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SAPRAA March 2013

SAPRAA March 2013. Validation. Presentation. What will be covered in this presentation….. Why do we validate? What do we validate? Approach to validation Qualification Process validation – a look at the FDA guidelines. Personnel. Validated processes. Procedures. Raw Materials.

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SAPRAA March 2013

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  1. SAPRAAMarch 2013 Validation

  2. Presentation What will be covered in this presentation….. • Why do we validate? • What do we validate? • Approach to validation • Qualification • Process validation – a look at the FDA guidelines

  3. Personnel Validated processes Procedures Raw Materials Equipment PackingMaterials Premises Environment Purpose of Validation • GMP Guide Chapter 5, Annex 11, Annex 15 • In compliance • Dossier submission • Ever look at those files….. Factors affecting quality OR Validation Change Control

  4. FDA Warning Letters

  5. Why do we validate • Manufacturers must assume responsibility for the quality of products & ensure they are: • fit for use • comply with registered requirements • do not place patients at risk

  6. Why do we validate • Validation establishes & provides documented evidence that premises, utilities and equipment: • are designed in accordance with GMP • are installed in compliance with design criteria • operate in accordance with design criteria • Validation establishes that a specific process will consistently produce a product meeting its pre-determined specification

  7. Validation • Validation a requirement not an option • Is validation a ‘tick box’? • Validation documentation always checked in GMP inspection (the ‘action of proving..’) • MCC and PIC/S….. design, installation, operational and performance…. qualification • MCC and PIC/s…. validation of processes, cleaning and analytical methods…. validation • A system or equipment must be qualified in order to operate in a validated process • Process validation protocols required for dossier submission

  8. Validation / Qualification Validation: Proving procedures, processes, equipment, materials, activities, systems lead to the expected results Qualification: Proving and documenting premises, systems, equipment properly installed and/or work correctly & lead to the expected results Qualification often initial stage of validation, individual steps alone do not constitute process validation

  9. What gets validated • Facilities • Utilities / Services / Systems • Equipment • Computer systems • Analytical methods • Cleaning methods • Processes Facilities, systems and equipment qualified prior to process validation being completed

  10. What gets validated • Utilities / Services / Systems • Critical systems with direct impact e.g. • Purified Water • HVAC • Compressed air (in contact with product or primary containers) • Steam (if used for cleaning product contact surfaces)

  11. What gets validated • Processes • Non-sterile manufacturing • Sterile manufacturing – media fills • Sterilizing loads • Waste

  12. Sequencing of Validation Stages Validation Master Plan Site Master File Overall Validation Master Plan User Requirement Specification Validation SOP Design Qualification Process Validation Documents that are required to be in place and are routinely updated Installation Qualification Operational Qualification Performance Qualification

  13. Approach to Validation • Validation requires: • Collaboration between the all relevant parties (validation, QA, production, engineering, consultants, contractors) • Resources – time, budget, people • Planning (including defining scope of work) and control

  14. Approach to ValidationPlanning • Risk-based approach to validation; not all components need to be validated • Avoids making validation unnecessarily complex • A Risk Assessmentor Impact Assessment determines which components are critical and non-critical, or have a direct impact or indirect impact on product quality • Critical Process Parameters & Critical Quality Attributes These decisions have implications on the extent, cost and time of the qualification process

  15. ISPE Commissioning and Qualification Fig. 1.1 ISPE Pharmaceutical Engineering Baseline Guide: Commissioning and Qualification Vol. 5 March 2001

  16. Impact Spectrum Fig. 2.1 ISPE Pharmaceutical Engineering Baseline Guide: Commissioning and Qualification Vol. 5 March 2001

  17. Qualification Requirements Direct Impact Systems Indirect Impact Systems No direct impact on product quality Designed & commissioned in line with GEP No qualification required • Direct impact on product quality • Designed & commissioned in line with GEP • Also subject to qualification

  18. Impact Assessment Indicators Direct Impact Systems Direct Impact Components Used to demonstrate compliance with registered process (e.g. hardness tester) Has a direct effect on product quality (e.g. blister embossing) Failure or alarm of component having a direct effect on product quality (e.g. in-line TOC) Information from component recorded as part of batch record (e.g. drying temperature) Has direct contact with product • Direct contact with product (e.g. air) • Produces an excipient / ingredient (e.g. WFI) • Used in cleaning / sterilizing - malfunction could result in failure which poses risk • Controls a risk to the product (e.g. Nitrogen blanket) • Produces data used to accept / reject product • Produces identification information (e.g. expiry date)

  19. Approach to ValidationVerification and GEP • Verification and GEP – processes that function within the engineering environment • Support the validation effort • Operate continually, not only at one point in time • Based on quality management principles e.g. documentation control, change management, authorization processes, deviations / discrepancies

  20. Approach to ValidationEngineering Risk-based Verification • Risk Management applied - identifies critical aspects for product quality & patient safety • List of critical aspects approved by QA • Acceptance criteria specified for the critical aspects • Non-critical aspects may be included (do not require same level of involvement by QA) • Acceptance and release must provide documented confirmation of fitness for intended use

  21. Approach to ValidationVerification Execution • Verification confirms critical aspects meet acceptance criteria • Extent of verification commensurate to risk to product quality • Execution: • Design review • Factory Acceptance Test (FAT) • Site Acceptance Test (SAT) • Installation testing • Functional testing • Performance testing • Handling of discrepancies, change management • Acceptance and release

  22. Good Engineering Practice • Focus on practices that add value - providing evidence of fitness for use & proper performance • GEP is expected in pharmaceutical enterprises; it is not required by GxP regulations • However value of effective GEP is supported by regulatory and engineering guidance / standards

  23. Qualification Approaches • International regulations: facilities, equipment & systems qualified and automation systems validated • ISPE Guide: ensures facilities, equipment, systems, and associated automation are ‘fit for intended use’ • ISPE Guide: states critical aspects, and the installation & operational acceptance criteria documented in the final risk assessment / design review could be labeled as the IQ / OQ • Emphasis on ensuring fitness for use through verification activities during the life cycle rather than ‘incidents’ that represent qualification

  24. Life Cycle Fig. 2.2 ISPE Guide: Science and Risk-Based Approach for the Delivery of Facilities, Systems and Equipment (2011)

  25. Sequencing of Validation Stages Validation Master Plan Site Master File Overall Validation Master Plan User Requirement Specification Validation SOP Design Qualification Process Validation Documents that are required to be in place and are routinely updated Installation Qualification Operational Qualification Performance Qualification

  26. User Requirement Specification (URS) • Details of requirements from an operational and GMP perspective • One of the most important documents but usually drafted as an after thought! • Examples: • Speed e.g. 200 bottles per minute • Temperature e.g. drying temperature range 50 to 80ºC • Finishes e.g. SS304 • Safety features e.g. guards • Documentation required e.g. manuals

  27. Design Qualification(DQ) • Verification that what is to be supplied is in line with the requirements specified in the URS and will meet GMP requirements • Does the design incorporate sufficient provisions to control all risks to the end user? • Examples: • Speed e.g. 50 to 200 bottles per minute • Temperature e.g. drying temperature range 35 to 90ºC • Finishes e.g. mild steel (does not meet requirements) • Safety features e.g. guards present • Documentation required e.g. manuals available

  28. Installation Qualification (IQ) • Installation complies with design specification and manufacturer’s recommendations • Examples: • Correct make / model installed • All components present • Connections made • Instruments calibrated • As-built drawings available and correct • Materials of construction correct

  29. Installation Qualification (IQ) A thoroughly executed IQ process ensures: • A fully verified installation that complies with the documented design • All deviations and changes recorded, assessed and approved • Accurate ‘as built’ drawings available and verified • Calibration of measuring instruments completed • Materials of construction verified

  30. Operational Qualification (OQ) • Installation performs as intended throughout the anticipated operating ranges • Examples: • Test, for example, speeds / temperatures / fill volumes through full operating range & comparable load (inert material used if required) • Test alarms • Test safety mechanisms • Test interventions, stoppages, start-up etc. • Operational and maintenance procedures available • PPM and calibration schedules are drafted • SOPs are compiled & authorized • Training performed & documented

  31. Operational Qualification (OQ) A thoroughly executed OQ process ensures: • Formal commissioning reports available • Ability of systems to maintain set points in all operational modes demonstrated • Correct functioning of the control system demonstrated • All alarms verified as functioning correctly • Operational ranges, specific alert and action limits identified • Operational and Maintenance manuals available • PPM and calibration schedules available • SOPs available and authorized • Personnel training successfully completed

  32. Performance Qualification (PQ) • Effective and reproducible performance, based on the approved process method and product specification • Does the qualification provide assurance that the system / equipment is fit for use and any deviations from specification have been identified and evaluated? • Examples: • Performance of filling equipment: • Consistent fill volume within registered specification using placebo product • Performance of Purified Water system: • Microbial contamination within specification • Performance of HVAC: • Non-viable particle count within specification

  33. Performance Qualification (PQ) A thoroughly executed PQ process ensures: • Demonstration of consistent delivery of process / product specification • Demonstration that the systems have been successfully validated and will not contribute any risk to the quality of products routinely produced • Re-validation criteria, where required, have been formalized

  34. Process Validation FDA Guidance for Industry Process Validation: General Principles and Practices January 2011 Revision 1 • ‘…aligns process validation activities with a product lifecycle concept…’ • ICH Q8 Pharmaceutical Development • ICH Q9 Quality Risk Management • ICH Q10 Pharmaceutical Quality System

  35. Process ValidationFDA Process Validation: General Principles and Practices • ‘The lifecycle concept links product and process development, qualification of the commercial manufacturing process, and maintenance of the process in a state of control during routine commercial production.’ FDA Guidance for Industry Process Validation: General Principles and Practices January 2011 Revision 1

  36. Process ValidationFDA Process Validation: General Principles and Practices • Guidance covers: • Human drugs • Veterinary drugs • Biological and biotechnology products • Finished products and APIs/drug substances • The drug constituent of a combination (drug & medical device) product • Medical devices, dietary supplements, human tissues, medicates feeds excluded FDA Guidance for Industry Process Validation: General Principles and Practices January 2011 Revision 1

  37. Process ValidationFDA Process Validation: General Principles and Practices • Products should be produced that are fit for their intended use • Quality, safety and efficacy are built into the product • Quality cannot be adequately assured through in-process and final product inspection and testing FDA Guidance for Industry Process Validation: General Principles and Practices January 2011 Revision 1

  38. Process ValidationFDA Process Validation: General Principles and Practices ‘… process validation is defined as the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product…’ • Stage 1- Process Design: Commercial manufacturing process defined through development & scale up activities • Stage 2 – Process Qualification: Process design evaluated to verify capability of reproducible commercial manufacturing • Stage 3 – Continued Process Verification: On going assurance during routine production that process remains in state of control FDA Guidance for Industry Process Validation: General Principles and Practices January 2011 Revision 1

  39. Process ValidationFDA Process Validation: General Principles and Practices • Gain high degree of assurance in performance of manufacturing process before any commercial batch is distributed for use • Attributes consistent • Identity • Strength • Quality • Purity • Potency FDA Guidance for Industry Process Validation: General Principles and Practices January 2011 Revision 1

  40. Process ValidationFDA Process Validation: General Principles and Practices • Successful validation depends on information / knowledge from product & process development • Understand sources of variation • Detect presence & degree of variation • Understand impact of variation • Control variation (commensurate with risk to process & product) FDA Guidance for Industry Process Validation: General Principles and Practices January 2011 Revision 1

  41. Process ValidationFDA Process Validation: General Principles and Practices • Focus on qualification without understanding the process and variation may not lead to quality assurance • Continue to maintain state of control during lifecycle regardless of changes (materials / equipment / facilities / personnel) • On-going programs collect and analyze data to evaluate state of control FDA Guidance for Industry Process Validation: General Principles and Practices January 2011 Revision 1

  42. Process ValidationFDA Process Validation: General Principles and Practices Stage 1 – Process Design • Do not need cGMP conditions • Sound scientific methods & principles, good documentation practices (ICH Q10) • Decisions & justification of controls documented and reviewed – value for use and later adaptation • Product development provides key inputs to quality attributes and manufacturing process • Functionality & limitations of commercial manufacturing equipment considered FDA Guidance for Industry Process Validation: General Principles and Practices January 2011 Revision 1

  43. Process ValidationFDA Process Validation: General Principles and Practices Stage 1 – Process Design • Predicted variability considered • Strategies for process control: • Reduce input variation • Adjust for input variation (to reduce impact on output) • Both • Process controls address variability → assures quality • Controls: • Examination of material quality • Equipment monitoring FDA Guidance for Industry Process Validation: General Principles and Practices January 2011 Revision 1

  44. Process ValidationFDA Process Validation: General Principles and Practices Stage 2 – Process Qualification • Determine capability for reproducible commercial manufacture • Two elements: • Facility design & equipment / utilities qualification • Process Performance Qualification • Successful completion before distribution of product (FDA expects concurrent release to be rarely used) FDA Guidance for Industry Process Validation: General Principles and Practices January 2011 Revision 1

  45. Process ValidationFDA Process Validation: General Principles and Practices Stage 2 – Process Qualification • Qualification: Demonstrate utilities and equipment are suitable for intended use and perform properly • Qualification must precede Process Performance Qualification (PPQ) • PPQ combines facility, utilities, equipment, trained personnel, commercial manufacturing process, control procedures and materials / components • Successful PPQ required before distributing product FDA Guidance for Industry Process Validation: General Principles and Practices January 2011 Revision 1

  46. Process ValidationFDA Process Validation: General Principles and Practices Stage 2 – Process Qualification • PPQ has: • Higher level of sampling • Additional testing • Greater scrutiny of process performance • Above could be extended in certain cases e.g. complexity of process, production volume • Manufacture under normal conditions using routine personnel FDA Guidance for Industry Process Validation: General Principles and Practices January 2011 Revision 1

  47. Process ValidationFDA Process Validation: General Principles and Practices Stage 2 – Process Qualification • PPQ protocol: • Manufacturing conditions (including operating parameters, processing limits, materials) • Data to be collected (when, how, evaluation) • Tests to be performed and acceptance criteria • Sampling plan (sampling points, number of samples, frequency of sampling) • Process performance indicators (statistically based) • Status of qualification & analytical method validation • Process for addressing deviations • Review & approval FDA Guidance for Industry, Process Validation: General Principles and Practices January 2011 Revision 1

  48. Process ValidationFDA Process Validation: General Principles and Practices Stage 3 – Continued Process Verification • Objective: Continual assurance that process remains in a state of control / validated state • Managing change • Routine monitoring systems, maintenance, calibration • Data collection & review (product reviews) • Evaluation of process – identify problems, corrective / preventative actions • Statistical process control techniques FDA Guidance for Industry, Process Validation: General Principles and Practices January 2011 Revision 1

  49. Process ValidationFDA Process Validation: General Principles and Practices Stage 3 – Continued Process Verification • Changes include: • API supplier • Excipient physical properties • Primary packaging material • Equipment • Process • Facility / plant • Changes require documented description, well-justified rationale, implementation plan, QA approval

  50. Concurrent & Retrospective Validation • Concurrent: Validation carried out during routine production of products intended for sale • Exceptional cases • Justified, documented, approved • Retrospective: Validation based on historical / collected data (manufacturing, testing, control data) • Only for well established processes • Inappropriate where changes to composition, equipment & processes made • Suggested source data

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