The draft FDA guidance on process validation:
1. Introduces a 3 stage lifecycle approach to process validation including process design, process qualification, and continued process verification.
2. Emphasizes the importance of effective scientific knowledge and understanding gained throughout development and manufacturing.
3. Aims to promote modern manufacturing principles, process improvement, innovation, and sound science.
The draft FDA guidance on process validation:
1. Introduces a 3 stage lifecycle approach to process validation including process design, process qualification, and continued process verification.
2. Emphasizes the importance of effective scientific knowledge and understanding gained throughout development and manufacturing.
3. Aims to promote modern manufacturing principles, process improvement, innovation, and sound science.
The draft FDA guidance on process validation:
1. Introduces a 3 stage lifecycle approach to process validation including process design, process qualification, and continued process verification.
2. Emphasizes the importance of effective scientific knowledge and understanding gained throughout development and manufacturing.
3. Aims to promote modern manufacturing principles, process improvement, innovation, and sound science.
Alice Redmond, C&Q Technical Director 09 th March 2010 Reviews potential impact on the current industry approaches to science and risk based design and qualification activities which support the process validation program The key changes in relation to the 1987 guidance This paper presents an overview of the draft FDA PV guidance Overview Key Changes Impact
Guidance for Industry Process Validation: General Principles and Practices DRAFT GUIDANCE This guidance document is being distributed for comment purposes only. Comments andsuggestionsregardingthisdraft document shouldbesubmittedwithin60daysof publicationintheFederal Register of thenoticeannouncingtheavailability of thedraft guidance. SubmitcommentstotheDivision of Dockets Management (HFA-305), FoodandDrug Administration, 5630FishersLane, rm. 1061, Rockville, MD20852. All commentsshould be identifiedwith thedocket number listedinthenoticeof availability that publishesintheFederal Register. For questionsregardingthisdraft document contact Brian Hasselbalchor GraceMcNally (CDER) 301-796-3286 or 301-796-3279, Christopher Joneckis (CBER) 301-827-0373, or DennisBensley(CVM) 301-827-6956. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Center for Veterinary Medicine (CVM) November 2008 Current Good Manufacturing Practices (CGMP)
1. 1. 2. 2. 3. 3. FDAs Guidance for Industry on Process Validation has been welcomed for The clarity of its integrated 3 stage lifecycle process The elimination of the 3 Golden Batches concept. Its emphasis on the need for effective scientific knowledge led programs
Guidance for Industry Process Validation: General Principles and Practices DRAFT GUIDANCE This guidance document is being distributed for comment purposes only. Comments andsuggestionsregardingthisdraft document shouldbesubmittedwithin60daysof publicationintheFederal Register of thenoticeannouncingtheavailability of thedraft guidance. SubmitcommentstotheDivision of Dockets Management (HFA-305), FoodandDrug Administration, 5630FishersLane, rm. 1061, Rockville, MD20852. All commentsshould be identifiedwith thedocket number listedinthenoticeof availability that publishesintheFederal Register. For questionsregardingthisdraft document contact Brian Hasselbalchor GraceMcNally (CDER) 301-796-3286 or 301-796-3279, Christopher Joneckis (CBER) 301-827-0373, or DennisBensley(CVM) 301-827-6956. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Center for Veterinary Medicine (CVM) November 2008 Current Good Manufacturing Practices (CGMP)
Once Published It will replace the FDAs 1987 Guideline on General Principles of Process Validation It sets out the approaches that the FDA consider to be appropriate elements of process validation It represents the FDAs current thinking in regard to process validation 1. 1. 2. 2. 3. 3. Stage 1 Process Design: The commercial process is defined during this stage based on knowledge gained through development and scale-up activities Stage 2 Process Qualification: During this stage, the process design is confirmed as being capable of reproducible commercial manufacturing Stage 3 Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control 3 Stages of Process Validation 1. 1. 2. 2. 3. 3. In Scope Human Drugs Veterinary Drugs APIs Biologicals Out of Scope Investigational Medicinal Products Medical Devices Effective Process Validation contributes significantly to assuring drug quality Basic Principles of Quality Assurance A drug should be produced that is fit for its intended use; Quality, safety, and efficacy are designed or built into the product. Quality cannot be adequately assured merely by in-process and finished-product inspection or testing Each step of a manufacturing process is controlled to assure that the finished product meets all design characteristics and quality attributes including specifications Ref : Guidance for Industry Process Validation: General Principles and Practices (Nov 2008) Guidance is Intended to Promote modern manufacturing principles process improvement & innovation sound science Product Product Lifecycle Lifecycle Approach Approach Product Product Lifecycle Lifecycle Approach Approach Emphasizing the importance of the links between Product and process design and development Qualification of the commercial manufacturing equipment and process Maintenance of the process in a state of control during routine commercial production Validation of the process is not a one off event but represents an ongoing continuum of scientific knowledge development and ongoing assurance. Ongoing Continuum. Key Definition : Process Validation 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 Ref : Guidance for Industry Process Validation: General Principles and Practices (Nov 2008) Key to this Success 0 50 100 150 200 250 2004 2005 2006 2007 2008 2009 2010 Description A Description B Description C 25 30 25 12 55 Description A Description B Description C Description D Description E 60% 30% 10% Description C Description B Description A 100% 5 7 2 4 2 3 7 9 5 6 8 6 5 3 Company A Company B Proficiency in the collection and evaluation of information and data about the performance of the process Importance of making the entire process validation program more effective and efficient General Considerations for PV Good project management Robust scientific knowledge collection, management and archiving Uniform collection and assessment of information methods Reducing the burden of redundant information gathering Use of an integrated team approach Appropriately documented Project Plans The support of senior management Statistical assessment of data 3 Stages of Process Validation Process Design Process Qualification Continuous Process Verification Product Product Lifecycle Lifecycle Approach Approach Key tenets of the lifecycle approach Gain a high degree of assurance in the performance of the process before distribution Based on objective information from lab, pilot, and/or commercial- scale studies Success relies on skilled interpretation of the information and knowledge gained Understanding sources of variation, their impacts and associated risks Establishing appropriate control strategies This scientific knowledge is verified by testing (in-process, release, characterization) of each significant step of the commercial manufacture process Key Tenets of the Lifecycle Approach 2 Ongoing data analysis of both intra-batch and inter-batch variability Appropriate provisions to address deviations and nonconforming data Importance of both QA and Operators in providing feedback for continued process verification Emphasis is on maintaining the process in a state of control It provides a strong lead in acknowledging that qualification programs devoid of process understanding will not guarantee the assurance of quality required Stage 1 Process Design Design a process suitable for routine commercial manufacturing that can consistently deliver a product that meets its CQAs a. Building and Capturing Process Knowledge and Understanding b. Establishing a Strategy for Process Control DOE G M P /
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C o n s t r a in t s Variability Stage 2 Process Qualification Process design is confirmed as being capable of reproducible commercial manufacturing a. Design of a Facility and Qualification of Utilities and Equipment b. Performance Qualification Approach c. Performance Qualification Protocol d. Protocol Execution and Report Fit for Intended Use Q u a l i f i c a t i o n P r o d u c t s
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Role of QA Enhanced Monitoring The decision to begin commercial distribution should be supportedby data from commercial batches Released Product and Continued Process Verification Batch C Batch B Batch A Facility and Equipment 'Qualified HowMany ? Approved for Commercial Distribution Batch C Batch B Released Product and Continued Process Verification Facility and Equipment 'Qualified Approved for Commercial Distribution The decision to begin commercial distribution shouldbe supportedby data fromcommercial batches HowMany ? Batch B Released Product and Continued Process Verification Facility and Equipment 'Qualified Approved for Commercial Distribution The decision to begin commercial distribution shouldbe supportedby data from commercial batches HowMany ? Stage 3 Continued Process Verification Continually assure that the process remains in a state of control (the validated state) during commercial manufacture Detection of Process Drift Ongoing program to collect and analyze product and process data that relate to product quality Statistician led analysis Detection, control, and/or mitigation strategies Continued enhanced monitoring Process Optimization Maintenance Overview Key Changes Impact Reviews potential impact on the current industry approaches to science and risk based design and qualification activities which support the process validation program The key changes in relation to the 1987 guidance This paper presents an overview of the draft FDA PV guidance to is controlled to assure. Wording revision from maximize the probability that to is designed or built. Principles of quality assurance wording revision from designed and built into the product to cannot be adequately assured merely by in-process and finished product inspection or testing Principles of quality assurance wording revision from cannot be inspected or tested into the finished product Defines validation in terms of establishing scientific evidence Defines validation as establishing documented evidence. 2008 Draft 1987 PV Guidance Key Changes between 1987 PV Guidance and 2008 Draft New Guidance in 2008 Draft 2008 Draft 1987 PV Guidance Emphasizes the use of qualitative statistical methods to monitor, evaluate and justify assurance of process performance Emphasizes Science Based Knowledge development Removes validation information for medical devices; Introduction of root cause (e.g., review of customer complaints and impact on process) Introduction of Process Analytical Technology (PAT) concepts for PV exclusion of revalidationand retrospective process validation. Introduction of product lifecycleconcept Introduction of integrated team approach Overview Key Changes Impact Reviews potential impact on the current industry approaches to science and risk based design and qualification activities which support the process validation program The key changes in relation to the 1987 guidance This paper presents an overview of the draft FDA PV guidance Key Definition : Qualification Activities undertaken to demonstrate that utilities and pieces of equipment are suitable for their intended use and perform properly is referred to in this guidance as qualification Ref : Guidance for Industry Process Validation: General Principles and Practices (Nov 2008) Fundamental Change Needed Current premise: Did we meet the design (design is presumed to be perfect)? Future premise: Have we met process requirements, and have we controlled risks to quality? Page 30 C&Q Model Traditional V Model or Risk Based Verification Lean Thinking is Equally Relevant related to System Build related to related to User Requirements Specification Performance Qualification Functional Specification Operational Qualification Installation Qualification Design Specification Good Engineering Practice Requirements Specification and Design Verification Acceptance and Release Operation & Continuous Improvement Product Knowledge Process Knowledge Regulatory Requirements Company Quality Reqs. Risk Management Design Review Change Management Figure 1 The Specification, Design and Verification Process Process - The New V Model Reference: Figure 1: ASTM E2500-07 A Standard Guide for the Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment, pg 3 GOOD ENGINEERING PRACTICE OPERATION & CONTINUOUS IMPROVEMENT RISK MANAGEMENT DESIGN REVIEW CHANGE REVIEW PRODUCT KNOWLEDGE PROCESS KNOWLEDGE REGULATORY REQUIREMENTS COMPANY QUALITY REGULATIONS REQUIREMENTS SPECIFICATIONS & DESIGN ACCEPTANCE & RELEASE VERIFICATION ASTM Process Flow Subject Matter Experts (SMEs) following GEPs Verification Plan List of Critical Aspects (CQA, CPP) Verification Testing (Design to Performance) to confirm Critical Aspects and meet Acceptance Criteria Acceptance and Release Factory Acceptance Test Site Acceptance Test Installation Verification Functional Verification Performance Testing Verification Phase Acceptance and Release Approved by Quality Unit Approved by Quality Unit Review all completed verification test documentation by a second, independent SME Approved by Quality Unit Operation Continuous Improvement Principles Risk-Based Approach Science-Based Approach Critical Quality Attributes Quality by Design Good Engineering Practices Subject Matter Experts Use of Vendor Documentation Continuous Improvement MOC, operating principles & performance characteristics Verifying built as designed; Verifying operation (comparable load / interventions / durations) (1) Tests (2) Criteria (3) Timing Summary report with conclusions that address criteria in the plan Qualification Include Include Q Plan Q Plan Q Report Q Report (4) Responsibilities (5) Procedures (6) Changes Approved Approved Summary FDA Draft PV vs. ASTM E2500 Y Y Flexibility on how effort is structured Y Y Risk assessment to scaleeffort Y Y QA approves [qualification]/[verification] report N* Acceptance Criteria only Y QA approves [qualification]/[verification] plan Y Y Equipment and facilities suitable for intended use Y Y Focus on science-based process understanding and meeting process requirements ASTM FDA PV Qualification vs. Verification Aspects Summary FDA Draft PV vs. ASTM E2500 N Y Specific aspects to check for spelled out Y NA Critical aspects defined from risk assessments and process requirements Y Y Use of project change management Y Y Use of subject matter experts: how to verify, adjudicate minor departures from specification for CQ Y NA Use of vendor documents Y Y Design of facility, process, equipment based on process understanding ASTM FDA PV Qualification vs. Verification Aspects Impact on Design & Verification Endorses an Integrated Lifecycle Approach Seeks early alignment of product & process requirements Requires Multi Disciplined Teams Welcome avoidance of traditional, prescriptive terminology such as DQ,IQ and OQ Necessary from start of Concept Design Requires access / engagement of R&D Impacted by Contracting Strategy Offers Opportunities to really improve the CQ process Real opportunities to look behind the prepared templates and execute qualification and validation programs which are not only validbut valuable to the ongoing operation and continuous improvement ISPE Singapore - C&Q Workshop 2009 Page 38 Other Drivers ISPE Product Quality Lifecycle Implementation (PQLI) Initiative - Practical Implementation of ICH Guidance and Quality by Design ASTM E2500 Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment GAMP 5 Guidance ISPE GEP best practise guide ISPE Draft C&Q best practise guide ISPE Baseline Guide 12 Draft Verification guide FDA: Quality Systems Approach to Pharmaceutical cGMP Regulations 2006 EU Annex 20, Quality Risk Management March 2008 ICH Q8 Pharmaceutical Development - Nov 2005 ICH Q10 Quality Systems J une 2008 Focus of Baseline Guide 12 The Guide focuses on the process and facilitating the translation of the scientific knowledge about the product and process into good design of equipment, systems, and facilities which: meet documented process requirements control documented risks to the patient produce life cycle evidence which verifies that the as-installed implementation of the design meets the above two objectives Link From Baseline Guide 5 to New Baseline Guide 12 Concepts P r o d u c t / P r o c e s s
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& R e s p o n s i b i l i t i e s The Challenge NEW GUIDANCE NEW IDEAS TIME TO APPROVAL Alignment Questions and Answers Questions Tomorrow ? Alice Redmond C&Q Technical Director, PM Group Alice.redmond@pmg.ie +353 21 452 2916 +353 86 8385088