Cleaning Validation-Steris-Selection of Pharma Cleaner and Cleaning Mechanism

Selection of Cleaning Agents and
Cleaning Mechanisms
Presented by Richard Chai
STERIS Corporation
Richard_Chai@steris.com
Oct 2017
Copyright © 2014 STERIS Corporations. All

Rights Reserved. CONFIDENTIAL and
PROPRIETARY to STERIS Corporation
Agenda
• Cleaning Mechanisms
• Selection of Cleaning Agents
• Cleaning Agent Limits Calculation
Connecting Pharmaceutical Knowledge ispe.org

Definition of Cleaning
“The process of removing contaminants from process

equipment and maintaining the condition of equipment such
that the equipment can be safely used for subsequent product
manufacture”
A contaminant is the presence of a minor ingredient in another

chemical or mixture, often at the trace level
Emphasis is on “CONTROL”

Introduction
• Understanding
• Cleaning Mechanisms
• Cleaning Parameters
• Assist in
• Selection of Cleaning Agent
• Design of Cleaning Process

Cleaning Mechanisms
Solubility /
Solubilization
Chelation Wetting
Cleaning
Mechanism
Emulsification
Oxidation & Dispersion
Hydrolysis

Cleaning Chemistry: Solubility /
Solubilization
• Solubility
– Ability of a solute to dissolve
– May be soluble BUT need stirring or heat
• Solubilization – similar to solubility
– Involves an additive to pure solvent to render
residue soluble
– Example: Water is solvent, involves addition of:
• Surfactant
• pH modifier
• Water miscible organic solvent

Cleaning Chemistry: Wetting
• Influence of Surfactants on Wetting

 Reduce surface tension
 Increase surface contact
No Surfactants Surfactant A Surfactant B
Soil Residue

Wetting - Surface Tension and Penetration
Remove soil from Water

surface irregularities With surfactant
Soil
Substrate

Cleaning Chemistry: Emulsification &
Dispersion
Dispersed in cleaning solution & prevent
re-deposition O
- +
CH3- CH2- CH2- CH2-CH2-(CH2)n- CH2- C- O Na
Lipophilic
(Oil-Loving) Hydrophilic
(Water-Loving)
Surface

Cleaning Chemistry: Hydrolysis
O O
R1 C O R2 + NaOH R1-C-O- Na+ + R2OH
Larger MW Smaller MW
Less polar More polar
Less water soluble More water soluble

Cleaning Chemistry: Oxidation
• Oxidation – involves cleavage of organic
bonds
– Effect is similar to hydrolysis but lass specific
• Generates smaller, more polar functional
groups such as ketone, aldehyde and
carboxylic acids which increase hydrophilicity
Oxidation Sources
Sodium Hypochlorite (NaOCl)

Hydrogen Peroxide (H2O2)
Peroxyacetic Acid

Cleaning Chemistry: Chelants
• Chelant: molecule designed to bind to
charged metal ions
– Most common ions: calcium and magnesium
– Prevents precipitation
– May also help remove trace amounts of iron from
system
• Chelants – products like
– NTA: nitrilo triacetic acid
– EDTA: ethylene diaminetetraacetic acid
– Certain polyphosphates

Common Formulation Components
Component Function
Bases Alkalinity source, hydrolysis
Acids Acidity source, hydrolysis
Water Solvent
Surfactants Wet, solubilize, emulsify, disperse
Chelants Tie up calcium, iron, magnesium
Builders Assist in detergency
Antimicrobials Kill, reduce microbes
Oxidants Oxidize, kill microbes

Cleaning Agent Options
– Water
– Commodity Chemicals
– Formulated Cleaners
– Organic Solvents
– Antimicrobial Agents

Cleaning Agent - Water
Component Function
Water
- Reverse Osmosis
- De-Ionized Solvent - Dissolve
- Purified Water
- Water For Injection

Cleaning Agent - Commodity
Chemicals
Component Function
Water
- Reverse Osmosis
- Purified Water
Alkalinity source,
Bases
hydrolysis

Cleaning Agent –
Formulated Chemistries
Components Function
Water
- Reverse Osmosis
- Purified Water
Bases Alkalinity source, hydrolysis
Chelants Tie up calcium, iron
Dispersants Suspend solids
Oxidants Oxidize, kill microbes
Surfactants Wetting, solubilize, emulsify, disperse

Cleaning Mechanisms
Water • Solubility
Commodity • Solubility
Chemicals • Hydrolysis
• Solubility Emulsification
Formulated • Hydrolysis Dispersion
Chemistry • Wetting Chelation

Common Cleaning Challenges:
Cleaning Efficiency
• Increased cleaning efficiency

• Reduced cleaning process time / Increase
Production Time
• Free rinsing
– Less water usage/reduction in rinse time
– Less water heating time required
– Less waste disposed

Air Liquid Interface
Common Approaches to cleaning
ALI rings
•Increase spray impingement by using rotating
spray device
•Increase time of the initial pre-rinse
•Increase temperature of cleaning (75-85°C)
•Use of formulated cleaning agent
•Increase cleaning agent concentration
•Use of an oxidizing cleaning agent or
detergent additive with a formulated alkaline
cleaning solution

Air Liquid Interface
– Rings caused by slip agents
– Synthetic, commonly used slip-agents
in the manufacture of plastics
– Insoluble in water and most buffers.
– Tend to float at air/liquid interface
– Deposit on side wall of tanks at the
meniscus levels
Water Commodity Formulated Chemistries

Not effective. Lubricant Effectiveness intermitten. Most effective. Low
insoluble in water Requires high concentration, elevated
concentration (detrimental temperature, may need an
to SS surface), long additive
rinsing time

Challenging Soils
• Oral Solid Dose
– Polymers (fillers, binding & disintegrating
agent)
– Enteric coating
– Dyes
– Titanium Dioxide
Not effective May require organic Most effective. Low
solvents. Safety and concentration but usually
environmental concerns used together with an
additive

Microbial Contamination
Biofilm
• Living and dead cells
• Extracellular polymer substrate (EPS)
• EPS consists of polysaccharides,
proteins, nucleic acid and lipids
• EPS can be harder to clean than process residues
• Residual organic material can reduce efficacy of biocides
• Residual EPS can reduce penetration of biocides
Not able to penetrate and Effectiveness intermittent Most effective. Low
remove the EPS Not able to penetrate and concentration but usually
remove the EPS used together with an
additive

Microbial Contamination
• General recommendation is to use of formulated
alkaline cleaning chemistry alone or with sodium
hypochlorite or hydrogen peroxide at 60-80oC
for 30-60 minutes
• If necessary derouge or de-scale surfaces and
passivate stainless surfaces before sanitization
• Utilize a sanitizer or sterilant effective against
the identified microbe(s)

Challenging Soils
• Cosmetics & Consumer Healthcare
• Products containing Titanium Dioxide, Carbomers.
Hydroxypropyl methycellulose etc
• Equipment
– Pumps & hoses cleaned out of place in parts washer

Challenging Soils
• Cosmetic & Consumer Healthcare Case
Study
• Equipment:
– 3,000 L stainless vessels, piping, spray nozzles,
agitator blades
• Current process:
– 800 L pre-rinse
– 5% NaoH at 80DegC, 60min
• Customer objective:
– Eliminate pre-rinse to save water
– Reduce cleaning time

Rouge
Reduces
Increases cleanability
surface and
roughness Sanitization
Increases
microbial
excursions
Derouging & Passivation

Product – Nitric acid, phosphoric acid, citric acid,
Contamination other proprietary chelant formulations
are typically used.

Cleaning Efficiency
Critical Parameters
T - Temperature
A - Action
C - Coverage
C - Chemistry
C - Concentration
T - Time

Temperature
• Higher generally better

– Exceptions
• Critical for wax excipients
– Must approach melting point for
emulsification
• Strong influence on mechanisms
• Control throughout process

Action
• Also called impingement
– Related to force on the surface
– Helps to dislodge residues
– Uniformity to assure effectiveness
– Limited in spray balls
• Distribution device, not an impingement
device
• Spray washing, cascading flow, manual
washing, agitated immersion

Manual Washing

Direct Impingement
by Spray Ball/
Spindle
Cascading Flow
CIP SKID
Agitated Immersion

Direct
Impingement
by Spray Arm
Cascading Flow
Direct Impingement by
Spray Ball/Spindle

Coverage
• Spray balls may provide adequate coverage
but not uniform impingement at all locations
– Use agitated immersion, cascading flow and
impingement

Chemistry
• Alkaline(Base) Detergents– pH>9
– Majority of cleaning applications >85%
• Organic acids
• Proteins
• Oil, waxes, fats
• Tableting excipients
• Polysaccharides
• Acid Detergents– pH < 6
– Small percentage of cleaning applications
• Inorganic compound (Bicarbonates, carbonates)
• Metal oxides
• Hard water scale

Chemistry
• Neutral Detergents– pH 6-9

– Manual cleaning or environmental
restrictions
– Substrate issues
• Detergent Additives
– Used to boost cleaning efficacy of other
products

Concentration
• Higher generally better

•Inverse relationship with time and
temperature
• Materials compatibility issues
• Neutralization issue
• Safety in handling

Time
• Dirty Hold Time
– Time until cleaning is performed
• Time of cleaning
– Pre-rinse
– Wash
– Rinse
– Time between steps

Other Factors
• Surface type
Surface • Surface finish
Soil • Wet” (freshly deposited)

Conditions • Dried on / Baked on
• Number of rinse
Rinsing • Type of water used

Selecting Cleaning Agents –
Issues to Consider
• Effective cleaning, broad spectrum
• Consistency, lot traceability
• Stability
• Analytical methods availability
• Low foaming for spray applications
• Low toxicity, safety
• Substrate compatibility

Selecting Cleaning Agents –
Issues to Consider
• Environmentally acceptable
• Assured availability
• Technical support
• Low overall cost
• Free rinsing

Rinsibility
Analytical methods (specific and non specific)
Active components and non active components
Percent residue removal as a function of the number of rinses
120
100
80
60
40
20 Analyzable Surfactant
TOC
0
0 1 2 3 4 5

Selection Based On…
• Chemistry of Cleaning
– Limitation- cleaning is more than chemistry
• Prior Experience
– Limitation- may not select optimized
conditions
• Lab Evaluation
– Best, provided conditions are simulated
– Then scale-up to confirm

Lab Evaluation
• Coat coupon with soil T - Temperature

• Simulate process A - Action
C - Chemistry
conditions and dirty hold C - Concentration
T - Time
time

Acceptance Criteria
•Soiled Coupon Visual Failure •Water Break

Free Failure

Cleaning Performance
Same coupon,
Same coupon, different angle
different angle
Residue visible on
Residue visible both angles, 15
in first angle, not coating and
in second cleaning cycles

Lab Scale Cleaning Evaluation
• Experimental design to vary parameters for optimization
• Start with agitated immersion: Calibrated digital
stirplate
• Vary detergent concentration and temperature
• Check cleaning progress at specific time intervals.
Concentration Temperature °C Time

1% 60 15
1% 80 15
2% 60 15
2% 80 15
1% 60 30
1% 80 30

Cleaning Performance
Soil and Residue Surface & Cleaning Factors

Equipment Design
Wet Material of construction Cleaning agent
Dry Irregularities Cleaner concentration
Baked Roughness Time (wash, rinse, etc.)
Steamed Flow rates Temperature (wash, rinse,
Compressed Coverage etc.)
Dirty hold time Drainability Water quality
Composition Minimize dead legs Action
Amount Orientation of dead legs Rinsing
Valve selection
Insert selection

Limits for Cleaning Agents
• No therapeutic index for cleaning agents
• Commonly, only information available is LD50
• LD50 specific to animal model (e.g. rat) and
route of administration (e.g. oral, IV)
• First calculate either Acceptable Daily Intake
(ADI) or No Observed Effect Level (NOEL):
ADI = LD50 (mg/kg)× body weight (kg)/105
NOEL = LD50 (mg/kg)×(5.6×10-4) x 70 kg1

Health Based Limits
• ISPE Risk MaPP and recent EMA document

are two main advocates & EU GMP Annex 15
– ADE: Acceptable daily exposure
– PDE: Permitted daily exposure
• Refers to limits based on toxicological
evaluation
– Focuses on how carryover might cause harm.
– Value represents dose that is unlikely to cause an
adverse effect if an individual is exposed at this
dose every day for a lifetime

Health Based Limits
• Why?
– Some felt that “traditional” method was not “risk-
based”
– Use of 1/1000th daily dose of active seen by some
to be “arbitrary”
– Some questioned the use of 10 ppm as the
“default” value as arbitrary and possibly not
reflective of potential risks
– Current approach could lead to either overly
prescriptive limits or inadequate limits

Calculation of ADE Value
NOAEL × BW
ADE (mg/day) =
UFC × MF × PK
• Where:
– BW = Body weight
– UFc = Composite uncertainty factor
– MF = Modifying factor
– PK = Pharmacokinetic adjustments (route to route
adjustments)
• No other safety factors applied.

Calculation of ADE Value
• Uncertainty Factors:
– Interspecies differences, intraspecies differences,
sub-chronic to chronic extrapolation, LOAEL to
NOAEL extrapolation, database completeness
• Modifying Factors:
– Based on professional judgment of toxicologists to
account for quality of database
• Pharmacokinetic Adjustment:
– Account for different routes of exposure, such as
animal study oral but drug dosing is parenteral

Calculating the Safety Threshold
Value (STV) (ISPE)
Batch Size
ADE × = STV
Maximum Daily Dose
Rather than:
Minimum Therapeutic Dose × Batch Size 1
× = MACO
Maximum Daily Dose Safety Factor
NOTE: Safety factor is already included in the ADE as

“uncertainty factors”

Calculation of PDE value
NOAEL×WeightAdjustment
PDE(mg/day)=
F1×F2×F3×F 4×F5
• Weight adjustment is 50 kg for human adults

Uncertainty factors
• Used to account for various uncertainties and
to allow extrapolation to a reliable and robust
no-effect level
– F1: (value 2-12) to account for extrapolation
between species
– F2: (factor of 10) variability between individuals
– F3: (factor of 10) to account for repeat dose
studies of short duration
– F4: (value 1-10) applied in case of severe toxicity
– F5: (factor up to 10) applied if no-effect level was
not established.

Case Study: Formulated alkaline
detergent
• The traditional method…
LD50 × BW × MBS
MAC =
Safety Factor x units × LDD
860 mg/kg × 60 kg × 10 kg
MAC = = 6,450 mg
800 mg × 100,000
• Where:
» LD50 is 860 mg/kg (alkaline detergent)
» BW is body weight (60 kg)
» MBS = Minimum batch size (10 kg)
» LDD = Largest daily dose (800 mg)

detergent
• EMA Method:
– NOAEL = 120mg/kg/day
– F1 = 10
As determined
– F2 = 10
by toxicologist
– F3 = 3
– F4 = 1
– F5 = 3
120 mg/kg/day × 60 kg
PDE (mg/day) = = 8 mg/day
10 × 10 × 3 × 1 × 3

detergent
• EMA Method (Continued):
– Safe threshold value (STV) – Upper limit for
statistical analysis used to determine the process
capability (Cpk) and cleaning validation limits
MBS
STV = PDE ×
LDD
10 kg 1000000 mg
STV = 8 mg/day × x = 100,000 mg/day
800 mg 1 kg

Selection of Cleaning Agents and
Cleaning Mechanisms
Richard Chai
Questions? Technical Service Manager
STERIS Corporation
Richard_Chai@steris.com

Cleaning Validation-Steris-Selection of Pharma Cleaner and Cleaning Mechanism

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Selection of Cleaning Agents and

Copyright © 2014 STERIS Corporations. All

Connecting Pharmaceutical Knowledge ispe.org

“The process of removing contaminants from process

A contaminant is the presence of a minor ingredient in another

Connecting Pharmaceutical Knowledge ispe.org

Connecting Pharmaceutical Knowledge ispe.org

Connecting Pharmaceutical Knowledge ispe.org

Connecting Pharmaceutical Knowledge ispe.org

• Influence of Surfactants on Wetting

No Surfactants Surfactant A Surfactant B

Connecting Pharmaceutical Knowledge ispe.org

Remove soil from Water

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Connecting Pharmaceutical Knowledge ispe.org

Connecting Pharmaceutical Knowledge ispe.org

Sodium Hypochlorite (NaOCl)

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Bases Alkalinity source, hydrolysis

Acids Acidity source, hydrolysis

Surfactants Wet, solubilize, emulsify, disperse

Chelants Tie up calcium, iron, magnesium

Builders Assist in detergency

Antimicrobials Kill, reduce microbes

Oxidants Oxidize, kill microbes

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Connecting Pharmaceutical Knowledge ispe.org

Connecting Pharmaceutical Knowledge ispe.org

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• Increased cleaning efficiency

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Water Commodity Formulated Chemistries

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Derouging & Passivation

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• Higher generally better

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• Neutral Detergents– pH 6-9

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• Higher generally better

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Soil • Wet” (freshly deposited)

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