global cleaning validation problems -- · pdf file• most difficult-to-clean locations...
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1
GLOBAL CLEANING VALIDATION
PROBLEMS -- 2015
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
OVERVIEW OF IDENTIFIED PROBLEMS
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
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OVERVIEW
CLEANING VALDIATION PROBLEMS
Problems or deficiencies identified by questions and
discussions with cleaning professionals at domestic and
international pharma cleaning meetings. Confirmation
by multiple experts
Four groupings of problems / deficiencies identified
• Product residue problems
• Equipment problems
• Cleaning process problems
• Laboratory problems
3
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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LIFECYCLE APPROACH TO CLEANING VALIDATION
FDA identified three stages of process validation
1. Process design and development (understanding)
2. Process qualification (performance)
3. Continued process verification (maintenance)
Problems discussed indicate most cleaning deficiencies in
Stage 1 process understanding, i.e., pre-work for
traditional validation.
Three problems are identified for Stage 2 processing.
Problems in Stage 3 validation not identified.
• Almost no companies have a stage 3 program other
than change control.
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LIFECYCLE APPROACH TO PROCESS VALDIATION
KEY CONCEPTS
• Stage approach
– Design and development
• General approaches
• Specific cleaning methods
– Process demonstration
– Continued process verification
• Scientific and technical basis
• Risk
• Variation identification and control
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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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PHYSICAL AND CHEMICAL PROPERTIES OF
RESIDUE AS BASIS FOR CLEANING
PROBLEM: No basis for cleaning procedure
• Arbitrarily chosen
• “Best” method at site
• Methods used for years for all products
• Bought soap at local store – sale price
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PHYSICAL AND CHEMICAL PROPERTIES OF RESIDUE –
BASIS FOR CLEANING PROCEDURE
Case study #1: 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 –
Significant improvement
• No residues. Unknown peaks determined to be flavors.
• API dissolves (acid-base neutralization)
Consider active drug and other residue chemistry in
development of cleaning process9
CLEANING METHOD
1. Three lots with new cleaning procedure
– Acid cleaning liquid, drain – Significant improvement in process
– Alkaline cleaning liquid, drain
– Water rinse
– Purified water rinse
– Dry
2. Swab sampling in worst case locations
3. No detectable residue, no unknown peaks
4. Unknown peaks from past trials determined to be
formulation flavors (hydrophobic oils)
5. Documentation
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PHYSICAL AND CHEMICAL PROPERTIES OF RESIDUE –
BASIS FOR CLEANING PROCEDURE
Case study #2: Small molecule API oral liquid product . 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
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EXPERIMENTAL DEVELOPMENT PROCEDURE
1. Evaluate formulation and chemical properties
2. Laboratory comparison – 2 L beaker and mixer
– Small amount of product into beaker + water to disperse
– Add cleaning agents to be screened – acid, neutral, alkaline,
solvent
– Visual observation
3. Coupons with residue in beaker
4. Simulated cleaning procedure.
– Swab sampling
– Analytical determination
5. Conclusions and recommendations
6. Confirmation in pilot equipment
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CLEANING PROCEDURE DEVELOPMENT PROCESS
Stage 1 R&D
1. API technical analysis.
2. pH solubility profile pH 1-12.
3. Solubility in proposed cleaning liquid.
4. pH-stability profile pH 1-12.
5. Laboratory cleaning studies confirmation.
6. Analytical method development based on stability data.
7. Testing of all excipients with analytical method.
– Source of unknown peaks
CLEANING PROCEDURE TECHNICAL BASIS
pH-SOLUBILITY AND Ph-STABILITY IS BASIC R&D WORK
ANALYTICAL METHOD MEASURES ACTUAL RESIDUE
ANALYTICAL METHOD DETECT OTHER EXCIPIENTS
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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
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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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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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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RESIDUE SOLUBILITY IN MOST DIFFICULT TO CLEAN MATRIX
BASIS FOR CLEANING PROGRAM
PROBLEM: Wrong basis for worst-case residue
Water solubility – USP Tables
• Is this adequate? Depends on cleaning procedure
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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pH SOLUBILITY PROFILE, pH 1-12
Solubility
mg/ml
Drug A
Drug B
pH 1 7 12
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SULFAMETHOXAZOLE pH-SOLUBILITY
Amount
Dissolved
Note pKa
1 pH 12
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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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“CLEANABILITY” IN DETERMINING
MOST DIFFICULT-TO-CLEAN RESIDUE IN MATRIX
PROBLEM: Incomplete evaluation of worst-case residue
What factors should be considered to determine worst case residue?
Most companies use
• Solubility (pH?)
• Toxicity
OK for site with simple dosage forms
All aqueous solution products (LVP, SVP)
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“CLEANABILITY” IN DETERMINATING MOST
DIFFICULT-TO-CLEAN RESIDUE IN MATRIX
Matrix = Products cleaned by same cleaning procedure
Other considerations
• Solubility in cleaning liquid
• Toxicity
• Concentration in dosage form
• Cleanability
– Formulation components major effect
– Cleaning personnel input
– Dirty hold time
– Soil-surface interactions (e.g., air-liquid interface)
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“CLEANABILITY” IN DETERMINATING MOST
DIFFICULT-TO-CLEAN RESIDUE IN MATRIX
IR Tablet ER TabletAPI API
Microcrystalline cellulose Same
Lactose Same
--- Wax
--- Cellulosic polymer
Crospovidone ---
Talc Same
Magnesium stearate Same
COMPARE EASE OF CLEANING
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OTHER CONSIDERATIONS
• Consider flavor and color oils
• Dyes/lakes may be more difficult to clean
than active drug
• Consider solubility of all components
• Alcohol explosivity
• Solvent toxicity
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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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NON-UNIFORM CONTAMINATION TRANSFER
PROBLEM: Non-uniform contamination not considered
Cleaning Processes
1. Make product A
2. Clean
3. Make product B. Remaining Product A residue contaminates
Product B
Equipment categorization
• Uniform contamination equipment
– Equipment with all contamination uniformly transferred.
– Example: Mixing tank
• Non-uniform contamination equipment
– Example: Filling needles, compressing machine.
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NON-UNIFORM CONTAMINATION
1. Make 50 L tank of lemonade.
2. Fill 2 L pitcher from tank.
3. Fill cups from pitcher
4. Clean tank and pitcher.
5. Make ice tea in 50 L tank – All lemonade residue in tank uniformly
transferred to ice tea.
6. Fill 2 L pitcher from tank – All lemonade residue in pitcher transferred to
ice tea. Fill cups. HIGHEST LEVEL OF CONTAMINATION.
7. Fill same 2 L pitcher from tank – Much less lemonade residue left in
pitcher transferred to ice tea. Fill cups.
8. Fill same 2 L pitcher from tank – Even less lemonade residue in pitcher
transferred to ice tea. Fill cups.
9. And so on…..
#6, 7, 8, 9….. – NON-UNIFORM CONTAMINATION
#6 – HIGHEST LEVEL
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UNIFORM CONTAMINATION CALCULATION
Typical calculation considers total surface area of all
shared product contact equipment, and assumes all lot A
residue from total surface area transferred uniformly to
all lot B product
Residue limit = Min dose A x Batch size B x Safety factor
Max dose B x Surface area
References:
Fourman and Mullen. Pharmaceutical Technology 17, #4, 1993.
LeBlanc. Validated Cleaning Technologies for Pharmaceutical Manufacturing.
Interpharm/CRC Press, 2000.
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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
x x x x x x x
MANUFACTURING TANK PRODUCT
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NON-UNIFORM CONTAMINATION CALCULATION
Residue non-uniformly flushed into initial product units
Residue content = Residue level x surface area
5 ml
Determine how many 5 ml vials to be discarded to be <
limit.
Reference: LeBlanc. Validated Cleaning Technologies for Pharmaceutical Manufacturing.
Interpharm/CRC Press, 2000.
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NON-UNIFORM CONTAMINATION
• Contaminated product may be eliminated
in set-up.
• Sites must be prepared to answer
questions from auditors based on
calculations.
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MOST-DIFFICULT-TO-CLEAN
EQUIPMENT LOCATIONS
PROBLEM: No rationale for sampling of
cleaned equipment.
• Sampling locations chosen arbitrarily.
• Easiest-to-clean locations chosen
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MOST DIFFICULT TO CLEAN EQUIPMENT
LOCATIONS
Equipment Technical Evaluation
• Deadlegs
• Corners
• Undersides
• Pipe bends
• Flow velocity
• Coverage studies
• Drainability
• Other considerations (e.g., baseline visual inspection)
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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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SAMPLING PAGES
DIGITAL PICTURES
• One sampling page for each equipment
• Assemble pages for process train
• All pages in cleaning validation protocol
• Arrows for specific sampling locations
• Random locations unspecified
• Use for all cleaning validation
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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
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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: _______________
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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MANUAL CLEANING QUALIFICATION
PROBLEM: Manual cleaning process
Variation sources
• Different persons
• Different motivation
• Different physical strength
• Day shift, 2nd shift, night shift
• And on and on and on …..
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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
Manual cleaning is high risk
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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.”
Q to operator: “You cleaned the gasket with pure soap – this is not the
procedure?”
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?
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 management: “Did you finish cleaning the equipment? We are here to
swab for cleaning validation.”
A: “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.”
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CLEANING PROCEDURE DOCUMENTATION
PROBLEM: Exact documentation for process
reproducibility
• Fill volume
• Amount of cleaning agent = concentration
• Time
• Temperature
• Flow rate (impact)
• Verification of key steps
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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
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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CLEANING PROCEDURE DOCUMENTATION
(Cleaning Batch 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)
45
DIRTY HOLD TIME –
TIME TO INITIATE CLEANING
PROBLEM: No control of dirty hold time
Residue changes
• Drying
• Chemical changes
• Physical changes
46
DIRTY HOLD TIME
What is “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?
– Hydrolysis, oxidation, photolysis, physical changes, etc.
• Especially important in “wet” processes – wet residue
becomes dry, hardens, cakes, changes?
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LABORATORY STUDY – DIRTY HOLD TIME
1. Develop simulated cleaning process
– Coupon in beaker with stirrer
2. Weigh coupons. Aliquot residue onto coupon surface
per time schedule. Allow to air dry. Weigh coupons.
3. Example time schedule:– 1-1-2014 Day 30
– 1-10-2014 Day 20
– 1-20-2014 Day 10
– 1-25-2014 Day 5
– 1-28-2014 Day 2
– 1-29 2014 Day 1
– 1-30-2014 Day 0
4. Perform simulated cleaning. Observe. Air dry.
Observe.
5. Weigh dry coupons. Calculate residuals. 48
CAMPAIGN LENGTH
How many lots in manufacturing campaign before
cleaning must be done?
What about “cleaning” between batches?
• Equipment should be visually clean (FDA)
• “Between lot procedure” (not cleaning
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.
50
ANALYTICAL METHOD DEVELOPMENT
PROBLEM: Analytical method does not
measure actual residues
Analytical method must measure actual residue
• Small molecules
– API
– API degraded – specific or non-specific method
• Biotech molecules
– API degraded – non-specific method
(e.g., TOC or amino acid)
UNDERSTAND RESIDUE CHEMISTRY
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ACTUAL RESIDUE PRESENT MUST BE MEASURED
• Solubility
• Stability
Solubility considerations
• Hydrophilic and hydrophobic molecules
• Ionization – Effect of pH
• Effect of temperature
Stability considerations
• Hydrolysis, oxidation, photolysis, physical changes
What residue is really present?
Consider chemistry of residues
52
RESIDUE STABILITY IN CLEANING RESIDUE ANALYSIS
RESIDUE RECOVERY STUDIES
PROBLEM: Is residue able to be quantitavely
recovered from surfaces?• Product contact materials
• High % of total surface area – identify all areas to be sampled
• Obtain representative coupons from equipment fabricators
– Order coupons with new equipment
• Recovery should be consistent and high (e.g., >50%)
• Recovery factor used in calculations
– Multiple approaches
• Done in lab by lab personnel – consideration for future training
ANALYSIS IS MEANINGLESS
WITHOUT RECOVERY STUDIES
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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.
54
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.
55
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
56
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.
57
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
58
ANALYTICAL METHODOLOGY
Case study: Swab sampling with extension pole
Interface
Biotech tank
59
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
60
SUMMARY
Cleaning personnel identified frequent
overlooked problems.
• Residue
• Equipment
• Process
• Analytical
61
WHICH ARE MOST IMPORTANT?
Risk analysis• 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
62
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?
63
FUTURE DEFICIENCY
• Lifecycle approach requires ongoing
monitoring of processes
• Cleaning processes must be periodically
reviewed (~2 years?)
• Review deviations
• Review non-conformities
• Review re-cleans
• Management awareness
• Improvement projects
64
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, Paul L., editor. Cleaning and Cleaning Validation, Volume 1. Basics, Expectations, and
Principles. PDA and DHI Publishing, 2009.
Pluta, Paul L., editor. Cleaning and Cleaning Validation, Volume 2. Application of Basics, and
Principles. PDA and DHI Publishing, 2013.
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.
“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.
65
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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