO Technical Report Series, No. 908, 2003, Annex 4. • Good Manufacturing Practices: starting materials. WHO Technical Report Series, No. 823, 1992. • ICH Q7A: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, International Conference on Harmonizationhttp://www.ich.org/cache/compo/276-254-1.html

4. WHO Guidelines and references (cont'd) • WHO Good Manufacturing Practices: water for pharmaceutical use. WHO Technical Report Series, No. 929, 2005, Annex 3 http://whqlibdoc.who.int/trs/WHO_TRS_929_eng.pdf • Supplementary guidelines on good manufacturing practices for heating, ventilation and air-conditioning systems for non-sterile pharmaceutical dosage forms. WHO Technical Report Series, No. 937, 2006, Annex 2 http://whqlibdoc.who.int/trs/WHO_TRS_937_eng.pdf • Supplementary guidelines on good manufacturing practices : validation. WHO Technical Report Series, No. 937, 2006, Annex 4 http://whqlibdoc.who.int/trs/WHO_TRS_937_eng.pdf

5. WHO Guidelines and references (cont'd) • WHO guidelines for sampling of pharmaceutical products and related materials. WHO Technical Report Series, No. 929, 2005, Annex 4 http://whqlibdoc.who.int/trs/WHO_TRS_929_eng.pdf • Good Practices for National Pharmaceutical Control Laboratories. WHO Technical Report Series, No. 902, 2002, Annex 3. http://whqlibdoc.who.int/trs/WHO_TRS_902.pdf#page=37 • As well as specific GMPs on: • Sterile pharmaceutical products (2002) • Biologicals (1993) • Investigational pharmaceutical products for clinical trials in humans (1996) • Herbal medicinal products (1996/97) • Radiopharmaceutical products (2003)

6. However there's more GMP's: • PIC/S GMP (Pharmaceutical Inspection Co-operation Scheme): www.picscheme.org ; adopted by many countries, e.g. European Union, or partially (Canada, Australia) • National GMP's in many countries (e.g. USA (www.fda.gov), China, India, Brazil, Argentina, etc.) • International Conference on Harmonization (ICH): www.ich.org • Also refer to ISO, e.g in cases of filter types in HVACs, clean room design, risk management, etc.

7. Overview of specific GMP topics to be covered in this presentation: • Part 1:Premises in relation to buildings, design, equipment, etc. • Part 2:Documentation • Part 3:Qualification and validation

8. Part 1: Premises Arrival of goods Visitors entrance Workers entrance Shipment of goods Material Flow People Flow Zone: Clean Zone: Packaging Zone: Controlled

9. Premises: specific areas Note that specific requirements are given for specific areas: • Ancillary areas (gowning rooms, toilets, refreshment rooms, maintenance areas, animal housing etc) • Storage areas • Weighing areas • Production areas • Quality control areas 12.11 – 12.36

10. Premises: ancillary areas • Rest and refreshment rooms separate from manufacturing and quality control areas • Changing, washing and toilet areas accessible and appropriate numbers • Maintenance workshops separated from production - if not possible – tools in reserved areas • Animal houses well isolated – separate air handling and entrance 12.11 – 12.14

11. Premises: ancillary areas

12. Premises: ancillary areas

13. Premises: Receipt and storage of goods • Separate receiving and dispatch bays • Materials and products protected from weather • Area to clean incoming materials provided

14. Premises: Receipt and storage of goods Cleaning of incoming containers • Cleaning with a cloth, or duster • Cleaning by using a vacuum cleaner • Use of air curtains and air tunnels

15. Premises: Receipt and storage of goods • Storage areas of sufficient capacity • Orderly storage of categories of materials and products • Separate and segregated areas: starting materials, packaging materials, intermediates, bulk, finished products, quarantined, released, rejected, returned and recalled products and materials 12.15, 12.16

16. Premises: Receipt and storage of goods

17. Premises: Receipt and storage of goods

18. Premises: Receipt and storage of goods • Appropriate temperature and relative humidity conditions within defined limits • Provided, controlled, monitored and recorded • Good storage conditions: clean, dry and appropriate lights 12.16, 12.17

19. Premises: Receipt and storage of goods • Quarantine area: clearly marked and access restricted • Separate sampling area is the norm: no risk for contamination or cross-contamination • Segregated areas for rejected, recalled and returned materials and products • Safe and secure areas for highly active, radioactive materials, narcotics and other materials (risk of abuse, fire, explosion) 12.18 – 12.20, 12.22

20. Premises: Receipt and storage of goods

21. Premises: Receipt and storage of goods Printed packaging materials • Critical to ensure correct labelling of products • Special attention to sampling of printed packaging materials • Special attention to safe and secure storage • Ensure compliance with specifications, prevent mix-ups 12.21

22. Premises: weighing • Weighing operations – in separated areas • Appropriate design (see also GMP on HVAC) • Provision for dust control • Smooth, impervious, durable, easy-to-clean finishes • Cleaning procedures and records • Documentation, e.g. SOPs, logs and records 12.23

23. Premises: weighing

24. Requirements on premises: • Design • Walls, floors, ceilings, ledges, drains, air supply, dust extraction • Prevention of build-up of dirt and dust to avoid unnecessary risks of contamination • Cleaning programme, appropriate cleaning, cleaning records • Effective cleaning and disinfection • Choice of materials and chemicals, validation • Drains – prevent backflow • Protection from insects, birds, vermin and weather • from receipt of raw materials to dispatch of released product 12.2, 12.3, 12.7, 12.9, 12.29

25. Walls, floors, ceilings – smooth and easy to clean No ledges or areas where dust can accumulate Prevention of build-up of dirt and dust to avoid unnecessary risks of contamination Design of premises:

26. Premises: production areas 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 12.24

27. Premises: production areas • Layout in accordance with sequence of production • Appropriate cleanliness level • Adequate work and in-process storage space • Orderly and logical positioning of equipment • minimizes risk of contamination, mix-ups and missing production steps • Specially designed areas for packaging • Layout to avoid mix-ups and cross-contamination 12.32, 12.26, 12.31

28. Premises: production areas • Starting and packaging materials, intermediates and bulk exposed to environment: • Interior surfaces (walls, floors, ceilings) – smooth, free from cracks and open joints • No shedding of particles • Easy and effective cleaning permitted • Disinfection if needed 12.27

29. Premises: production areas • Design of pipework, light fittings, and ventilation points – no recesses that are difficult to clean • Access for maintenance from outside production areas • Drains of adequate size, and equipped to prevent back-flow • Open channels avoided 12.28, 12.29

30. Effective ventilation with air control facilities Including filtration of air to a sufficient level to prevent contamination and cross-contamination – also external environment Control of temperature and relative humidity where necessary Regular monitoring of conditions during production and non-production periods Premises: production areas 12.30

31. Avoiding cross contamination • Special precautions should be taken to prevent generation and dissemination of dust • Proper air control – supply and extraction, suitable quality • Due to uncontrolled release of: • dust, gas, particles, vapours, sprays, organisms, residue, insects • Dedicated and self-contained areas for: • Live vaccines • Live bacterial preparations • Certain other biological materials • Penicillin products 16.10 - 11 16.12(a)

32. Avoiding cross contamination (cont'd) • Campaign production: • Separation in time • Followed by appropriate cleaning • Validated cleaning procedure • Ventilation systems and airlocks • Appropriately designed ventilation system with air supply and extraction systems • Supply or incoming air should be filtered • Recirculation of air versus 100% fresh air supply • Proper airflow patterns • Pressure differentials • Appropriately designed airlocks 16.12(b) 16.12 (c and d)

33. Avoiding cross contamination (cont'd) • Clothing • Protection of operator and product • Fit for its intended use • Highly potent products or those of particular risk - need for special protective clothing • Personnel should not move between areas producing different products • Garments need to be cleaned 16.12(e)

34. Avoiding cross contamination (cont'd) • Cleaning and decontamination • Procedure for removing soil and dirt • Remove all cleaning chemical residues or disinfectant residues • Remove and/or reduce micro-organisms • Validated (known effectiveness of the procedure) • Use cleanliness status labels • Test for residues • Closed processing systems • For example: totally enclosed water purification systems • Tanks fitted with appropriate filtration - without removable lids • Present special cleaning difficulties, sometimes use clean-in-place (CIP) 16.12(f, h and i) 16.12(g)

35. Sanitation in production operations • Work-flow • designed to avoid potential contamination • Access • to production areas restricted to authorized personnel • direct operators, QC staff, warehouse staff, maintenance personnel, cleaners • the more critical the area - fewer number of persons there • Simultaneous operations • not permissible to process different products in different areas with a common ventilation system • permissible to carry out secondary packaging activities for different products within a packing hall with adequate physical separation

36. Sanitation in production operations(cont'd) Area clearance checks: • Process of checking • all materials and documentation from the previous batch removed • all plant and equipment thoroughly cleaned and appropriate status labelling • checklist useful • The area clearance check should be carried out by two persons • between batches of same product, acceptable for both checks to be carried out by production personnel • for product changeover, second check carried out by QC staff • all checks carried out in accordance with written SOP and results recorded on the batch documentation.

37. E.g. line clearance in packaging • Absence of all materials from previous run, including printing masters • Includes checks on materials and components • Batch number • Expiry date • Printed packaging material including cartons, leaflets, foil . . .

38. Sanitation in production operations(cont'd) • Cleaning and cleaning validation • degree of cleaning depends on whether consecutive batches are of same or different product • Check cleaning agent is fully removed • If possible hot water alone used for cleaning • all cleaning and disinfecting solutions carefully prepared and expiry dated • For sterile products: Final rinse with purified water, or water for injection • Full records kept

39. Sanitation in production operations(cont'd) • Maintenance and repair • activities inevitable in manufacturing area • Should present no risk to product • Whenever possible, all planned maintenance outside normal operating hours • Emergency work in working area followed by thorough clean down and disinfection before manufacturing recommences • Area clearance by QC

40. Basic Principles on premises in GMP • 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

41. Premises: maintenance • Careful maintenance done • Repairs and maintenance should not present any hazard to the quality of the products 12.6

42. Premises of Quality Control Labs • QC laboratories should be separate from production areas • Separate areas for biological, microbiological and radioisotope methods • Suitable design with sufficient space to avoid mix-ups and cross-contamination • Suitable space for storage samples, reference standards, solvents, reagents and records 12.33, 12.34

43. Premises of Quality Control Labs

44. Part 2: Documentation Objectives 1. To review general requirements for documents 2. To review specific requirements for each document 3. To consider current issues applicable to your countries

45. Documentation • Essential part of the QA system, for all aspects of GMP • Purpose of documentation • Defines specifications and procedures for all materials and methods of manufacture and control • Ensures all personnel know what to do and when to do it • Ensure that authorized persons have all information necessary for release of product • Ensures documented evidence, traceability, provide records and audit trail for investigation • Ensures availability of data for validation, review and statistical analysis • Design and use • Depends upon manufacturer • Some documents combined into one, sometimes separate 15.1

46. Documentation

47. Documentation Why are documents so important? • Communication • Cost • Audit trail

48. Documentation: general principles • Documents should be • Designed, prepared, reviewed, distributed with care • Approved by appropriate responsible persons • Comply with marketing authorization • Design of documentation important • Look at the “Style” of the document • Instructions in the imperative • Short sentences preferred to long sentences 15.2

49. Documentation: general principles (cont'd) • Contents of documents should be clear (easy to understand) and include, e.g. • Title, nature, objective or purpose • Layout in orderly fashion • Easy to be filled in and checked • Clear and readable – including copies made • No errors if master documents are copied for working documents 15.4

50. Documentation: general principles (cont'd) Documentation control • Regular review of documents • Kept up to date (current) - amended • Superseded documents removed and not used • Distribution and retrieval of documentation • Retention time for superseded documents 15.5