EQUIPMENT AND ITS QUALIFICATION

1. EQUIPMENT AND ITS QUALIFICATION Rutendo Kuwana Technical Officer, WHO, Geneva Training workshop: Training workshop on regulatory requirements for registration of Artemisinin based combined medicines and assessment of data submitted to regulatory authorities, February 23-27, 2009, Kampala, Uganda.

2. Basic Principles of GMP Equipment 13

3. Equipment Objectives • To review the requirements for equipment • selection • design • use • Maintenance

4. Validation Objectives (2) To discuss the principles of qualification of equipment, with specific focus on: • The different stages of qualification • Requalification and • Qualification of “in use” equipment

5. Equipment Principle • Equipment must be • located • designed • constructed • adapted • maintained to suit the operations to be carried out 13.1

6. Equipment Principles • Equipment layout and design must aim: • to minimize risks of error • to permit effective cleaning and maintenance • To avoid: • cross-contamination, dust and dirt build-up • any adverse effect on the quality of products • Equipment must be installedto: • minimize risks of error • minimize risks of contamination 13.1, 13.2

7. Equipment Balances and Measuring Equipment • Appropriate range and precision available • In production and quality control • Calibrated • scheduled basis • checks • records maintained 13.5

8. Equipment Production equipment • Appropriate design • easily and thoroughly cleaned on a scheduled basis • procedures and records • No hazard to the products • contact parts of suitable non-reactive materials • non additive and • not absorptive • Defective equipment • removed, or • labelled to prevent use 13.9, 13.10

9. Equipment Production equipment • Closed equipment used when possible • Open equipment, or when equipment opened, precautions taken to prevent contamination • Non-dedicated equipment cleaned according to validated cleaning procedures between different products • Current drawings of critical equipment and support systems maintained 13.11 – 13.13

10. Equipment Control laboratory equipment • Equipment and instruments • suitable for the tests to be performed • Defective equipment • removed • labelled 13.7, 13.10

11. Equipment Washing, cleaning and drying • Equipment used for washing and drying – not the source of contamination • Equipment design should promote easy cleaning • Cleaning on scheduled basis, procedures and records • Washing and cleaning • manual • automated (Clean in place (CIP), Steam in place (SIP)) 13.6, 13.8

12. Basic Principles of GMP

13. Equipment Possible Issues • Poor design • Lack of safety • Poor quality finishes • Lack of cleaning • Lack of maintenance • No usage log or record • Use of inappropriate weighing equipment • Open-plan location of compressing machines

14. Basic Principles of GMP • Remember to look at punches and dies • Are there specifications for these? • How are they cleaned, stored, issued for use and returned to storage? • Are they in a good condition and checked at regular intervals?

15. Validation General • Qualification policy for systems and equipment • To include instruments used in production and quality control • New systems and equipment: All stages of qualification applicable (DQ, IQ, OQ and PQ) • In some cases: Not all stages of qualification may be required • e.g. electrical supply systems 3.1 – 3.4

16. Validation General • Qualification policy for systems and equipment • To include instruments used in production and quality control • New systems and equipment: All stages of qualification applicable (DQ, IQ, OQ and PQ) • In some cases: Not all stages of qualification may be required • e.g. electrical supply systems 3.1 – 3.4

17. Validation General (continued) • Qualification should be done in accordance with predetermined and approved qualification protocols • The results of the qualification should be recorded and reflected in qualification reports • The extent of the qualification should be based on the criticality of a system or equipment, e.g. • Blenders, autoclaves or computerized systems 3.10 – 3.11

18. Validation General (continued) • Qualification should be done in accordance with predetermined and approved qualification protocols • The results of the qualification should be recorded and reflected in qualification reports • The extent of the qualification should be based on the criticality of a system or equipment, e.g. • Blenders, autoclaves or computerized systems 3.10 – 3.11

19. Qualification and Validation Definitions Validation Action of proving, in accordance with the principles of GMP, that any procedure, process, equipment, material, activity or system actually leads to the expected results It is a process using documented evidence that provides a high degree of assurance that a specific process will consistently produce the predetermined outcome. Glossary

20. Qualification and Validation Definition Qualification • Action of proving that any premises, systems and items of equipment work correctly and actually lead to the expected results (Validation usually incorporates the concept of qualification) A process of establishing confidence that the equipment is capable of consistently operating within established limits and tolerances. Studies therefore done prior to use

21. Qualification Vs. Validation • Qualification - confirm compliance with specified requirements or criteria (Do you have the right tool for the job?) • Performed on one element or component of the process to be validated • Conduct tests to establish if the component of a process has the attributes to produce a specified outcome. • Validation - Proof. Document that the process will consistently produce a predetermined outcome.

22. Validation Stages of qualification Design qualification Installation qualification Operational qualification Performance qualification 3.11

23. Validation Stages of qualification Design qualification Installation qualification Operational qualification Change control Performance qualification 3.11.

24. Validation General Systems: Qualified before equipment • Equipment: Qualified before routine use • Systems and equipment: Periodic requalification, as well as requalification after change • Certain stages done by the supplier or a third party • Maintain the relevant documentation, e.g. • standard operating procedures (SOPs), specifications and acceptance criteria, certificates and manuals 3.5 – 3.9

25. Validation Design qualification • User requirements should be considered when deciding on the specific design of a system or equipment • A suitable supplier should be selected for the appropriate system or equipment (approved vendor) 4.1 – 4.2

26. Validation Installation qualification • Verifies that the correct equipment has been received and installed as per plan and protocol. Also that it is complete and undamaged (parts, services, controls, gauges and other components) - Normally advised to prepare requirements for calibration, maintenance and cleaning at this stage • Verifies that equipment has been properly installed and calibrated including connections to utilities. • Calibrate the measuring, control and indicating devices • against appropriate, traceable national or international standards 5.1 – 5.4

27. Validation Installation qualification (2) • Documented records for the installation • installation qualification report • Indicate satisfactory installation • Include details, e.g. • The supplier and manufacturer • System or equipment name, model and serial number • Date of installation • Spare parts, relevant procedures and certificates 5.5

28. Validation Operational qualification • Systems and equipment should operate correctly – operation verified as in the qualification protocol • Verifies that the equipment operates consistently within established limits and tolerances over the defined operating ranges. Studies on critical variable to include conditions encompassing upper and lower operating limits and circumstances (i.e. “worst case conditions”) • Challenges equipment functionally to verify compliance with manufacturer’s specifications and end – user defined requirements. To include verification of operation of all system elements, parts, services, controls, gauges and other components 6.1 – 6.3

29. Validation Operational qualification (2) • Documented records (Operational qualification report) • Finalize and approve SOP (operation) • Training of operators provided – training records • Systems and equipment released for routine use after completion of operational qualification, provided that: • All calibration, cleaning, maintenance, training and related tests and results were found to be acceptable 6.4 – 6.7

30. How may runs are to be performed during Operational Qualification (OQ) testing? • Guidelines stress the importance of equipment qualification simulating actual production conditions, including 'worst case' situations and that "tests and challenges should be repeated a sufficient number of times to assure reliable and meaningful results." • "three consecutive batches" is recommended for process validation rather than for equipment qualification. No specific number of "runs" for equipment qualification, but multiple tests to simulate actual operating ranges and to establish consistency are expected

31. Qualification of Equipment If one type and model of equipment is qualified, can it be used in a different process without additional qualification? For IQ document whether each equipment is installed correctly and operates consistently according to established limits and tolerances. OQ should also be performed for each different use of the equipment or system to document the suitability for that use Not be required for additional pieces of the same type/model of equipment when used in the same process or for each piece of the same type/model of equipment used in the same process, provided installation qualification has been performed

32. Validation Performance qualification • Verifies that the equipment performs according to design specifications and user defined requirements in a reliable and reproducible manner under normal production conditions. • Verified in accordance with a performance qualification protocol • Documented records – performance qualification report • Show satisfactory performance over a period of time i,e. carried out long enough to prove that the equipment is under control and turns out product of specified quality consistently. • Manufacturers to justify the selected period 7.1 – 7.2

33. Qualification Plan • To ensure that requirements are met and confirm by examination and collection of objective evidence - Challenges to equipment to be designed - Re-create intended use - Test, Test, Test

34. Qualification Plan • Purpose • Scope • Equipment Description • Operational Specifications • Acceptance Criteria • Testing Results • Discrepancies/Corrective Actions • Conclusions/Final Report

35. Validation The next slide shows a typical format for: "A qualification protocol / report" • It reflects the minimum information that should be included • This is an example – and should be used as such • Specific formats need to be designed for a specific system or piece of equipment 7.2

36. Qualification Plan

37. Worst Case Scenarios • Conditions that include upper and lower processing limits • Circumstances that present the highest chance of process or product failure relative to ideal situations • Identify those conditions that are likely to be experienced during routine manufacture/process

38. More Examples The following case illustrates the importance of performing adequate equipment qualification on each piece of processing equipment • A pharmaceutical firm used two blenders to produce a tablet. Both blenders from same equipment manufacturer, same model number and same design. Supplier told the drug manufacturer that the units were "identical." though one was older. Manufacturer did not include the older blender as part of its process validation. • Company marketed about 100 batches of tablets using the old blender. Retention samples showed some batches failed content uniformity • investigation showed out of specification batches were from one of the two "identical" blenders – the old one. The older blender had a slightly smaller capacity and different operational characteristics (RPMs) when run at the same settings as the newer blender. • Subsequently, the firm recalled its total production of the product it made using the older blender. The firm decided to qualify the old blender using production size lots.

39. Qualification of “Old” Equipment • What about "old manufacturers" who have not performed DQ, or IQ for existing, in-use systems and/or equipment? • It is not always possible to have all details for IQ or OQ for established equipment. The manufacturer should however have data that verifies the operating parameters and limits for the critical variables of the equipment. In addition, calibration, cleaning, preventative maintenance, operating procedures and operator training procedures for the use of the equipment should be documented and used as SOPs ……. PIC/S

40. Validation Qualification of “in-use” systems and equipment • Data to support and verify the suitable operation and performance of systems and equipment • Should include operating parameters and limits for critical variables, calibration, maintenance and preventive maintenance, standard operating procedures (SOPs) and records 9.1 – 9.2

41. Risk assessment of operations or functions If any question is answered “Yes”, the operation/function should be considered as GMP relevant. During risk assessment, the probability of occurrence and detectability should be considered and measures to reduce the risk identified.

42. Qualification flow Scheme(extracted from CEFIC Guidance)

43. Example of Document Matrix

44. Requalification • Required for: - significant change in batch size - change in operating parameters - component specifications have changed - new accessories or components are added to previously qualified equipment - process changes that potentially impact product effectiveness or quality

45. Some Experiences What if the results are not good? • Study report destroyed and manufacturer pretends it never happened So what should be done? • Document the study, but don’t approve it • Identify and describe any corrective actions needed or any noteworthy observations or deviations • Start another study using the findings and conclusions from the failed study

46. More experiences – poor qualification reports • Specifications not approved • Failure to provide clear, complete instructions in the protocol • Instrument calibration records or status not included • Full range of intended operating parameters not challenged • Inadequate sample sizes • Atypical data points • Unexplained deviations from protocol • Inconsistencies between final report and data collection/recording forms

47. Qualification and Validation WHO References • Good manufacturing practices (GMP): guidelines on the validation of manufacturing processes • Validation of analytical procedures used in the examination of pharmaceutical materials Annex 6