Supplementary T raining Workshop on Good Manufacturing Practices (GMP)

1. Supplementary Training Workshop on GoodManufacturing Practices (GMP) QUALIFICATION of EQUIPMENT János Pogány, pharmacist, PhD, consultant to WHO Pretoria, South Africa, 28 June 2005 E-mail: pogany@t-online.hu Dr. Pogány - WHO, Pretoria

2. WHO GMP and Guidelines • WHO good manufacturing practices (GMP): main principles for pharmaceutical products • Section 4.Qualificationand validation • Section 13. Equipment(see notes page) • Supplementary guidelines ongood manufacturing practices(GMP):Validation (2003) – Draft. Dr. Pogány - WHO, Pretoria

3. Causes of variation • Man (different operators - lack of proper training) • Machine / equipment • Measurement (lack of calibration) • Method (accuracy of validated processes/methods) • Material (batch-to-batch variation of APIs/excipients) • Manufacturing environment (T and RH) Dr. Pogány - WHO, Pretoria

4. Qualification • QUALIFICATIONis the „Action of proving that any premises, (pharmaceutical utility) systems and items of equipment(e.g.,machines, stability chamber)work correctly and actually lead to the expected results. The meaning of the word “validation” is sometimes extended to incorporate the concept of „qualification”. • REQUALIFICATIONis the main part of the preventive maintenance programme of proving that any premises,(pharmaceutical utility) systems and items of equipmentwork correctly and keep on leading to the expected results.(normal wear and tear) Dr. Pogány - WHO, Pretoria

5. Validation • VALIDATIONis the „Action of proving, in accordance with the principles of GMP, that any procedure, process, equipment, material, activity or (pharmaceutical utility) system actually leads to the expected results (see also qualification)”. • REVALIDATION is a part of the change control system of proving that any procedure, process, equipment, material, activity or (pharmaceutical utility) system actually keeps on leading to the expected results. Dr. Pogány - WHO, Pretoria

6. Qualification - Validation Regulatory requirements DQ,IQ,OQ inputs DQ,IQ,OQ process DQ,IQ,OQ outputs Process Qualification Validation Premises, equipment and supporting utilities must be qualified to operate in a validated process. Dr. Pogány - WHO, Pretoria

7. Relationship between qualification and validation • DESIGN SPECIFICATION/QUALIFICATION • INSTALLATION QUALIFICATION • OPERATIONAL QUALIFICATION • PROCESS VALIDATION • CHANGE CONTROL Qualification is a sub­set of validation. Dr. Pogány - WHO, Pretoria

8. Calibration „The set of operations that establish, under specified conditions, the relationship between values indicated by an instrument or system for measuring (especially weighing), recording, and controlling, or the values represented by a material measure, and the correspondingknown values of a reference standard. Limits for acceptance of the results of measuring should be established.” (see also the notes page) Verification. Dr. Pogány - WHO, Pretoria

9. Calibration test equipment Instrument or device used to calibrate other instruments, the calibration of which is traceable back to accepted national standards. The test equipment should have greater precision, accuracy, and repeatability, than the instruments being calibrated. These instruments should have documentary evidence of traceable calibration to at least the same standard as the site calibration. Dr. Pogány - WHO, Pretoria

10. DESIGN QUALIFICATION

11. 4.3 Documentary evidence (a) the premises, supporting utilities, equipment and processes have been designed in accordance with the requirements for GMP (design qualification or DQ); (b) the premises, supporting utilities and equipment have been built and installed in compliance with their design specifications (installation qualification or IQ); Dr. Pogány - WHO, Pretoria

12. 4.3 Documentary evidence (c) the premises, supporting utilities and equipment operate in accordance with their design specifications (operational qualification or OQ); (d) a specific process will consistently produce a product meeting its predetermined specifications and quality attributes (process validation or PV, also called performance qualification or PQ). (PQ is frequently applied to utility systems) Dr. Pogány - WHO, Pretoria

13. Basic principles • Throughout this presentation the term equipment is used to represent both manufacturingmachinery, equipment and QC instruments. • The equipment should be correctly installed in accordance with aninstallation plan, as per supplier and any special (purchaser)requirements. • The requirements for calibration, maintenance and cleaningdeveloped as draft procedures should be reviewed and finallyissued as authorised standard operating procedures (SOPs). Dr. Pogány - WHO, Pretoria

14. Basic principles • Operating requirements should be established and testsconducted to assure equipment is operating correctly, undernormal and “worst case” conditions (≠ failure mode analysis) • Operator training requirements pertaining to the new equipmentshould be finalised and documented. Dr. Pogány - WHO, Pretoria

15. DQ and IQ • DQ protocols and reports • GMP • VMP • National law • Engineering design and construction documents Do not start IQ before DQ has been completed! • IQ/OQ protocols and reports • Above inputs + machine manuals • Separate VMPsfor HVAC and water systems Do not start OQ before IQ has been completed! Dr. Pogány - WHO, Pretoria

16. INSTALLATION QUALIFICATION

17. Prequalification of vendor • Vendor specification • familiarity with GMP • installation, training and start-up support • performance testing at the vendor’s site • experience of current users • cost analysis • Once selected, the vendor may assist in preparing the qualification protocols Dr. Pogány - WHO, Pretoria

18. Pre-delivery check For complicated or large pieces of equipment, a pharmaceuticalmanufacturer may elect to undertake a pre-delivery check of theequipment at the supplier's assembly facility.This pre-delivery checkcannot substitute for the Installation Qualification. However, it isacknowledged that the checks conducted and documented at this stagemay duplicate a number of the checks conducted at the InstallationQualification stage, hence, there could be a reduction in the scope of theInstallation Qualification checks. Dr. Pogány - WHO, Pretoria

19. Checking at users Installation Qualification requires a formal and systematic check of allinstalled equipment against the equipment supplier's specifications andadditional criteria identified by the user as part of the purchasespecifications. At the Installation Qualification, all equipment, gauges andservices should be given a serial (or other reference) number and acheck conducted that the installed equipment (or plant) has beeninstalled in accordance with the current (approved) version of the Piping &Instrument Diagram (P&ID). Dr. Pogány - WHO, Pretoria

20. IQ - Overview Statement Identification and documenting of maintenance requirements for eachinstalled item and the collection and collation of supplier operating andworking instructions, maintenance and cleaning requirements, shouldform the minimum documentation for a satisfactory InstallationQualification. Dr. Pogány - WHO, Pretoria

21. Installation of equipment An effective ChangeManagement procedure should be in place. All changes to the originaldesign criteria should be documented and after that, appropriatemodifications made to Equipment Specifications, Plant FunctionalSpecifications and Piping & Instrument Diagrams (P&IDs). Dr. Pogány - WHO, Pretoria

22. Calibration Requirements • Confirmation of calibration with referenceto the appropriate national standard. • Calibration of measuring devices utilised in the OperationalQualification stage, where confirmation of calibration isunavailable. • Calibration of measuring devices related to installed equipment. • Identification of calibration requirements for measuring devices forthe future use of the equipment Dr. Pogány - WHO, Pretoria

23. OPERATION QUALIFICATION

24. OQ - Overview Statement Operational Qualification is an exercise oriented to the engineeringfunction, generally referred to as commissioning. Studies on the criticalvariables (parameters) of the operation of the equipment or systems willdefine the critical characteristics for operation of the system orsub-system. All testing equipment should be identified and calibratedbefore use. Test methods should be authorised, implemented andresulting data collected and evaluated. Dr. Pogány - WHO, Pretoria

25. OQ - Overview Statement • It is important at this stage to assure all operational test data conformwith pre-determined acceptance criteria for the studies undertaken. • It is expected that during the Operational Qualification stage themanufacturer should develop draft standard operating procedures(SOPs) for the equipment and services operation, cleaning activities,maintenance requirements and calibration schedules. Dr. Pogány - WHO, Pretoria

26. OQ - Essential Elements • The conduct of an Operational Qualification should follow an authorisedprotocol. • The plans forthe Operational Qualification should identify the studies to be undertakenon the critical variables, the sequence of those studies and themeasuring equipment to be used and the acceptance criteria to be met. • Studies on the critical variables should incorporate specific details andtests that have been developed from specialist knowledge of the processand how the equipment will work (defined in design criteria andspecifications). Dr. Pogány - WHO, Pretoria

27. OQ - Essential Elements • Where applicable, simulated product may be used to conduct theOQ. Studies on the critical variables should includea condition or a set of conditions encompassing upper and lowerprocessing or operating limits and circumstances; commonly referred toas "worst case" conditions. Such conditions should not necessarilyinduce product or process failure. • The completion of a successful OQ should allowthe finalisation of operating procedures and operator instructionsdocumentation for the equipment. This information should be used asthe basis for training of operators in the requirements for satisfactoryoperation of the equipment. Dr. Pogány - WHO, Pretoria

28. OQ - Essential Elements • Draft cleaning procedures developed at the IQ stage should be finalised. Whereapplicable, these procedures should be validated as part of thePQ phase. • The completion of satisfactory IQ and OQ exercises should permit a formal "release" of theequipment/plant for the next stage in the validation exercise (ProcessValidation). The release should take the form of writtenauthorisations for both Installation Qualification and OperationalQualification. Dr. Pogány - WHO, Pretoria

29. OQ - Essential Elements • Some OQ testing should be performed following equipment maintenance • Current regulations require the validation of computers and software that are used to control laboratory equipment or process data. • The overall program should be evaluated periodically to ensure that current requirements are met. Dr. Pogány - WHO, Pretoria

30. Re-Qualification • Modifications to, or relocation of, equipment should only followsatisfactory review and authorisation of the documented changeproposal through the change control procedure. Part of the reviewprocedure should include consideration of re-qualification of theequipment. Minor changes or changes having no direct impact on final orin-process product quality should be handled through the documentationsystem of the preventative maintenance programme. Dr. Pogány - WHO, Pretoria

31. Qualification of in-use equipment While it is not possible to undertake the details of an IQ for established equipment nor the detailed approach for anOQ, nevertheless there should be data availablethat support and verify the operating parameters and limits for the criticalvariables of the operating equipment. Additionally, the calibration,cleaning, preventative maintenance, operating procedures and operatortraining procedures for the use of the equipment should be documentedand in use as standard operating procedures (SOPs). Dr. Pogány - WHO, Pretoria

32. Main points again • Equipment is one of the potential causes ofvariation. • DQ, IQ, OP and PQ protocols and reports are required that equipment was designed, installed and operated in accordance with supplier’s and user’s requirements. • Effective change control keeps documentation up to date. • Qualification is a sub­set of validation Dr. Pogány - WHO, Pretoria

33. Literature • Validation Master Plan, Installation and OperationalQualification, Non-sterile Process Validation, Cleaning Validation, Pharmaceutical Inspection Convention (PIC/S), August 2001 • Model IQ/OQ protocol and report (distributed among participants of the training course) • Comparison of WHO, EU and US-FDA GMP Requirements for Pharmaceutical Equipment(distributed among participants of the training course) Dr. Pogány - WHO, Pretoria