Supplementary T raining Workshop on Good Manufacturing Practices (GMP)

1. Supplementary TrainingWorkshop on GoodManufacturing Practices (GMP) VALIDATION MASTER PLAN (VMP) János Pogány, pharmacist, PhD, consultant to WHO Pretoria, South Africa, 28 June 2005 E-mail: pogany@t-online.hu Dr. Pogány - WHO, Pretoria

2. Incidents/accidents leading to regulatory actions 1937 Sulfanilamide elixir 1962 Thalidomide 1982Tylenol cyanide tampering 1989 Generic drug scandal (there is no new thing under the sun) 1970- Sterility problems found by FDA employees in the large-volume parenteral (LVP) industry • systems inspections by teams (engineers and microbiologists) • validation as a requirement in the 1978 US-GMP • terms protocol, qualification, and validationfirst used Dr. Pogány - WHO, Pretoria

3. Systems approach • water (generation, receipt, and distribution) • heating, ventilation, and air conditioning (HVAC) • sterilizers (operations, engineering, and configuration) • terminal sterilization of product • compressed air (generation and distribution) • premises • QC laboratories (analytical and microbiological) • production and control operations involved in the manufacture of LVPs Dr. Pogány - WHO, Pretoria

4. WHO GMP and Guidelines • WHO good manufacturing practices (GMP): main principles for pharmaceutical products – Section 4. Qualificationand validation(see notes page below) http://www.who.int/medicines/library/TRS/trs908/trs908-4.pdf • Supplementary guidelines ongood manufacturing practices(GMP):Validation Rev.1 (2003) – Draft http://www.who.int/medicines/organization/qsm/expert_committee/Guidelines/QAS_055_Rev1_validation.doc • No specific guideline on the VMP. Dr. Pogány - WHO, Pretoria

5. Why do we validate? • Interchangeability of generic FPPs = Pharmaceutical equivalence + bioequivalence • Pharmaceutical equivalence • Product and manufacturingprocess equivalence (prospective and concurrent validation) • GMP equivalence (concurrent validation) • Maintenance and continuous improvement of the validated status [concurrent and retrospective validation, Process Analytical Technology (PAT)] Dr. Pogány - WHO, Pretoria

6. Why do we validate processes? • Small quantity of waste creates serious danger to health(1/3 of 5% dextrose infusion was not sterile, Evans Medical, 1972) • Low chance that patient or doctor recognizes non-conformance to specification in time (1996 -Haiti) • Limitations of sampling • Percent of nonconformance: 0,1 1,0 5,0 10,0 • Percent probability of release: 98 82 36 12 Dr. Pogány - WHO, Pretoria

7. SAMPLING PROBLEM The whole batch is released to the patient But only the sample is tested BATCH Sample Dr. Pogány - WHO, Pretoria

8. 4.4 What should be validated? „Any aspect of operation, including significant changes to the premises, facilities, equipment or processes, which may affect the quality of the product, directly or indirectly, should be qualified and validated.” Dr. Pogány - WHO, Pretoria

9. VALIDATIONSTARTS WITH DESIGN + CONSTRUCTION OF FACILITIESAND PURCHASING EQUIPMENT GMP, QUALIFICATION and Dr. Pogány - WHO, Pretoria

10. Dr. Pogány - WHO, Pretoria

11. 4.1-4.2 Validation master plan • „In accordance with GMP, each pharmaceutical company should identify what qualification and validation work is required to prove that the critical aspects of their particular operation are controlled. • The key elements of a qualification and validation programme of a company should be clearly defined and documented in avalidation master plan (VMP).” Dr. Pogány - WHO, Pretoria

12. WHO draft guide • „The Validation Master Plan (VMP) complements the manufacturer’s site master file and should be the first document to be reviewed during inspection by a regulatory authority.” • „The VMP reinforces the commitment of the company to GMP. It is a formal policy document which describes the overall philosophy of the company towards validation and which also describes the key elements of the validation programme, organizational structure of validation, schedules and responsibilities.” Dr. Pogány - WHO, Pretoria

13. 4.5-4.7 Validation policy • Qualification and validation should not be considered as one-off exercises. An on-going programme should follow their first implementation (continuous improvement within the design space … speaker’s remark)and should be based on an annual review. • The commitment to maintain continued validation status should be stated in the relevant company documentation, such as the quality manual or validation master plan. • The responsibility of performing validation should be clearly defined. Dr. Pogány - WHO, Pretoria

14. Validation master plan The VMP is a summary document and should therefore be brief, concise and clear. It should not repeat information documented elsewhere but referto existing documents such as • Policy documents, • SOP's and • Validation Protocols/Reports. Dr. Pogány - WHO, Pretoria

15. ISO9001 :2001 - 4.2.2 Quality manual The organization shall establish and maintain a quality manual that includes • the quality policy • the scope of the quality management system, including details of and justification for any exclusions (see 1.2), • the documented procedures established for the quality management system, or reference to them, and • a description of the interaction between the processes of the quality management system. Dr. Pogány - WHO, Pretoria

16. Types of VMP • Construction of new premises • Introduction of a group of new FPPs (individual validation protocols may suffice for single new FPPs) • Major renovation or additions to existing premises • First time validationof previously unvalidated processes or unit operations • Automation or computerized implementations that span a number of applications Dr. Pogány - WHO, Pretoria

17. Functions of VMP • Education of management • Projectmonitoring and management • Project training • Audit of the validation program • Update of regulatory agency requirements Dr. Pogány - WHO, Pretoria

18. Basic questions to be answered • What will be validated? • Who is responsible for the validation tasks? • How will the equipment be qualified and the processes validated? • How will the validation be documented? • What are the criteria by which a successful validation will be judged? Dr. Pogány - WHO, Pretoria

19. Content of VMP • Title, approval (top management and members of thevalidation team) and table of contents • Glossary of terms • Introduction (policyandobjectives) • Scope [separate VMPs for manufacturing processes, pharmaceutical utility systems (e.g. HVAC, water)]. • Responsibilities Dr. Pogány - WHO, Pretoria

20. Content of VMP • Production and QCpremises, including controlled environments • Process and QCequipment, including location • Pharmaceutical air (HVAC) and water systems • Allpotentiallycritical utilities(such ascompressed air, steam and cooling liquids, and so on) • Computer control systems Dr. Pogány - WHO, Pretoria

21. Equipment No. Description IQ OQ PQ Unidirectional air flow hood √ √ √ High-speed mill √ √ √ High-speed, high shear granulator √ √ √ Sizer (re-granulator) √ √ √ Jacketed tank with stirrer √ √ √ Blender √ √ √ Matrix for qualification of equipment Dr. Pogány - WHO, Pretoria

22. Content of VMP • Manufacturing processes • List of validation protocols, including format • List of relevant SOPs • Product specifications includingprospective (and tentative) IPC acceptance criteria • QC and IPC methods, validation, if applicable • Reasonable unexpected events Dr. Pogány - WHO, Pretoria

23. Content of VMP • Equipmentcleaning • Planning and scheduling (Gant chart) • Preventative maintenance program • Workerandenvironment safety • Change Control/including Revalidation • Training requirements • Documentationrequirements Dr. Pogány - WHO, Pretoria

24. EU-VMP should contain at least the following data • validation policy • organisational structure of validation activities • summary of facilities, systems, equipment and processes to be validated • documentation format: the format to be used for protocols and reports • planning and scheduling • change control • reference to existing documents Dr. Pogány - WHO, Pretoria

25. Main Points Again • Target all personnel involved in the validation when creating the master plan. • Keep the VMPshort, but provide enough information so that the document isfunctional. • Provide for flexibility to deal with changes, but do not avoidmaking the required decisions early on in the project. • The life cycle mandates that the validation process becomes an ongoing project, which requires constant attention. Dr. Pogány - WHO, Pretoria

26. Literature • Qualification and validation, Annex 15 to the EU Guide to Good Manufacturing Practice http://pharmacos.eudra.org/F2/eudralex/vol-4/pdfs-en/v4an15.pdf • Validation Master Plan, Installation AndOperationalQualification, Non-sterile Process Validation, Cleaning Validation (PIC/S, August 2001) • Model VMPfor Tableting Plants (distributed among participants of the training course) Dr. Pogány - WHO, Pretoria