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Introduction to GMPs and ValidationWILLIAM GARVEY AND ASSOCIATES
William Garvey and Associates LLC © 2016
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IntroductionAbout your instructor – William (Bill) Garvey
Important regulations and events
Good Manufacturing Practices (GMP)
Validation project management
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William (Bill) GarveyOver 35 years pharmaceutical industry experience◦ Qualification and validation◦ Facility design and construction◦ Quality Assurance (QA)◦ GMP compliance
1980 – BS degree, Northeastern University, Boston, MA
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William (Bill) Garvey1981 - Began career with DuPont Pharmaceuticals
1988 - Began to work in validation
Previous employers◦ Biogen◦ Fluor Corporation◦ Pfizer Inc◦ Merck KGaA
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William (Bill) Garvey1989 – 1993
Worked closely with US FDA to solve problems in US generic drug industry
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Important regulations and eventsEARLY HISTORY TO MODERN DAY
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US Pharmacopeia (USP) - 1820Eleven physicians meet in Washington, D.C. to establish the U.S. Pharmacopeia (USP)
A private organization
USP standards are legally enforceable
Must comply with USP to sell drug products in US
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Pure Food and Drug Act - 1906Established uniform standards for drugs
Defined adulterated and misbranded
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Federal Food, Drug and Cosmetic Act - 1938
Basic US food and drug law◦ Replaced earlier 1906 Act
Drugs must be safe and effective
Labeling and packaging must be truthful and informative
Authority for factory inspections
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Kefauver-Harris Drug Amendments - 1962
Additional laws added to FD&C Act of 1938◦ Result of thalidomide
Good Manufacturing Practices (GMPs)
Facility registration
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Large Volume Parenteral (LVP) Regulations -1976
FDA regulations issued in 1976, but never approved◦ Result of contaminated LVPs
Informal start for process validation
Common validation testing and acceptance criteria established
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GMP Regulations - 1978Much more specific than 1962 regulations
Reduce confusion and inconsistent interpretations
Process validation requirements implied
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Guidelines on Principles of Process Validation - 1987Issued by FDA in May 1987
Formal start of qualification and validation
High degree of assurance that drug products consistently meet all specifications
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Good Manufacturing Practices (GMP)INTRODUCTION AND IMPORTANT CONCEPTS
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Good Manufacturing PracticesFDA regulations all drug companies must follow
A system to control drug product manufacturing
Assure product identity, quality, strength and purity
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Good Manufacturing PracticesAssure batch-to-batch uniformity
Prevent, detect and correct errors during manufacturing and testing
Increase productivity
Non-specific and interpretive
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Why were GMPs created?GMPs (and drug regulations in general) resulted from US and foreign tragedy◦ Sulfanilamide (1938)◦ Thalidomide (1962)
Tylenol capsules filled with potassium cyanide (1982)◦ Tamper-resistant packaging
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Why were GMPs created?Adulterated and misbranded drugs are public health hazards◦ Widely distributed◦ Consumed in large amounts in a
short time◦ Used by the sick - could worsen
illness rather than cure it
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FDA and GMP enforcementPeriodic, unannounced plant inspections
Delay approving New Drug Applications (NDA)
Drug product purchase and testing
Import alerts
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How GMP can benefitReduce manufacturing errors –product rework is costly
Batch records are important◦ For process control◦ For product investigations◦ To investigate complaints◦ To monitor product quality
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How GMP can benefitCleaning log books and equipment pre-use inspection◦ Prevent contamination and cross-
contamination◦ Product investigations…what was
made before? And after?
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How GMP can benefitComponent, container and labeling records◦ Identify batches where component
was used◦ Investigate surpluses or
shortages…”Where did it go?”◦ Prevent label mix-ups – correct
product but incorrect label
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How GMP can benefitDistribution records assist with product recalls
Product complaints may indicate unknown problems
Reserve samples are retested when investigating complaints
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How GMP can benefitEquipment maintenance records ◦ Used for reliability analysis◦ Establish maintenance schedules◦ Maximize equipment “uptime”◦ Manage spare parts inventory◦ Maintain equipment validated state
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GMP and yield calculationCalculate yield at critical process steps
Compare to expected yield
If % theoretical yield is incorrect, investigate – something went wrong
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GMP and label reconciliationReconcile labels when labeling is complete
If label and product counts do not agree, investigate
Did labels get applied to the wrong product?
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GMP and Standard Operating Procedures (SOP)Encourages management review and discussion
Assures consistent operations
The standard for GMP audits
Used for employee training
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GMP and second verification Critical process steps require verification by second person
Reduce human error
Intentional errors require cooperation of two individuals
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GMP and process validation1962 – Process validation implied but not enforced
1976 – LVP regulations issued –informal start to validation
1978 – Revised GMP regulations require validation for processes causing product variability
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GMP and process validation1978 – Parenteral Drug Association (PDA) issues Technical Report 1, Validation of Moist Heat Sterilization Processes
1987 – FDA issues Guidance on Principles of Process Validation
2011 – FDA reissues 1987 Guidance – validation now “risk based”
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Introduction to validationBEST PRACTICES AND LESSONS LEARNED
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Introduction to validationValidation project management
Facility and equipment design
Validation project risk
Validation master plan
Process validation (PV)
Cleaning validation (CV)
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Validation project managementCompanies of all types perform work◦ Operations are repetitive◦ Projects are temporary
Projects are implemented to achieve company’s strategic plan
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Validation project managementAll validation activities are projects◦ Defined start date◦ Expected end date◦ Rarely or never repeated
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Qualification and validationQualification and validation are Quality Assurance (QA) activities
Verify and document that systems, equipment and processes agree with approved designs◦ Correct installation◦ Reliable and predictable operation◦ Perform as expected
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Validation and designValidation testing and acceptance criteria are based on design
Design documents must be complete and comprehensive
Detailed designs increase probability that validation project will be successful
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Design phasesPhase 1 – Conceptual design◦ Various alternatives are evaluated
Phase 2 – Preliminary engineering◦ Prepare design documents used for Phase 3
Phase 3 – Detailed engineering◦ Construction contracts◦ Equipment purchasing, fabrication, installation and testing
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Design phases and validationPhase 3 – Detailed engineering◦ Verified during Installation Qualification (IQ) – Phase 1
Phase 2 – Preliminary engineering◦ Verified during Operational Qualification (OQ) – Phase 2
Phase 1 – Conceptual design◦ Verified during Performance Qualification (PQ) – Phase 3
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Facility and equipment designDesign facilities, equipment, systems and processes to assure GMP compliance◦ Product quality, purity, strength
and identity◦ Batch-to-batch uniformity
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Recognized design standardsISPE Guidelines
3A Sanitary Standards
ISO
European Commission – EudraLex
United States Pharmacopeia (USP)
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Common design documentsPiping and instrumentation diagrams (P&IDs)
HVAC air flow diagrams (AFDs)
Equipment specifications and drawings
Software user and functional specifications
Control system drawings and panel layouts
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Design reviewReview design documents to verify equipment or system is◦ Correctly designed for application◦ Does not react with product◦ Cleanable◦ Easy to maintain and repair
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Design reviewExperienced engineering companies and equipment suppliers rarely make design errors and omissions
Common or mass-produced equipment rarely require thorough design review
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FDA Field Management Directive-135Pre-operational Reviews of Manufacturing Facilities◦ Design review◦ Pre-construction review◦ Construction/equipment installation and qualification review◦ Pre-production review
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Design reviewBest for engineered or custom systems and equipment
Assess design for effect on ◦ Product quality ◦ Batch-to-batch uniformity
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Validation project riskValidation projects have two risks◦ Regulatory/product risk◦ Validation project risk
Use a scoring system to assess risk
Use subject matter experts (SME) to evaluate risk
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Regulatory/product riskRisk assessment identifies high impact systems and equipment ◦ Product contact equipment◦ Product contact utilities◦ Process control systems◦ Building floor plans◦ Processes with substantial
variability
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Regulatory/product riskHigh impact systems require design review for GMP compliance
Qualify and validate high impact systems
Test and commission low or no-impact systems
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Risk assessment - blenderQualify and validate?
Yes. High impact system◦ Product contact◦ Operation must be reliable and
controlled◦ Content uniformity and batch-to-
batch uniformity are important
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Risk assessment - boilerQualify and validate?
No. Low impact system◦ No product contact◦ Test and commission only
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Regulatory/product riskComprehensive risk assessment not required for◦ Common equipment◦ Proven technologies
Risk assessment required ◦ Equipment is used for other than
intended purpose◦ High value product or process
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Validation project riskValidation project risks◦ Delay project completion◦ Increase costs
Identify and control validation project risks to assure completion on schedule and at expected cost
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Validation project riskLate protocol preparation, review and approval◦ Late approval delays projects◦ Facility construction and
equipment installation will not wait for protocol approval
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Validation project riskUnexpected system or equipment failure
Overtesting or undertesting◦ Testing must be beneficial and
proportionate to risk◦ Standard is high degree of
assurance
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Validation project riskInexperienced or insufficient validation personnel◦ Estimate labor hours to complete all validation activities◦ Estimate may exceed available personnel to meet scheduled completion
date
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Validation project riskIncorrect acceptance criteria◦ Frequent cause of test failures◦ Test failures delay projects
Do not approve acceptance criteria that system or equipment is not designed to meet
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Validation project riskIdentify and carefully manage project critical path◦ Series of activities that determine
project duration◦ Activities with the least amount of
scheduling flexibility
Project management software can identify critical path
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Validation project riskWater systems are frequently on the critical path◦ Most widely used ingredient in
pharmaceutical companies
Water system delays could delay process and cleaning validation studies
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Validation project managementValidation projects have two risks◦ Regulatory/product risk◦ Project risk
Design review reduces regulatory and product risk
Project planning and control reduces validation project risk
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Validation master planA comprehensive validation document
Evaluates facility validation, ISO and cGMP requirements
Prepared during conceptual design or preliminary engineering
Large or complicated projects only
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Validation master planProject description
System and equipment descriptions
Risk assessment results
Planned tests and inspections
Preliminary acceptance criteria
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Validation master planIdentifies required SOPs
Describes important programs◦ Instrument calibration◦ Employee training◦ Change control◦ Facility cleaning
Includes selected design drawings
Describes process validation
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Process validation (PV or PPQ)“Combines actual facility, utilities, equipment and trained personnel with the commercial manufacturing process, control procedures, and components to produce commercial batches”
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PV prerequisitesEquipment and system validation
SOPs
Employee training
Component/supplier qualification
Test method validation
Product development report
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Process validationUsually three consecutive batches produced at commercial scale
Increased sampling and testing
No deliberate challenge to critical control parameters
Unit operation PV is preferred
PV failures should not occur
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Cleaning validation (CV)A separate program with its own Validation Master Plan
Essential for multi-product facilities
Must prevent product cross-contamination
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Cleaning validation (CV)Cleaning strategy and acceptance criteria must be scientific
Matrix or worse-case methods are commonly used to simplify CV
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Cleaning validation (CV)CV is evaluated during product and process development
CV often begins during equipment OQ◦ Riboflavin added to equipment
then removal verified
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Cleaning validation (CV)CV performed simultaneously with process validation◦ Equipment visual inspection◦ Final rinse testing◦ Equipment surface testing for
residual active ingredient
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Summary - GMPLegal requirement intended to protect the public
Prevents, detects and corrects manufacturing errors
Increases productivity and reduces costs
Requires system, equipment and process validation
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Summary - ValidationValidation activities are projects - manage to complete on schedule
Review design documents to confirm GMP compliance
Assess and manage regulatory/product and project risk
Develop Validation Master Plan for large and complicated projects
Process validation confirms GMP programs and systems are effective
Cleaning validation prevents product cross-contamination
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Questions?