1. VALIDATION BOOT CAMP #3
LIFECYCLE APPROACH TO
PHARMACEUTICAL VALIDATION –
PRINCIPLES, IMPLEMENTATION, AND PRACTICE
LIFECYCLE APPROACH
TO CLEANING VALIDATION
Paul L. Pluta, PhD
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2. 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
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3. 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
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4. 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
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5. OUTLINE
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
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6. OBJECTIVES
1. Application of lifecycle approach to cleaning
validation
2. Cleaning lifecycle stage details
• Process development and understanding
• Process qualification
• Maintaining the validated state
3. Cleaning validation problems
• Global experiences
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7. Lifecycle Approach to Cleaning Validation –
Value? Does this make sense?
• 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
• Lifecycle approach (i.e., understanding, performing,
maintaining) vs. traditional approach – Which would
you rather present to an auditor?
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8. WHAT IS THE CLEANING PROCESS?
Cleaning Process Performance Qualification (PPQ)
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 à Quality attributes
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9. WHAT IS THE CLEANING PROCESS?
Cleaning Process Performance Qualification (PPQ)
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 à Quality attributes
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10. CLEANING VALIDATION OVERVIEW
1990s à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
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11. FDA PROCESS VALIDATION GUIDANCE
LIFECYCLE APPROACH TRANSITION
APPPLICATION TO CLEANING VALIDATION
Pre Lifecycle
Cleaning development (?) à PQ à change control
________________________
Lifecycle Approach
Development à PQ à Maintenance
EXPANDED SCOPE OF VALIDATION
INCREASED SPECIFIC STAGE REQUIREMENTS
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12. LIFECYCLE APPROACH TO CLEANING VALIDATION
Scientific and technical approach
Design and development
– Residue + cleaning agent + cleaning procedure à 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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13. 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
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14. 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
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15. 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
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16. 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
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17. pH SOLUBILITY PROFILE, pH 1-12
Solubility
mg/ml
Drug A
Drug B
pH 1 7 12
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18. 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
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19. 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
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20. 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
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21. 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
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.
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22. 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.
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23. CLEANING CHEMISTRY MECHANISMS
• Wetting
• Emulsification
• Dispersion
• Solubility
• Chelation
• Oxidation
• Hydrolysis
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24. CLEANING AGENT OPTIONS
• Water
• Commodity alkalis and acids
• Organic solvents
• Surfactants
– Anionic
– Cationic
– Amphoteric
– Nonionic
• Formulated detergents
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25. 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
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26. 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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27. 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
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28. 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
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29. 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
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30. 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
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31. 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”
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32. 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
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33. 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
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34. 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
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35. ANALYTICAL METHOD DEVELOPMENT
Cleaning agent residue
• Analytical method to determine residual cleaning
agent.
• Information from cleaning agent vendor
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36. 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
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37. 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
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38. 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
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39. 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)
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
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40. 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
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41. 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
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42. 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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43. 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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44. 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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45. 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.
• Recommendations for Stage 3 monitoring and
maintenance.
– Additional limited testing based on data and risk
– Routine monitoring based on risk
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46. 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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47. 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”
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48. 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
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49. 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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50. 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
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51. 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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52. 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
CONSISTENT LIFECYCLE STRATEGY AND APPROACH
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53. 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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54. 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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55. 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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56. 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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57. 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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58. PAUL L. PLUTA, PhD
Editor-in-Chief
Journal of Validation Technology
Journal of GXP Compliance
Advanstar Communications
Adjunct Associate Professor
University of Illinois at Chicago (UIC) College of Pharmacy
Chicago, IL, USA
Pharmaceutical industry experience
Contact: paul.pluta@comcast.net
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