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1
RISK-BASED CLEANING VALIDATION
Paul L. Pluta, PhD
Journal of Validation Technology and Journal of GXP Compliance
University of Illinois at Chicago (UIC) College of Pharmacy
Chicago, IL, USA
OUTLINE
• Strategy and Approach
• Lifecycle Approach to Process Validation
• Cleaning Validation Stage 1 Process Design /
Process Understanding
• Cleaning Validation Stage 2 Process Qualification
• Stage 3 Continued Process Verification / Process
Maintenance
• Implementation Strategy
• Cleaning Validation Documents Overview, Hierarchy,
and Content
• Global Cleaning Problems
2
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
3
CLEANING VALIDATION GLOBAL PROBLEMS
HIGHEST RISK CONSIDERATIONS
PRODUCT PROBLEMS• Residue chemistry as basis for cleaning
• Solubility in worst-case residue determination
• Cleanability in worst-case residue determination
EQUIPMENT-RELATED PROBLEMS• Non-uniform contamination transfer
• Most difficult-to-clean locations
CLEANING PROCESS PROBLEMS• Manual cleaning qualification
• Cleaning procedure documentation
• Dirty hold time (time to initiate cleaning)
LABORATORY PROBLEMS• Residue stability in cleaning residue analysis
• Residue recovery studies
• Swab sampling technique, reliability, and training
4
AUDIT QUESTIONS
• Is residue chemistry considered in developing cleaning procedure?
• Is pH-solubility profile considered in worst-case matrix analysis?
• Is residue “cleanability” considered in worst-case residue
determination?
• Is non-uniform contamination considered in residue calculations?
• Are most difficult-to-clean equipment locations proceduralized?
• Are manual cleaning personnel qualified and requalified?
• Are cleaning procedures quantitative and documented?
• Are dirty hold times controlled?
• Is residue stability considered in cleaning residue analytical?
• Have analytical recovery studies been conducted? On
representative materials?
• Are swab sampling personnel trained / qualified?
5
STRATEGY AND APPROACH
• Science and technical basis
• Cultural change may be needed
• Process Validation Lifecycle approach
– Stages 1,2,3
– Application to cleaning validation
– Understand / demonstrate / monitor and
maintain
• Documentation
– Hierarchy alignment
6
STRATEGY AND APPROACH
• Science and technical basis for cleaning validation
– R&D support
– Technical reports
– QbD model
– Chemical and physical basis
– Lifecycle approach to cleaning process
– Technical expertise throughout lifecycle
• Culture change
– Cleaning is a process
– Not “we do whatever it takes”
– Organizational training
7
LIFECYCLE APPROACH TO CLEANING VALIDATION
Key point: Application of lifecycle approach to
process validation to cleaning validation.
– Value in this approach?
– Does it make sense?
Three stages in lifecycle approach
1. Design and development (understanding)
2. Validation performance (conformance lots)
3. Monitoring and maintenance (ongoing verification)
Actual experiences should lead to process improvements
8
Lifecycle Approach to Cleaning Validation –Value and Logic?
• Cleaning is a process
• Validation lifecycle concepts being applied to equipment,
facilities, utilities, computers, etc., by validation and
technical experts
• Who can argue with understanding, performing, and
maintaining the validated state?
• Consistent with QbD and ICH approaches
• Auditor interaction: Lifecycle approach (i.e.,
understanding, performing, maintaining) vs.
traditional approach – Which would you rather
present to an auditor?9
TERMINOLOGY: PROCESS VALIDATION
Process Validation – Process Qualification –
Process Performance Qualification (PPQ)
Qualification Qualification
Equipment #1 HVAC
Utilities
Equipment #2 Facilities
Computers
Equipment #3
Analytical methods validation
Cleaning process validation
Packaging process validation
Acceptable lots = Process is validated
10
UO #1Process steps
UO #2Process steps
UO #3Process steps
FDA PROCESS VALIDATION GUIDANCE (2011)
Definition: Collection and evaluation of data, from the process design
stage throughout commercial production, which establishes
scientific evidence that a process is capable of consistently
delivering quality products. Process validation involves a series of
activities over the lifecycle of the product and process.
Three stages of activities:
• Stage 1 – Process Design – Development and scale-up activities
• Stage 2 – Process Qualification – Reproducible manufacturing
• Stage 3 – Continued Process Verification – Maintaining the
validated state during ongoing manufacturing
Other topics in Guidance
• Concurrent release
• Documentation
• Analytical methodology
11
VALIDATION GUIDANCE TRANSITION
1987
Development Performance Maintenance
2004-2011
Development Performance MaintenanceAbove based on RISK
12
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
EXPANDED SCOPE OF PROCESS VALIDATION
CLEANING IS A PROCESS --
APPLICATION OF THE ABOVE TO CLEANING
13
WHAT IS THE CLEANING PROCESS?Cleaning Process Performance Qualification
Automated CIP System
Process steps Qualification
1. Residue on equipment Equipment
2. Water procedure Purified Water
3. Cleaning agent procedure Computer / software
4. Water procedure Compressed air
5. Purified Water procedure Conductivity analysis
6. Dry TOC analysis
Equipment is clean -- Process is validated
Process parameters Quality attributes
14
WHAT IS THE CLEANING PROCESS?Cleaning Process Performance Qualification
Manual Cleaning
Process steps Qualification
1. Residue on equipment Personnel
2. Water rinse Purified Water
3. Scrub with cleaning agent Compressed air
4. Water rinse
5. Scrub
6. Water rinse
7. Purified Water rinse
8. Dry
Equipment is clean -- Process is validated
Process parameters Quality attributes15
CLEANING VALIDATION OVERVIEW
1990s present
1. Defined cleaning procedure (SOP) – basis?
2. Product A batch does not contaminate subsequent
Product B batch
3. Acceptance limit calculated
4. Assume uniform contamination of all equipment
5. Three conformance lots = Validated cleaning procedure
6. Validated analytical method (original API)
7. Worst-case matrix approach
One-time event
16
FDA PROCESS VALIDATION GUIDANCE
LIFECYCLE APPROACH TRANSITION
APPPLICATION TO CLEANING VALIDATION
Pre Lifecycle
Cleaning development (?) PQ change control
________________________
Lifecycle Approach
Development PPQ Maintenance
EXPANDED SCOPE OF VALIDATION
INCREASED SPECIFIC STAGE REQUIREMENTS
17
LIFECYCLE APPROACH TO CLEANING VALIDATION
Scientific and technical approach
Design and development
– Residue + cleaning agent + cleaning procedure Clean equipment
– Risk considerations
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.
18
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
Rational analytical method and supporting work
Characterization of equipment to be cleaned and supporting work
Trained sampling personnel
DOCUMENT ALL OF THE ABOVE
19
DEVELOPMENT (STAGE 1)
CLEANING PROCESS DEVELOPMENT
• Physical and chemical properties of the residue is basis for cleaning
process
• Considerations for determination of most difficult-to-clean residue
• Residue solubility and stability in determining worst-case soils
• Residue chemistry critical for analytical method
• Cleaning agent chemistry consistent with residue chemistry
• Cleaning process chemistry and engineering and consistent with
residue and cleaning agent.
RESIDUE CHEMISTRY
– BASIS FOR CLEANING PROGRAM
– BASIS FOR ANALYICAL METHOD
20
RESIDUE PROPERTIES -- BASIS FOR CLEANING PROCESS
Case study: Antibiotic suspension containing insoluble API (base)
Original cleaning method: Water, PurW, dry
• No documented cleaning validation for many years
• Unknown peaks on original cleaning validation attempts
• API insoluble
Second method: Alkaline soap wash, water, PurW, dry
• Unknown peaks again
• API insoluble
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)
Consider active drug and other residue chemistry in development
of cleaning process
21
DETERMINATION OF
MOST DIFFICULT TO CLEAN RESIDUE
BASIS FOR CLEANING PROGRAM
Water solubility – USP Tables
• Is this adequate? NO!
pH effect – API with ionizable groups?
Solubility in cleaning agent?
• Determine solubility at range pH 1-12
• Understand solubility at pH of cleaning liquid
• Understand solubility in cleaning agent liquid
22
pH SOLUBILITY PROFILE, pH 1-12
Solubility
mg/ml
Drug A
Drug B
pH 1 7 12
23
CASE STUDY #2: SMALL MOLECULE API ORAL
LIQUID API INSOLUBLE
Original cleaning method
• Alkaline cleaning agent with manual intervention
• Acid cleaning agent (full strength) when white residue noted.
• Small parts soaked in acid cleaning agent (full strength)
• Cleaning method difficult, ineffective, and unsafe
Liquid product – alcohol / glycol solvent system
• Change cleaning method to alcohol initial rinse. API soluble
Final method: Alcohol rinse/soak, alkaline wash, water, PurW, dry –
Significant improvement
• No residues
• Easy and safe method
Consider active drug and other residue chemistry in development
of cleaning process
24
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
What residue is really present?
Consider chemistry of residues
25
CLEANING MATRIX
Determine Worst-Case Soil
SOLUBILITY (mg / ml)
pH 1 Water pH 12 Alkaline
Cleaning Agent
Drug A 25 25 25 25
Drug B 15 15 15 15
Drug C 5 5 150 250
Drug D 150 10 10 50
Drug E 125 10 100 250
Consider acid cleaning agent for drugs D and E
26
WORST CASE CLEANING
Determination of worst-case cleaning based
on API toxicity, worst-case dose, etc.
– Standard calculation
Cleaning procedure may be based on
excipients having greatest effect on
cleaning
– Hydrophilic polymers
– Dyes
– Hydrophobic vehicles
27
BIOTECH CLEANING CHEMISTRY -- API
Protein molecules degrade in alkaline conditions
Degradation rate is slower in acidic conditions
Degradation rate increases with temperature
API residues typically consist of protein fragments and
aggregates
Analytical method: Non-specific analysis
Reference: Kendrick, Canhuto, and Kreuze. Analysis of
Degradation Products of Biopharmaceutical API Caused
by Cleaning Agents and Temperature. Journal of
Validation Technology, V15, #3, Summer 2009.
28
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
Consider medium composition at end of cycle.
Reference: Azadan and Canhoto. A Scientific Approach to the Selection of
Cleaning Validation Worst-Case Soils for Biopharmaceutical manufacturing.
Cleaning and Cleaning Validation, Volume 1. 2011.
29
CLEANING CHEMISTRY MECHANISMS
• Wetting
• Emulsification
• Dispersion
• Solubility
• Chelation
• Oxidation
• Hydrolysis
30
CLEANING AGENT OPTIONS
• Water
• Commodity alkalis and acids
• Organic solvents
• Surfactants
– Anionic
– Cationic
– Amphoteric
– Nonionic
• Formulated detergents
31
COMPONENTS OF FORMULATED DETERGENTS
• Surfactants
• Alkalis
• Acids
• Sequestrants / chelants
• Dispersants / anti-redeposition agents
• Corrosion inhibitors
• Oxidizing agents
• Enzymes
• Buffers / builders
• Preservatives
MUST HAVE CONTROL OF CLEANING AGENT
HAVE CONFIDENTIALITY AGREEMENT WITH SUPPLIER
32
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
33
CLEANING PROCESS
SOURCES OF VARIATION
• Cleaning agent preparation – must be exact
• Automated cleaning vs. manual cleaning
• Manual cleaning process variation
• Human physical strength variation
• “Cleaning” between same-product batches in
campaign – residue level build-up
• Campaign length – residue level build-up
• Time to initiate cleaning (dirty hold time)
• Residue chemical and physical changes
34
EQUIPMENT TO BE CLEANED
Cleaning-related qualification
• Product-contact materials
• Compatibility with cleaning agents
• Surface areas – need for residue calculations
• Equipment equivalence
• Most-difficult-to-clean locations on equipment -- Highest
risk locations for sampling
• Non-uniform contamination equipment
• Non-uniform contamination sampling locations
• Sampling methods (swab / rinse)
Part of IQ/OQ/PQ for manufacturing equipment
35
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
Usually no consideration for residue that is not uniformly
transferred
Examples: Filling neededs, encapsulation equipment,
compressing equipment, others post final mixing
Consider and justify residue concerns in non-uniform
contamination equipment
36
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
x x x x x x x
MANUFACTURING TANK PRODUCT
37
PROCEDURE TO DETERMINE SAMPLING
LOCATIONS
Specific documented procedure recommended
• Equipment technical evaluation
• Observation of equipment after processing
• Equipment disassembly review
• Cleaning procedure review
• Equipment evaluation review
• Operator interviews
SOP describing above
Documentation of above for equipment sampling
38
EQUIPMENT SAMPLING INSTRUCTIONS FOR CLEANING VALIDATION
EQUIPMENT: IMPACT MILL
X SAMPLED
EQUIPMENT ASSET# EQUIPMENT NAME LOCATION
Equipment #XXX Impact Mill Room XXX
Equipment #XXX Impact Mill Room XXX
Equipment #XXX Impact Mill Room XXX
39
EQUIPMENT SAMPLING
LOCATION
PRODUCT
CONTACT
MATERIAL
SAMPLE TYPE RATIONALE
1. Rotor Stainless Steel SwabMaximum residue accumulation.
Maximum product contact
2. Screen Stainless Steel SwabMaximum residue accumulation.
Maximum product contact
3. Discharge Chute Stainless Steel SwabMaximum residue accumulation
Maximum product contact
1
2
3
Pictures are representative of all impact mills.
SAMPLED BY: _________________________________ DATE: _______________
VERIFIED BY: _________________________________ DATE: _______________
TIME TO INITIATE CLEANING
“DIRTY HOLD TIME”
1. Make Product A
2. Clean
3. Make Product B
How long between end of #1 and start #2?
Is residue same? Does residue change?
What can happen to the residue?• Wet and dry processes
• Chemical changes (hydrolysis, oxidation, etc.)
• Physical changes
40
CAMPAIGN LENGTH
How many lots in manufacturing campaign before
cleaning must be done?
What about “cleaning” between batches?
• Equipment should be visually clean
• Terminology: “Between lot procedure”
• How much residue “build-up?”
DO NOT IDENTIFY AS “BETWEEN LOT CLEANING”
41
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
Manual cleaning is high risk
42
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)
All methods and data (including stage 1) subject to
regulatory audit
43
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
UNDERSTAND RESIDUE CHEMISTRY
44
ANALYTICAL METHOD DEVELOPMENT
Cleaning agent residue
• Analytical method to determine residual cleaning
agent.
• Information from cleaning agent vendor
45
RESIDUE RECOVERY STUDIES
Case study
Tablet formulation, stable API, all processing on stainless steel except
compressing machine (cast iron)
Stainless steel recovery = 100%
Audit identified no recovery on cast iron
Cast iron recovery = 0%
Lab analyst spiked dye tablet with active drug.
Dry 5 minutes
Swab
Recovery = 0%
Resolution: Install stainless steel dye table.
46
RESIDUE RECOVERY STUDIES
Caution with plastics, resins, porous materials.
Obtain materials from equipment fabricators• Material composition
• Material porousity
• Surface roughness
Example: % Recovery
Neoprene smooth 79.4%
Neoprene rough 11.7%
Reference: Forsyth. J. Validation Technology, Vol15, #4, 2009.
47
RECOVERY STUDIES -- CALCULATION
Recovery data = 50% recovery
= 0.5 recovery factor
Actual residue level = analytical results
Recovery factor
= 25 mcg/sq. cm
0.5
= 50 mcg/sq. cm
48
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?
All sampled surfaces must have recovery data
49
SAMPLING
Sampling methods
• Sampling (swab) critical activity
• Training program
• Trained sampling personnel– Demonstrated acceptable performance
• Documented training and retraining
• Worst case compounds / procedures in training– Volatile solvents (importance of rapid technique)
• Worst case sampling equipment– Extension poles
• Retraining considerations– Who does sampling? Personnel skills
50
SWAB SAMPLING TECHNIQUE, RELIABILITY,
AND TRAINING
PROBLEM:
• Swab sampling must recover product residue.
• Sampling personnel must be trained and qualified.
• Periodic retraining should be considered.
51
ANALYTICAL METHOD DEVELOPMENT
Sampling methods
• Sampling (swab) critical activity
• Training program
• Trained sampling personnel– Demonstrated acceptable performance
• Documented training and retraining
• Worst case compounds / procedures in training– Volatile solvents
– Problem: Solvents evaporate quickly = false negative
• Worst case sampling equipment– Extension poles
52
ANALYTICAL METHODOLOGY
Case study: Swab sampling with extension pole
Interface
Biotech tank
53
SAMPLING PERSONNEL TRAINING
Representative sampling sites
• Use of auxiliary equipment
Representative of most difficult analytical methods
• Volatile solvents – time constraints
Retraining considerations
• Who does sampling?
• Personnel skills
54
SAMPLING TRAINING
Sampling is extremely critical to cleaning
validation program
Inadequate sampling = false negative
– Insufficient pressure on surface
– Swab solvent evaporation
– Insufficient area sampled
Auditors routinely ask for sampling program training
methods and training records
55
EQUIPMENT SAMPLING INSTRUCTIONS FOR CLEANING VALIDATION
EQUIPMENT: IMPACT MILL
X SAMPLED
EQUIPMENT ASSET# EQUIPMENT NAME LOCATION
Equipment #XXX Impact Mill Room XXX
Equipment #XXX Impact Mill Room XXX
Equipment #XXX Impact Mill Room XXX
56
EQUIPMENT SAMPLING
LOCATION
PRODUCT
CONTACT
MATERIAL
SAMPLE TYPE RATIONALE
1. Rotor Stainless Steel SwabMaximum residue accumulation.
Maximum product contact
2. Screen Stainless Steel SwabMaximum residue accumulation.
Maximum product contact
3. Discharge Chute Stainless Steel SwabMaximum residue accumulation
Maximum product contact
1
2
3
Pictures are representative of all impact mills.
SAMPLED BY: _________________________________ DATE: _______________
VERIFIED BY: _________________________________ DATE: _______________
STAGE 2, PROCESS QUALIFICATION –
(VALIDATION PERFORMANCE)
APPLICATION TO CLEANING1. 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)
Process Performance Qualification (PPQ) – commercial scale
Conclusion that process consistently produces clean equipment
Conformance batches
• All support systems, documents, training, personnel, etc. in place
• Target / nominal operating parameters within design space
• Additional testing (swab / rinse)
• Decision to “release cleaning process” for routine commercial use
• Post validation monitoring plan – Based on risk
– Drug residue properties
– Manual or CIP
57
CLEANING EQUIPMENT
CIP system must be qualified (IQ/OQ/PQ or ASTM
E2500)
Riboflavin (or other) coverage testing
Temperature controls
Flow rates, etc.
PAT inline systems– Drug disappearance – spectrophotometry, other methods
– Cleaning agent rinse -- conductivity
58
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
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
59
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)
60
MANUAL CLEANING -- Do you really know what is happening?
Q to operator: “Why is there so much foam in the tub?”
A: “I put in extra soap because the equipment was really dirty.”
Q to operator: “Why is there powder on the (clean) equipment?”
A: “No problem -- We’ll get the residue when we set up.”
Q to operator: “Why don’t you follow the cleaning procedure?”
A: “The cleaning procedure really doesn’t work.”
ABOVE NOT ACCEPTABLE – TRAINING NEEDED
61
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.”
ABOVE NOT ACCEPTABLE – TRAINING NEEDED
62
MANUAL CLEANING -- Do you really know what is happening?
Q to management: “Did you finish cleaning the equipment? We are
here to swab for cleaning validation.”
A (very proudly): “We cleaned the equipment three times so that we
won’t have any problems.”
Q to validation person: “Did you know that the manufacturing people
always clean the equipment multiple times before it is swabbed?”
A: “Sure, we knew.
Q: “Why didn’t you stop this?”
A: “These people are our friends. We have to work with these people.”
ABOVE NOT ACCEPTABLE – TRAINING NEEDED
63
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
64
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
65
VALIDATION RESULTS / REPORT
Test results as required in validation protocol.
• Discussion. Consistency with Stage 1
development work.
• Clear statement the cleaning process is (or is
not) validated.
• Recommendation for Stage 3 monitoring and
maintenance.
– Additional limited testing based on data and risk
– Routine monitoring based on risk
66
67
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
POST-VALIDATION MONITORING AND MAINTENANCE
1. Stage 2 specific requirements
– Additional testing based on actual data
– Ex: One location has high (acceptable result)
2. Routine monitoring and maintenance
– Risk based
3. Change control program
CHANGE CONTROL MOST IMPORTANT AND
DIFFICULT TO ADMINISTER
PERSONNEL MUST RECOGNIZE “CHANGE”
68
POST-VALIDATION MONITORING AND MAINTENANCE
Residue toxicity risk
• Residue that can be visually seen
– Room lighting must be adequate
– Provide additional lighting if necessary
• Residue that cannot be visually seen
– Swab after each batch?
CONSIDER PATIENT RISK AND COMPANY RISK
69
CHANGE MANAGEMENT
• 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.
70
POST-VALIDATION MONITORING
Periodic review of cleaning performance
• Deviations
• Non-conformances (dirty equipment)
• Re-cleaning
• Change control
• Other monitoring (CIP data)
• Product APR data
• Statistical Process Control data treatment
• Management review -- documented
71
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
72
CLEANING DOCUMENTATIONHigh 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
CONSISTENT LIFECYCLE STRATEGY AND APPROACH
73
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
Change to the lifecycle approach is a culture
change for the organization.
Management change experts recommend
“crisis” approach.
Risk of failure greater with “crisis” approach.
Opportunity for validation leadership.
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SUMMARY: WHERE WE ARE -- CURRENT PRACTICE
R&D Validation Commercialization
VALIDATION ONE-TIME EVENT
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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
Development Performance Maintenance
VALIDATION CONTINUUM
Stage 1 Stage 2 Stage 3
SUMMARY
VALIDATION TRANSITION
1987
Development Performance Maintenance
2011
Development Performance MaintenanceAbove based on RISK
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SUMMARY
STAGE 1 -- DESIGN AND DEVELOPMENT
INCLUDING COMMON PROBLEMS
Understanding cleaning process
• Residue properties
– Residue degradation
• Rational cleaning process based on residue
• Scientific and technical cleaning matrix
Understand and control sources of variation
• Dirty hold time
• Campaigns
Rational analytical method based on residue properties
Equipment to be cleaned characterized
• Worst case sampling
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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
Cleaning Process Conformance Lots
Cleaning equipment qualified
Cleaning procedure specified (Not SOP)
Cleaning documentation– Request
– Protocol
– Results / Report
Manual cleaning – high risk
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SUMMARY
STAGE 3 -- MAINTAINING VALIDATION
Change control -- evaluate impact of change and validate (test) as necessary
Improve process
Improve control to detect and reduce variability
Cleaning non-conformances and deviations
Periodic Management Review
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SUMMARY
DOCUMENTATION
Consistent approach – High level documents through
protocols and post validation monitoring
Scientific and technical basis
Document everything – Stages 1, 2, 3.
Documentation must be readily available
Documentation must be
• Scientific and technical
• Thorough and clear
• Simple sentences, good grammar
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SUMMARY -- IMPLEMENTATION
1. Plan implementation strategy
– Deliberate program – guarantee success
2. Approvals and agreements
– Upper management
– Validation Approval Committee
– Functional Management
– QA
3. Training
4. Start slowly Pilot approach Build on continuing success
Opportunity for validation leadership!
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SUMMARY – 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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1. PRODUCT RESIDUE PROBLEMS
Physical and chemical properties of residue as a basis for
cleaning
• Residue chemistry, cleaning agent chemistry, and process must be
consistent. Would you clean an acid with a base or with another
acid?
Residue solubility in most-difficult-to-clean matrix
• Determination of the true worst-case residue is critical for the
cleaning matrix. The consequences of incorrect identification of
worst-case products are disastrous.
“Cleanability” in determining the most-difficult-to-clean residue
• Solubility and toxicity not only considerations for determination of
worst-case compounds
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2. EQUIPMENT PROBLEMS
Non-uniform contamination transfer
• Non-uniform contamination is a worst-case situation and should be
addressed. Calculations are demonstrated.
Most difficult-to-clean locations in equipment
• Sites should have an SOP with a defined procedure for identification
of most-difficult to clean locations in equipment. These locations are
then used in sampling for cleaning validation.
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3. CLEANING PROCESS PROBLEMS
• Manual cleaning qualification
Manual cleaning is an inherently high risk activity.
• Cleaning procedure documentation
Cleaning procedure documentation should be equivalent to
manufacturing process documentation -- Exact requirements with
personnel accountability.
• Dirty hold time (time to initiate cleaning)
At lease one run at worst-case DHT
Worst-case DHT is not always longest DHT
• Campaign length
Max number of lots must be controlled
“Between lot procedure.”
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4. LABORATORY PROBLEMS
Residue stability in cleaning residue analysis
• Analytical methods must measure actual residues that are present.
Residue recovery studies
• Analytical methods must include recovery studies, i.e., proof that
process residue may be quantitatively recovered by sampling.
Without recovery studies, analysis of cleaning validation samples is
questionable
Swab sampling technique, reliability, and training
• Personnel who perform swab sampling must be qualified through
training with quantitative performance requirements. Training
should utilize worst-case sampling methods and worst-case
sampling equipment.
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WHICH ARE HIGHEST RISK?
• Type (potency) of drug in facility?
• Multi-product facility – multi use equipment?
• Matrix?
• Manual cleaning?
• SOP cleaning processes – how detailed? Signatures?
• Analytical recovery?
• Swab sampling by trained personnel?
Depending on situation, many of these could
be extremely serious issues
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AUDIT QUESTIONS
• Is residue chemistry considered in developing cleaning procedure?
• Is pH-solubility profile considered in worst-case matrix analysis?
• Is residue “cleanability” considered in worst-case residue
determination?
• Is non-uniform contamination considered in residue calculations?
• Are most difficult-to-clean equipment locations proceduralized?
• Are manual cleaning personnel qualified and requalified?
• Are cleaning procedures quantitative and documented?
• Are dirty hold times controlled?
• Is residue stability considered in cleaning residue analytical?
• Have analytical recovery studies been conducted? On
representative materials?
• Are swab sampling personnel trained / qualified?
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PAUL L. PLUTA, PhD
Editor-in-Chief
Journal of Validation Technology
Journal of GXP Compliance
Advanstar Communications, Iselin, NJ, USA
Adjunct 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: [email protected]
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