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?