Introduction to GMPs and ValidationWILLIAM GARVEY AND ASSOCIATES
William Garvey and Associates LLC © 2016
IntroductionAbout your instructor – William (Bill) Garvey
Important regulations and events
Good Manufacturing Practices (GMP)
Validation project management
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
William (Bill) Garvey1981 - Began career with DuPont Pharmaceuticals
1988 - Began to work in validation
Previous employers◦ Biogen◦ Fluor Corporation◦ Pfizer Inc◦ Merck KGaA
William (Bill) Garvey1989 – 1993
Worked closely with US FDA to solve problems in US generic drug industry
Important regulations and eventsEARLY HISTORY TO MODERN DAY
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
Pure Food and Drug Act - 1906Established uniform standards for drugs
Defined adulterated and misbranded
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
Kefauver-Harris Drug Amendments - 1962
Additional laws added to FD&C Act of 1938◦ Result of thalidomide
Good Manufacturing Practices (GMPs)
Facility registration
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
GMP Regulations - 1978Much more specific than 1962 regulations
Reduce confusion and inconsistent interpretations
Process validation requirements implied
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
Good Manufacturing Practices (GMP)INTRODUCTION AND IMPORTANT CONCEPTS
Good Manufacturing PracticesFDA regulations all drug companies must follow
A system to control drug product manufacturing
Assure product identity, quality, strength and purity
Good Manufacturing PracticesAssure batch-to-batch uniformity
Prevent, detect and correct errors during manufacturing and testing
Increase productivity
Non-specific and interpretive
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
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
FDA and GMP enforcementPeriodic, unannounced plant inspections
Delay approving New Drug Applications (NDA)
Drug product purchase and testing
Import alerts
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
How GMP can benefitCleaning log books and equipment pre-use inspection◦ Prevent contamination and cross-
contamination◦ Product investigations…what was
made before? And after?
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
How GMP can benefitDistribution records assist with product recalls
Product complaints may indicate unknown problems
Reserve samples are retested when investigating complaints
How GMP can benefitEquipment maintenance records ◦ Used for reliability analysis◦ Establish maintenance schedules◦ Maximize equipment “uptime”◦ Manage spare parts inventory◦ Maintain equipment validated state
GMP and yield calculationCalculate yield at critical process steps
Compare to expected yield
If % theoretical yield is incorrect, investigate – something went wrong
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?
GMP and Standard Operating Procedures (SOP)Encourages management review and discussion
Assures consistent operations
The standard for GMP audits
Used for employee training
GMP and second verification Critical process steps require verification by second person
Reduce human error
Intentional errors require cooperation of two individuals
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
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”
Introduction to validationBEST PRACTICES AND LESSONS LEARNED
Introduction to validationValidation project management
Facility and equipment design
Validation project risk
Validation master plan
Process validation (PV)
Cleaning validation (CV)
Validation project managementCompanies of all types perform work◦ Operations are repetitive◦ Projects are temporary
Projects are implemented to achieve company’s strategic plan
Validation project managementAll validation activities are projects◦ Defined start date◦ Expected end date◦ Rarely or never repeated
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
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
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
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
Facility and equipment designDesign facilities, equipment, systems and processes to assure GMP compliance◦ Product quality, purity, strength
and identity◦ Batch-to-batch uniformity
Recognized design standardsISPE Guidelines
3A Sanitary Standards
ISO
European Commission – EudraLex
United States Pharmacopeia (USP)
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
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
Design reviewExperienced engineering companies and equipment suppliers rarely make design errors and omissions
Common or mass-produced equipment rarely require thorough design review
FDA Field Management Directive-135Pre-operational Reviews of Manufacturing Facilities◦ Design review◦ Pre-construction review◦ Construction/equipment installation and qualification review◦ Pre-production review
Design reviewBest for engineered or custom systems and equipment
Assess design for effect on ◦ Product quality ◦ Batch-to-batch uniformity
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
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
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
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
Risk assessment - boilerQualify and validate?
No. Low impact system◦ No product contact◦ Test and commission only
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
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
Validation project riskLate protocol preparation, review and approval◦ Late approval delays projects◦ Facility construction and
equipment installation will not wait for protocol approval
Validation project riskUnexpected system or equipment failure
Overtesting or undertesting◦ Testing must be beneficial and
proportionate to risk◦ Standard is high degree of
assurance
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
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
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
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
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
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
Validation master planProject description
System and equipment descriptions
Risk assessment results
Planned tests and inspections
Preliminary acceptance criteria
Validation master planIdentifies required SOPs
Describes important programs◦ Instrument calibration◦ Employee training◦ Change control◦ Facility cleaning
Includes selected design drawings
Describes process validation
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”
PV prerequisitesEquipment and system validation
SOPs
Employee training
Component/supplier qualification
Test method validation
Product development report
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
Cleaning validation (CV)A separate program with its own Validation Master Plan
Essential for multi-product facilities
Must prevent product cross-contamination
Cleaning validation (CV)Cleaning strategy and acceptance criteria must be scientific
Matrix or worse-case methods are commonly used to simplify CV
Cleaning validation (CV)CV is evaluated during product and process development
CV often begins during equipment OQ◦ Riboflavin added to equipment
then removal verified
Cleaning validation (CV)CV performed simultaneously with process validation◦ Equipment visual inspection◦ Final rinse testing◦ Equipment surface testing for
residual active ingredient
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
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
Questions?