Overview of Validation Requirements in Pharmaceutical Industry Kaushik Desai Chairman, Industrial Pharmacy Division

1. Overview of Validation Requirements in Pharmaceutical Industry Kaushik Desai Chairman, Industrial Pharmacy Division Indian Pharmaceutical Association www.ipapharma.org

2. A definition Where did validation come from ? Why do it ? What are the benefits ? How far do we have to go ? Agenda

3. “ Establishing the documented evidence which provides a high degree of assurance that a specific process will consistently produce a product of predetermined specifications and quality attributes.” (FDA Guidelines 1987) Definition ( FDA)

4. “Process validation is defined as the collection & evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that process is capable of consistently delivering quality product.” (FDA Guidelines, 2011) Definition ( FDA)

5. “Action of proving, in accordance with the principles of Good Manufacturing Practice (GMP), that any procedure, process, equipment, material, activity or system actually leads to expected results.” (EU GMP 1997) Definition (EU GMP)

6. Began in 1970’s Originally sterilized based. Now evolved into all Product, Process and Facility matters. Where did validation come from ?

7. Assures Quality Regulatory Requirement Reduces Cost It’s the LAW ! Why Validate ?

8. Validation can reduce costs by reducing, Rejects Reworks Reliance on In-process controls Down time Benefits

9. Reliance on product testing Loss of confidence Possibility of adulterated products Inspection : Observations / 483’s When it goes wrong …..?

10. User Requirement Specification (URS) Design Qualification Impact Assessment Factory Acceptance Testing Installation Qualification Validation Terminology

11. Calibration Site Acceptance Testing Operational Qualification Standard Operating Procedures Performance Qualification Process Validation Change Control Validation Terminology

12. User Requirement Specification (URS) A description of the requirements of the facility (project) in terms of product to be manufactured, required throughput and conditions in which the product should be manufactured. Approved statements prepared by the user which defines what is required by the project. Validation Terminology

13. Design Qualification (DQ) Documented review of the design, at an appropriate stage in a project, for conformance to operational and regulatory expectations. (Note : Not an obligation) Validation Terminology

14. Impact Assessment The process of evaluating the impact of the operating, controlling, alarming and failure conditions of a system on the quality of a product Validation Terminology

15. Factory Acceptance Testing (FAT) • Inspection and static and/or dynamic testing of systems or major system components to support the qualification of an equipment system conducted and documented at a supplier site. (Note : Not an obligation) Validation Terminology

16. Documented verification that all aspects of a facility, utility or equipment that can affect the product quality adhere to approved specifications and are correctly installed. The process of checking/verifying the installation to ensure that the critical components meet the approved specifications and that they are installed correctly in accordance with design documentation. Installation Qualification (Definition)

17. To establish that the critical components are installed correctly and in accordance with design documentation requirements (i.e. PO’s, Contracts etc.), that supporting documentation is in place and of suitable quality. To record the checks and verifications for critical components in Direct Impact Systems. Installation Qualification (PURPOSE)

18. Approval Page Objectives System Description Responsibilities Acceptance Criteria Engineering Documentation Requirements Records of Signatures Qualification Test Equipment/Instrument List Product Contact Materials Review Utilities Verification Control System Verification IQ Protocol (Contents)

19. Instrument/Control Devices Verification Equipment Verification Piping Installation Verification Discrepancy/Justification and corrective Action As built P&I Diagrams Specifications Conclusions References Modification/ Change Control Attachments / Appendices IQ Protocol (Contents)

20. Parameters Does the vessel meet the design specification? Does the agitator assembly meet the design specification? Is the motor housing earthed? Is the motor over current device set to correct setting? Is all the pipe work connected? Are all instruments installed as per P&I diagram? Have all the temperature indicators been calibrated? Is calibration procedure available? Are operation and maintenance manuals available? all electrical connections securely and safely fitted? Is insulation complete? Is vessel clean and free from dirt? Basic IQ – Mfg. vessel

21. After protocol execution is complete and deviations evaluated, post execution approval is required. Requires sign off by original signatories. IQ execution should be complete and approved prior to the start of OQ. IQ Protocol Approval

22. Calibration Demonstrating that a measuring device produces results within the specified limits of those produced by a reference standard over an appropriate range of measurements. The devices are normally tagged and supported by a maintenance procedures. Validation Terminology

23. Site Acceptance Testing (SAT) Inspection and dynamic testing of systems or major system components to support the qualification of an equipment system conducted at a client site. (Note : Not an obligation) Validation Terminology

24. Documented verification that all aspects of a facility, utility or equipment that can affect product quality operate as intended throughout all anticipated ranges. It is the process of testing to ensure that individual components and systems operate as specified, and how that information is recorded. Operational Qualification (Definition)

25. To establish through documented testing, that all critical components and direct impact systems are capable of operating within established limits and tolerances. To test parameters that regulate the process or product quality. To verify the proper operation of controllers, indicators, recorders, alarms and interlocks, is performed and documented during the operational qualification testing. Operational Qualification (PURPOSE)

26. Approval page Pre-requisites Objectives System Description Responsibilities Acceptance Criteria Records of signatures Qualification test Equipment/Instruments list Alarm and Interlocks test Operation testing Capacity testing Power failure testing Operational Qualification (Protocol)

27. Sequence testing Test data sheets SOP’s Conclusions Modification / change control Discrepancy/Justification and corrective action Operational Qualification Summary References Attachments/Appendices - Verification of test instruments - Chart recordings - P&I diagrams - Printouts Operational Qualification (Protocol)

28. Parameters Have all Installation Qualification been completed for this system? Is the system clean and free from dirt? Is the direction of the rotation of agitator correct? Check the operation of the agitator emergency stop? Check the operation of all agitator controls, both on the main and local panels? Check that the agitator in the vessel free to turn? Pressurize the vessel and record the pressure drop for 10 min. Perform a vacuum test and record the vacuum drop. OQ – Mfg. vessel

29. Documented verification that all aspects of a facility, utility or equipment that can affect the product quality perform as intended in meeting the predetermined acceptance criteria. Performance Qualification (Definition)

30. To integrate procedures, personnel, systems and materials to verify that the utility / environment / equipment / support systems produces the required output. This output may be a product contact utility, sterilization condition or environment. Performance Qualification (Purpose)

31. Approval page • Pre-requisites • Objectives • System Description • Responsibilities • Acceptance Criteria • PQ test plan • Challenge test plan • Records of signatures • Test equipment/Instrument list • Test data sheets • SOP’s • References • Conclusions • Attachments Performance Qualification (Protocol)

32. Process Validation The documented verification providing a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes. The new guidelines aligns process validation activities with a product life cycle concept. Validation Terminology

33. 211.42, 211.63, 211.68, 211.84 211.100(a) , 211.110(a), 211.110(b) 211.160(b), 211.165(c), 211.165(d), 211.180(e) US FDA (21 cfr)– Process Validation

34. Life Cycle of the product & the process Stage 1 – Process Design Stage 2 – Process qualification Stage 3 - Continuous process verification Process Validation

35. It is the activity of defining the commercial manufacturing process that will be reflected in planned master production and control records. The goal of this stage is to design a process suitable for routine commercial manufacturing that can consistently deliver a product that meets its quality attributes. It is based on the knowledge gained through development & scale-up activities. Stage 1 - ProcesSdESIGN

36. During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing. The products manufactured during this stage, if acceptable , can be released for distribution. Two Aspects Design of facility and qualification of equipment and utilities. Process Performance Qualification ( PPQ). Stage 2 – Process qualification

37. Def.: “Releasing for distribution a lot of finished product, manufactured following a qualification protocol, that meets the standards established in the protocol, but before the entire study has been executed”. Orphan Drugs Specific drug for specific use Short Shelf-life radio pharmaceuticals Concurrent rELEASE

38. The goal of this stage is continual assurance that the process remains in a state of control ( the validated state) during commercial manufacture. The cGMP requirements, specifically the collection & evaluation of information & data about the performance of the process will allow detection of undesired process variability. This stage is also applicable for legacy products. SATGE 3 – Continued process verification

39. Change Control Formal evaluation of the potential impact of planned modifications on the validated status of a product, process or facility. Validation Terminology

40. Training personnel for IQ/OQ execution. The purpose of the equipment/ system. Use of test equipment Applicable SOP’s cGMP documentation of training Document all training Periodically review training requirements Training

41. A document that summarizes and analyses the test results at the end of PQ. • Provides a conclusion about the ability of the system to consistently meet acceptance criteria. • May be a stand alone document at each stage of IQ/OQ and PQ to summarize results. Final Summary Report

42. Commissioning and Qualification Project Phases Validation Phases Technology Transfer Collecting data Conceptual Design Basic Design Preliminary VMP Detailed Design Detailed VMP Procurement Detailed planning,DQ Construction IQ Pre commissioning Commissioning OQ Process operation / Validation Basic IQ/OQ/PQ

43. Validation Master Plan Introduction Qualification Personnel Schedule Preventive Maintenance Installation Responsibilities Change Control Operation Training Procedures Documents Appendices Process

44. The company’s overall policy, intentions and approach to validation, including : • Validation of production processes • Cleaning procedures • Analytical methods • In-process control test procedures • Computerized systems • Persons responsible for design, review, approval • Documentation of each validation phase Validation Policy

45. Product validation is NOT …… - just 3 batches that meet specifications Product validation is …… - an ongoing process to build confidence into the manufacturing activities - an ability to demonstrate consistency at any time. Product Validation

46. Cleaning validation is establishing documented evidence that the equipment is consistently cleaned from product, microbial and cleaning agent residues to predetermined acceptable levels. Cleaning Validation

47. A written procedure for cleaning validation which includes : Responsibility for development, performance and approval of the validation study. Establishment of SOP’s Acceptance criteria - defined to prevent cross contamination - definition of residue limits FDA Expectations

48. Cleaning procedure for each piece of equipment - Flow charts and diagrams - Cleaning agents, concentration, volume - Frequency - time left ‘dirty’ Prior to Cleaning ValidationEstablish specific SOP’s

49. Sampling procedures - swabs, rinse, location Residue limits Analytical methods Cleaning Validation

50. Validation report - Results Vs. acceptance criteria - Deviations and how handled - Conclusion that cleaning process is validated Cleaning Validation