MASTER PLANNING FOR VALIDATION By: Gamal Amer, Ph.D. Principal, Premier Compliance Services, Inc. 1
Process Validation: General Principles and Practices Guidance to industry issued by the FDA in January 2011. Outlines the life cycle approach to validation. Inline with the principles advanced in ICH Q8, ICH Q9, ICH Q10 and in ASTM E2500. Defines PROCESS VALIDATION as the collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products. 2
FDA Guidance on Process Validation January 2011 Three Stages of Process Validation Process Design Stage (process is defined based on development and scale-up) Process Qualification Stage (Design is confirmed as being capable of reproducible production) Continued Verification and improvement (Continuously gaining assurance the process remains in a state of control) 3
The Life Cycle Approach to Process Validation Planning & Design (ICH Q8) PAT Continuous Verification & Improvement ICH Q9, CAPA, PAT & Change Control ICH Q9 ICH Q10 The Quality System Implementation & Qualification 4
Stage 1: Process Design Understanding the science Understanding the risk Building Quality into the process Establishing Control Strategy 5
Stage 2: Implementation and Process Qualification Implement the process and Facility Qualification of utilities and equipment Performance qualification and PQ protocol Protocol execution and report 6
Stage 3: Continued Process Verification Monitoring appropriate parameters to ensure process in a validated state of control. Use CAPA, PAT and Change control as well as data collected in monitoring to continually improve the process. Proper maintenance of the facility, utilities, and process equipment 7
Process Validation vs. Process Qualification Process validation combines the three stages outlined in the FDA guidance. (V) Qualification as stage 2 of the guidance where you qualify the equipment and the utilities and ultimately conduct the PPQ. (v) This discussion will focus on the plan to conduct the qualification of a new process. 8
Types of Master Plans Process Qualification (validation) Master Plan Focus of this discussion Cleaning Validation Master Plan Computer Validation Master Plan Analytical Methods Validation Plan Etc. Most of the concepts presented here would apply to all types of plans 9
Stage 2 Process Qualification Goal: Evaluate the design developed in stage 1 to determine if it is capable of reproducible commercial manufacturing and performs as expected. Must follow CGMP-Compliant procedures 10
Stage 2 Process Qualification Stage 2 confirms the process design as being capable of commercial manufacture Stage 2 has two elements Implementation and qualification of: Facilities, equipment and utilities Process Performance Qualification (PPQ) Demonstrate consistency and unifor quality of product. 11
Stage 2 Process Qualification Implementation and qualification of Facility, Utilities, and Equipment Construct and install facility, utilities, and processing equipment Qualification (activities to demonstrate equipment are suitable for intended use) of utilities and equipment Demonstrate proper selection of material and design Demonstrate proper construction and installation Demonstrate that equipment and utilities operate in accordance with the process requirements (include appropriate challenges to represent normal operation) 12
Stage 2 Process Qualification Demonstrate utility and equipment are properly designed and installed through qualification Demonstrate utility and equipment operate within requirements through qualification Equipment and systems are to be challenged Qualification of utilities and equipment covered under individual plans or overall project plan Qualification activities to be summarized in a report 13
Stage 2 Process Qualification Qualification Plan (QP) Qualification can be covered under individual or overall project plan Risk management Prioritize activities Identify level of effort 14
Stage 2 Process Qualification Plan to identify Study tests to be used Appropriate criteria to show acceptability Timing of activities Responsibilities Procedures for documenting and approving Activities to be summarized in a report Quality Unit (QU) must review and approve the QP 15
Stage 2 of Guidance Stipulates Process Performance Qualification Approach: PPQ should combine qualified facility, utilities, and equipment with trained personnel to confirm the commercial manufacturing performs as expected. PPQ must be completed before commercial distribution of drug. PPQ should be based on science and technical understanding. Employ statistical metrics to achieve adequate assurance through data analysis. PPQ should have additional (when compared to normal production) sampling, monitoring, and analysis If using PAT, a different approach to PQ maybe warranted: Qualification to focus on measurement and control loop. Establish process is reproducible and will deliver quality product. 16
Stage 2 of Guidance Stipulates Process Performance Qualification Protocol: Written Protocol delineating manufacturing conditions, controls, sampling, testing, and expected outcome. PPQ should discuss manufacturing conditions, operating parameters, limits, and components. PPQ should discuss the data to be collected and when and how it will be evaluated. PPQ establishes the tests to be performed and acceptance criteria. PPQ should detail the sampling plan (No. of samples and frequency of sampling). Discuss status of analytical methods validation. Should be reviewed and approved by appropriate departments and Quality Unit. 17
Stage 2 of Guidance Stipulates Protocol Execution and Report: Only execute approved protocol. Departures from the approved protocol to be justified and approved. Follow expected routine procedures for commercial process using personnel who will be responsible for manufacture. Report to be prepared in a timely manner, should include: Summary and analysis of data. Evaluation of unexpected results. Evaluate manufacturing non-conformances (deviations, OOS results, etc.). Description of corrective actions taken. A clear statement as to the process being fit for the intended use. Review and approval by appropriate departments and quality unit. 18
What it all means? PPQ to confirm manufacturing process PPQ to confirm process design PPQ To be completed before manufacture and distribution Previous creditable experience with similar products & processes can be considered Entire operating range need not be verified, only normal operation. 19
How to do it. 20
Conducting Qualification Define critical process and utility systems Ascertain correct equipment was obtained and installed correctly Establish confidence that equipment is capable of consistently achieving product specifications by performing adequately within the operating limits of the process 21
Conducting Qualification Establish evidence that the process is both effective and reproducible through rigorous testing and documentation Test parts of the process that may affect product quality or may cause variability Summarize results Ensure that process remains in a validated state through monitoring, maintenance, and a change control procedure (stage 3) 22
Qualification/validation Approach Design Review Protocol Preparation Protocol Execution Summary Report Preparation Qualification Record VMP IQ, OQ, PQ, PPQ Executed IQ,OQ, PQ, PPQ Qualification Reports Engineering Drawings Specifications Manuals, P& ID, SOPs Weld Logs, Certifications, Analytical and Integrity Tests Product Data 23
What is the Master Plan? Scope Defining Document Intent of Effort Approach for Execution Support Requirements Timing for Execution Not a Regulatory Document but always asked for by the regulators Stand Alone Document Describing Facility, Utilities, and Process Aspects of the Operation 24
What is its the Ultimate Objective? To outline a plan that will set the road map to conducting a thorough qualification of your operation including the utilities, facility, processing equipment, and trained personnel to demonstrate the process capability of reproducible commercial manufacture of the product. 25
Validation Master Plan Contents Objective and Scope Definition Scope Facility/Utility Description Process Description Systems to be Qualified General Acceptance Criteria Qualification Test Functions Complimentary/Support Programs SOPS Maintenance Change Control Personal Training Health and Safety Qualification Schedule Personal Qualifications 26
Master Plan Contents (Cont.): Appendix Sample Protocol/Report Applicable SOPS Facility Layout Drawing Personnel/Material Flow Drawing Room Pressurization Drawing Piping and Instrumentation Drawings 27
Objective and Scope The purpose of this document is to establish a plan for implementing the facilities and process qualification effort The Scope of the effort will include qualification of utility systems in the manufacturing facility and the processing equipment/systems which directly impact production of the therapeutic agent 28
Should Include SCOPE Description of Facility Purpose and Process to be Performed Description of Utility and Support Systems Major Equipment Description Drawing and Process Flow Diagrams 29
Definitions AHU The air handling unit. The part of the HVAC system that brings in unconditioned air for dehumidification and cooling or heating, followed by filtration and mixing with conditioned return air. ASME The American Society of Mechanical Engineers. This term often appears with code stamp to indicate a vessel or pipe can tolerate specified pressures without rupture. CALIBRATION Demonstrating that a measuring device produces results within the specified limits of those produced by a reference standard device over an appropriate range of measurements. This process results in corrections that may be applied if maximum accuracy is required. cgmp Current Good Manufacturing Practices CRITICAL INSTRUMENT An instrument whose failure would adversely affect the product, safety, or functioning of the system. An instrument involved with an alarm, recording device, or indication used as reference for equipment performance, or batch documentation. CRITICAL UTILITIES Utility systems that have the potential to directly impact product quality through contact, such as USP water or HVAC, where the conditioned air contacts the product. HEPA High Efficiency Particulate Air Filter (achieves 99.97% particulate removal). HVAC The Heating, ventilation, and air conditioning system. Provides conditioned air for comfort in non-production areas as well as air that meets Federal Standard 209E classifications in production and sterile suite areas. 30
Responsibilities Who will prepare the qualification protocols? Who will review and approve the protocols? Who will provide, collect, and control documents required for the qualification effort (manuals, SOPS, drawings, etc) Who is responsible for coordinating the execution effort? Who will execute the protocols? Who will prepare the summary reports? Who will review and approve the summary report? 31
Systems to be Qualified and Protocol Requirements (Risk Assessment) Define Critical Systems Which May Impact Product Quality (High Risk) critical systems are those process or utility related systems that may directly impact the quality, safety, and/or efficacy of the therapeutic agent Indirect impact systems are those systems which may affect the operation and performance of a direct impact system. No Impact systems are those which neither directly or indirectly affect the quality, safety and/or efficacy of the product. 32
Systems to be Validated and Protocol Requirements (Risk Assessment)-Cont. Define Protocol Requirements to Accomplish Validation Critical systems requires full validation (IQ, OQ, PQ) Non-critical systems do not require qualification but may benefit from a formal commissioning. Leveraging commissioning into validation. Use your supplier generated information when ever possible. 33
Systems/Equipment to be Validated (The following tables summarize documents typically prepared in a validation effort.) GMP Area System/Equipment IQ/OQ PQ AHU/HVAC System X X USP Purified water System X X Compressed Air System X X Dust Collector X N/A Building Automation System X X Fluid Bed Dryer X N/A 34
Systems/Equipment to be Validated Continued: GMP Area System/Equipment IQ/OQ PQ High Shear Mixer X N/A Comminuting Mill X N/A V Blender X N/A Tablet Press X N/A Tablet Coater X N/A 35
Scheduling of Validation Activities Document collection Filing and Control Preparation, Review, and Approval of VMP Preparation, Review, and Approval of IQ, OQ, and PQ Document Qualification of Utility Systems Qualification of Process Equipment Validation of Utility Systems Process Validation Report Writing 36
Timing of Validation Activities Validation Activity Phase I: Planning Phase II: Design & Procurement Phase III: Construction Phase IV: Startup Collect Documentation Validation Master Plan Prepare SOPS Prepare IQ, OQ, PQ Protocols Approve Protocols Execute IOQ Execute PQ Validation Reports 37
Personnel Qualifications [cgmp 21 CFR SUBPART B; 211.25 & 34] Persons engaged in manufacture, processing, or holding of drug products or consultants advising on such will have sufficient education, training, and experience records of training maintained there shall be an adequate number of qualified personnel to perform the required tasks 38
Addendums to the Plan How to Address Scope Changes How to Incorporate New Items How to Address Major Schedule Variances 39
Assembling the Project Team Meetings and discussions to agree on critical systems for process and facility Project team consists of functional areas from the organization Validation group Operations Engineering Quality unit Regulatory / Compliance Importance of Including These Areas Into VMP Development ensures buy-in gives sense of ownership guarantees validation will proceed smoothly and successfully 40
Effective VMP VS. Poor VMP An Effective VMP: will be easy to follow will be enduring in nature does not require too many modifications as validation progresses A Poor VMP: is difficult to follow unclear in it s instruction and approach ineffectively define responsibilities is not clear in defining sequence of events results in repeatedly having to modify the plan. 41
Getting it Done Involve all senior technical managers approving the document in the review process Involve department managers in defining responsibilities Conduct frequent meetings with representatives involved in the validation effort Put the document in draft form and circulate it Make sure the final plan looks good 42
In Summary The Qualification Plan is defined by the new FDA guidance on Process Validation as an overall project plan. It is a scope document for qualification of your operation; it defines the effort, prioritizes activities, outlines acceptance criteria, identify timing of qualification activities, lists the procedures to be used, and defines the responsibilities. Should be a stand alone document Communicates with upper management regarding the effort. 43