Session 3 Pluta Paul Pres
Session 3 Pluta Paul Pres
Session 3 Pluta Paul Pres
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PRESENTATION OUTLINE
Process Validation Lifecycle Approach
PV Guidance comparison to current practice
Lifecycle Approach Applied to Cleaning Validation
Stage 1 Activities
• Cleaning Method Development
• Analytical Method Development
• Site equipment
Stage 2 Activities
• Cleaning documentation
• Validation conformance lots
Stage 3 Activities
• Maintaining Validation
• Change Control
• Management review
Documentation
Implementation
Interactions – throughout discussion
Please comments and questions any time during the above.
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OBJECTIVES
1. Lifecycle approach principles and description
2. Application of lifecycle approach to cleaning
validation
3. Cleaning lifecycle stage details
• Process development and understanding
• Process qualification
• Maintaining the validated state
4. Cleaning validation problems
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LIFECYCLE APPROACH TO CLEANING VALIDATION
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Lifecycle Approach to Cleaning Validation –
Value? Does this make sense?
• Cleaning is a process
Qualification Qualification
Equipment #1 HVAC
Utilities
UO #1
Equipment #2 Process steps Facilities
UO #2 Computers
Equipment #3 Process steps
UO #3
Process steps
1987
Development Performance Maintenance
2004-2011
Development Performance Maintenance
Above based on RISK
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FDA PROCESS VALIDATION GUIDANCE (1-2011)
Stage 1. Process design
• R&D / technical development work
Stage 2. Process qualification
• Equipment considerations
• PPQ protocol, testing, results
Stage 3. Continued process verification
• Monitoring and maintaining validation
• Change control
Analytical considerations
Documentation
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WHAT IS THE CLEANING PROCESS?
Cleaning Process Performance Qualification
Automated CIP System
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WHAT IS THE CLEANING PROCESS?
Cleaning Process Performance Qualification
Manual Cleaning
One-time event
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FDA PROCESS VALIDATION GUIDANCE
LIFECYCLE APPROACH TRANSITION
APPPLICATION TO CLEANING VALIDATION
Pre Lifecycle
Lifecycle Approach
Development PQ Maintenance
EXPANDED SCOPE OF VALIDATION
INCREASED SPECIFIC STAGE REQUIREMENTS
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LIFECYCLE APPROACH TO CLEANING VALIDATION
Scientific and technical approach
Design and development
– Residue + cleaning agent + cleaning procedure Clean equipment
Performance demonstration
Monitoring and maintenance
Rationale, responsibility, and accountability
Future process improvements
Not the following:
– Standard site method (no basis or rationale)
– Personnel driven (no control)
– “Do whatever it takes” (high variation)
– SOP (no accountability)
– Validation (?) – One-time event.
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STAGE 1, PROCESS DESIGN (PROCESS UNDERSTANDING)
APPLICATION TO CLEANING
FDA Guidance Topics
1. Building and capturing process knowledge and understanding.
2. Establishing a strategy for process control.
Application to Cleaning
Understand residue chemistry (solubility, stability)
Determine cleaning agent based on residue chemistry
Determine cleaning process
• Identify sources of variability
• Establish methods to control variability
– Process Analytical Technology
RESIDUE CHEMISTRY
– BASIS FOR CLEANING PROGRAM
– BASIS FOR ANALYICAL METHOD
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RESIDUE PROPERTIES -- BASIS FOR CLEANING PROCESS
Final method: Acid wash, alkaline soap wash, water, PurW, dry
• No residues
• Unknown peaks determined to be degradants and flavors.
• API dissolves (acid-base neutralization)
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pH SOLUBILITY PROFILE, pH 1-12
Solubility
mg/ml
Drug A
Drug B
pH 1 7 12
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RESIDUE SOLUBILITY AND STABILITY FOR
DETERMINING WORST-CASE SOILS
Solubility considerations
• Hydrophilic and hydrophobic molecules
• Ionization – Effect of pH
• Effect of temperature
• Surface active molecules
• Liquid and semisolid product vehicle polarity
Stability considerations
• Hydrolysis, oxidation, photolysis, physical changes
Drug B 15 15 15 15
Drug D 150 10 10 50
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WORST CASE CLEANING
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BIOTECH CLEANING CHEMISTRY -- API
Protein molecules degrade in alkaline conditions
Degradation rate is milder in acidic conditions
Degradation rate increases with temperature
API residues typically consist of protein fragments and
aggregates
Analytical method: Non-specific analysis
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BIOTECH CLEANING CHEMISTRY – GROWTH MEDIUM
Medium Composition
• Acids or bases
• Monovalent salts
• Polyvalent salts
• Amino acids
• Proteins (polypeptides)
• Carbohydrates
• Aqueous soluble organics
• Non-aqueous soluble organics
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CLEANING CHEMISTRY MECHANISMS
• Wetting
• Emulsification
• Dispersion
• Solubility
• Chelation
• Oxidation
• Hydrolysis
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CLEANING AGENT OPTIONS
• Water
• Commodity alkalis and acids
• Organic solvents
• Surfactants
– Anionic
– Cationic
– Amphoteric
– Nonionic
• Formulated detergents
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COMPONENTS OF FORMULATED DETERGENTS
• Surfactants
• Alkalis
• Acids
• Sequestrants / chelants
• Dispersants / anti-redeposition agents
• Corrosion inhibitors
• Oxidizing agents
• Enzymes
• Buffers / builders
• Preservatives
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CLEANING ENGINEERING
Factors affecting cleaning
• Soil residue
– Soil levels, soil condition, hold times, soil mixing,
water quality and residue,
• Cleaner and parameters (TACT)
– Time, Action, Concentration, Temperature
– Others
• Surface and equipment design
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CLEANING PROCESS
SOURCES OF VARIATION
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NON-UNIFORM CONTAMINATION
Typical calculation considers total surface area of all
product contact equipment, and assumes all lot A
residue from total surface area transferred uniformly to
all lot B product
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EQUIPMENT TO BE CLEANED
SAMPLING LOCATIONS
UNIFORM AND NON-UNIFORM CONTAMINATION
Product A = X
Product B = X
Product B flushes filling lines with A residue
xxxxxxxxxx x x x x x x x
xxxxxxxxxx x
xxxxxxxxxx x
xxxxxxxxxx
xxxxxxx
MANUFACTURING TANK PRODUCT
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PROCEDURE TO DETERMINE SAMPLING
LOCATIONS
• Physical changes
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CAMPAIGN LENGTH
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MANUAL CLEANING
• Manual cleaning procedures should be
monitored and maintained with increased
scrutiny compared to non-manual procedures
• More frequent training of cleaning personnel
• Increased supervision
• Periodic (annual?) revalidation batches
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ANALYTICAL METHOD DEVELOPMENT
Early stage 1 (development) analysis –
validation not required but must be sound
Validated method when used for Stage 2
cleaning validation and post-validation
testing (change control)
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ANALYTICAL METHOD DEVELOPMENT
Analytical method must measure actual residue –
what residue is actually present on equipment
surfaces?
• Small molecules
– API
– API degraded – specific or non-specific method
• Biotech molecules
– API degraded – non-specific method
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ANALYTICAL METHOD DEVELOPMENT
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ANALYTICAL METHOD DEVELOPMENT
Recovery studies
Can sampling procedure adequately recover residue
from equipment surfaces?
• Product contact materials
• High % of total surface area
• Obtain representative coupons from equipment
fabricators
• High (e.g., >80%) acceptance criteria
• Factor may be used in calculation
– Multiple approaches
– Factor every calculation?
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SAMPLING TRAINING
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STAGE 2, PROCESS QUALIFICATION –
(VALIDATION PERFORMANCE)
APPLICATION TO CLEANING
1. Design of a facility and qualification of utilities and equipment
2. Process performance qualification
3. PPQ protocol
4. PPQ protocol execution and report
Qualification of equipment, utilities, facilities
• Cleaning equipment (CIP)
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CLEANING EQUIPMENT
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CLEANING PROCEDURE DOCUMENTATION
(Cleaning Batch Record)
SOP
• Fill tank half full
• Add half scoop of soap
• Scrub as needed
• Rinse until clean
• Re-scrub and re-rinse if needed
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CLEANING PROCEDURE RECORD
• Fill tank with 500 L water. Sign/date __________
• Add 20.0 kg cleaning agent. Sign/date __________
• Disassemble Part A. Steps 1,2,3,4,5
• Scrub for 20 minutes. Sign/date __________
• Disassemble Part B. Steps 1,2,3,4,5
• Soak Part B in cleaning liquid for 10 minutes. Sign/date __________
• Rinse Part A and Part B with 50 L water. Sign/date __________
• Rinse with 50 L Purified Water. Sign/date __________
• Dry with compressed air
KEY POINTS
Exact concentration of cleaning agent liquid
Signature on quantitative steps
Grouping non-quantitative steps (e.g., disassembly)
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MANUAL CLEANING -- Do you really know what is happening?
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MANUAL CLEANING -- Do you really know what is happening?
Q to operator: “Why is there powder on the clean equipment?”
A: “It’s clean enough.”
Q to QA (equipment inspection person): “Did you approve that the equipment
is clean?”
A: “It’s clean enough.”
Q to management: “Do you know that your equipment is not clean?”
A: “It’s clean enough.”
Q to operator: “You cleaned the gasket with pure soap – this is not the
procedure? Also it is dangerous – these are corrosive chemicals.”
A: “That is the only way to get it clean.”
Q: “So why don’t you tell someone to change the procedure?”
A: “We don’t have time.”
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MANUAL CLEANING -- Do you really know what is happening?
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VALIDATION REQUEST / PLAN
Initiates cleaning validation
• New cleaning validation or change control process
improvements
• Strategy and approach
• Scientific and technical basis
• Specify required protocols and other work to accomplish
validation
• Risk-based
• References: Stage 1 Design / development reports
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VALIDATION PROTOCOL
Cleaning validation protocols and other work
as specified in Validation Plan
– Risk based
Include sampling pages indicating worst
case sampling locations.
Specify acceptance criteria
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VALIDATION RESULTS / REPORT
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STAGE 3, CONTINUED PROCESS VERIFICATION
(VALIDATION MONITORING AND MAINTENANCE)
APPLICATION TO CLEANING
Activities to assure process remains in validated state
Change control -- evaluate impact of change and validate (test) as
necessary
Trend and assess data
– PAT rinse times
– Conductivity data
Study OOS and OOT (Out of Trend) data
Improve process
Improve control to detect and reduce variability
Cleaning non-conformances and deviations
Re-validation – definition: Actual batch or “paper”
• Is re-testing necessary?
• When should re-testing be considered?
Periodic Management Review
• Documentation reviewed by management
• Documented review
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POST-VALIDATION MONITORING AND MAINTENANCE
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CHANGE CONTROL
• All associated personnel must be aware of
change control
• Change control system developed
• Process improvements expected based on
ongoing experience
• Process improvements should be evaluated by
technical people (i.e., Stage 1)
• Stage 2 PPQ conducted when appropriate
based on Stage 1 technical evaluation.
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POST-VALIDATION MONITORING
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CLEANING DOCUMENTATION
• High level documents
• Specific cleaning validation documents
– Design/Development, performance, monitoring/maintenance
• Specific cleaning validation support documents (equipment
qualifications)
• Cleaning validation approach documents (Worst case matrix,
calculations, sampling locations, etc.)
• Production documents (Cleaning Procedure Records)
– Production cleaning policies
• Management review documents
• Associated documents
– Personnel training in direct and associated areas
– HR records
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CLEANING DOCUMENTATION
High level documents
• Corporate policy
• VMP (Cleaning VMP)
Stage 1 documents
• Cleaning process development report
• Analytical method development report
• Supporting equipment documents (materials, surface areas, equivalent equipment,
sampling, etc.)
Stage 2 documents
• Validation PPQ request, protocol, results
• Cleaning equipment qualification
• Cleaning procedure record
Stage 3 documents
• Change control documents
• Process monitoring
• Management review
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IMPLEMENTATION – LIFECYCLE APPROACH
1. Plan implementation strategy
Deliberate program – guarantee success
Prioritize problems
2. Get upper management agreement
Management sets direction
3. Get Validation Approval Committee agreement
Standards and responsibilities
4. Get QA agreement
QA has GMP responsibility
5. Train development group (Stage 1)
6. Train Annual Product Review group (Stage 3)
7. Train site on validation lifecycle approach
8. Train protocol writers
9. Start slowly Pilot approach Build on continuing success
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IMPLEMENTATION – LIFECYCLE APPROACH
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SUMMARY: WHERE WE ARE -- CURRENT PRACTICE
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SUMMARY -- WHERE WE ARE GOING –
LIFECYCLE APPROACH TO PROCESS VALIDATION
Objectives:
• Scientific and technical process
• Demonstrate process works as intended
• Process must remain in control throughout lifecycle
• Cleaning equipment
• Equipment to be cleaned
• Effective documents consistent with the above
• Analytical methods validated (includes sampling)
Lifecycle approach:
• Validation is never completed
• Validation is always ongoing
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SUMMARY: VALIDATION -- FUTURE
VALIDATION CONTINUUM
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SUMMARY
VALIDATION TRANSITION
1987
Development Performance Maintenance
2011
Development Performance Maintenance
Above based on RISK
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SUMMARY
STAGE 1 -- DESIGN AND DEVELOPMENT
INCLUDING COMMON PROBLEMS
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SUMMARY – EQUIPMENT TO BE CLEANED
INCLUDING COMMON PROBLEMS
• Equipment characterization
• Residue calculations
• Materials of product contact
• Surface areas
• Worst-case areas for sampling based on risk
– Non-uniform contamination
• Equivalent equipment
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SUMMARY – ANALYTICAL
INCLUDING COMMON PROBLEMS
Understand residue
• Solubility and stability
• Validated analytical method for actual residue
– Specific or non-specific analytical methods
• API and cleaning agent residue
Recovery studies from product contact materials
• API and cleaning agent
Swab / rinse testing on equipment
• Most difficult to clean sampling sites
• Use of auxiliary sampling equipment (extension pole)
Swab / rinse training of sampling personnel
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SUMMARY
STAGE 2 – PERFORMANCE
INCLUDING COMMON PROBLEMS
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SUMMARY
STAGE 3 -- MAINTAINING VALIDATION
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SUMMARY
DOCUMENTATION
Documentation must be
• Scientific and technical
• Thorough and clear
• Simple sentences, good grammar
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SUMMARY -- IMPLEMENTATION
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SUMMARY FINAL
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SUMMARY FINAL – CLEANING PROBLEMS
1. Residue and process understanding
– Technical approach
– Worst-case matrix
– Important ingredients
– Variation – Dirty hold time, campaigns
2. Equipment
– Worst-case sampling
– Non-uniform contamination
– Compatibility with cleaning agent
3. Analytical
– Residue degradation
– Recovery
– Sampling training
4. Cleaning Procedure Record
– Cleaning process culture
5. Post-validation Monitoring
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REFERENCES
LeBlanc, Destin A.
Validated Cleaning Technologies for Pharmaceutical Manufacturing.
Interpharm/CRC Press, 2000.
Cleaning Validation – Practical Compliance Solutions for Pharmaceutical
Manufacturing. PDA and DHI Publishing, 2006.
Cleaning Validation – Practical Compliance Solutions for Pharmaceutical
Manufacturing, Volume 2. PDA and DHI Publishing, 2010.
www.cleaningvalidation.com
Pluta, editor. Cleaning and Cleaning Validation, Volume 1. Basics,
Expectations, and Principles. PDA and DHI Publishing, 2009.
“Cleaning Validation Forum.” Coordinated by Jennifer Carlson. Journal of
GXP Compliance.
“New Perspectives on Cleaning:” Coordinated by Rizwan Sharnez. Journal of
Validation Technology.
Pluta and Sharnez. Avoiding Pitfalls in Cleaning Validation. Journal of GXP
Compliance, V 14, #3, Summer 2010.
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PAUL L. PLUTA, PhD
Editor-in-Chief
Journal of Validation Technology
Journal of GXP Compliance
IVT / CBI / UBM
Associate Professor
University of Illinois at Chicago (UIC) College of Pharmacy
Chicago, IL, USA
Editor and Chapter Author
Cleaning and Cleaning Validation, Volume 1. Basics, Expectations, and
Principles, 2009
Cleaning and Cleaning Validation, Volume 2. Application of Basics and
Principles, 2013
PDA and Davis Healthcare International (DHI) Publishing
Contact: ppluta@uic.edu
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