FT - SM - ISPEIndonesiaAug2020 - 20200818 (Day 1)

7/16/2020
Equipment Cleaning Process

Development – Where and How
to Start ?
Presented by Richard Chai
STERIS Corporation
Richard_Chai@steris.com
ISPE Indonesia,
16 Jul 2020
Agenda – Part 1
• Lifecycle approach to Cleaning

Validation
• Cleaning design space
• Soil characterization
• Cleaning mechanisms and critical
cleaning parameters
• Optimization of cleaning parameters
Connecting Pharmaceutical Knowledge ispe.org
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What is Cleaning Process

Development ?
Cleaning Process
Objective
Development
Soil Successful cleaning

Characterization validation
Cleaning
Optimization of cleaning
parameters /
process
methods
Residue detection
Minimized product cross‐
methods /
contamination
acceptance criteria
Regulations
• FDA 21 Code of Federal Regulations (CFR)
• US FDA, Biotech Inspection Guide (11/91)
• US FDA, Guide to Inspections Validation of Cleaning
Processes (1993)
• Pharmaceutical Inspection Convention/Co-operation
Scheme (PIC/S)
 PE 009-14 Part I (2018) - Guide to Good Manufacturing Practice for
Medicinal Products Part I
 PI 052-1 (Jun 2020) - Inspection of Health Based Exposure Limit (HBEL)
Assessment and Use In Quality Risk Management
 PI 053-1 (Jun 2020) Questions and Answers on Implementation of Risk-
Based Prevention of Cross Contamination in Production and ‘Guideline
on Setting Health-Based Exposure Limits for Use in Risk Identification in
the Manufacture of Different Medicinal Products in Shared Facilities’
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Regulations
• EU Guidelines for Good Manufacturing Practice

for Medicinal Products for Human and
Veterinary Use Medicinal Products for Human
use
• Part 1 Chapter 3 (2014): Equipment and Premises
• Part 1 Chapter 5 (2014): Production
• Annex 1 (2008): Manufacture of Sterile Medicinal
Products
• Annex 1 draft v12 (2020)
• Annex 15 (2015): Qualification and Validation
21 CFR 211.67
• Part 211.67 Equipment Cleaning and
Maintenance
• Written procedures shall be established and
followed for cleaning and maintenance of
equipment…
• A description in sufficient detail of the
methods, equipment, and materials used in
cleaning and maintenance operation…
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PIC/S PE 009-14 Part I (2018)

• Prevention of cross-contamination in
production
• Cross-contamination should be prevented by
attention to design of the premises and
equipment as described in Chapter 3.
• This should be supported by attention to
process design and implementation of any
relevant technical or organizational measures,
including effective and reproducible cleaning
processes to control risk of cross-
contamination.
Chapter 5 - Production
• Prevention of cross-contamination in
production
• Cross-contamination should be prevented by
attention to design of the premises and
equipment as described in Chapter 3. This
should be supported by attention to process
design and implementation of any relevant
technical or organizational measures, including
effective and reproducible cleaning processes
to control risk of cross contamination.
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Warning Letter
Failure to have adequate cleaning procedures to prevent contamination
or carry-over of a material that would alter the quality of the API.
Your firm uses shared equipment for the API you manufacture. Data
from cleaning verification and validation studies found that your
cleaning procedures were ineffective. For example, our investigator
discovered that 105 of (b)(4) cleaning verification samples taken
between 2015 and the start of our 2016 inspection failed your firm’s
specification of no more than (b)(4) ppm for residual drug.
After obtaining failing cleaning verification results, you repeated
cleaning until you obtained passing verification results. Your firm failed
to investigate recurring cleaning procedure ineffectiveness and did not
remediate the deficient procedures.
Warning Letter 320-17-23 (Feb 2017)
Warning Letters
1. Your firm failed to establish and follow adequate written
procedures for cleaning and maintenance of equipment (21
CFR 211.67(b)).
You are a contract manufacturer who makes several

products for multiple customers. Your cleaning and
maintenance program is inadequate. For example,
deficiencies in your program included extended hold times
for dirty equipment, such as your encapsulator, that were
unsupported by validation data. In addition, you did not
establish timeframes for replacing parts and cleaning your
tablet coating equipment.
Warning Letter 566492 (Feb 2019)
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Lifecycle Approach to Cleaning Validation
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Lifecycle Approach to Cleaning

Validation
• Process defined through development & scale‐up activities

Process • Process variables identified & critical variable limits defined
Design
• Process designed evaluation on reproducibility

Process • Verify process produces expected results
Qualification
• Critical variables monitored

Continuous • Process remain in state of control
Verification
Lopolito and Rivera, “Cleaning Validation: Process Life Cycle Model”, Chapter 9 in Contamination Control in Healthcare Product Manufacturing, Volume 3,
PDA/DHI Publishing (2014)
12
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Lifecycle Model – Stage 1
Cleaning Critical Cleaning Residue

Method Parameters Detection
• Clean in place • Cleaning • Residue type
• Clean out of agent • Sampling
place screening method
• Manual • Lab scale • Analytical
Cleaning study (TACCT) method
• Pilot plant /
field trials
Lopolito and Rivera, “Cleaning Validation: Process Life Cycle Model”, Chapter 9 in Contamination
Control in Healthcare Product Manufacturing, Volume 3, PDA/DHI Publishing (2014)
13
Lifecycle Model – Stage 1

Acceptance Grouping Process
Criteria Strategy Equipment
• Residue • Equipment • Sanitary
limits – • Product design
Product & • Equipment • Surface
Cleaning train finishes
agent • MOC
• Visual • Other CIP
inspection design
concepts
Lopolito and Rivera, “Cleaning Validation: Process Life Cycle Model”, Chapter 9 in Contamination
Control in Healthcare Product Manufacturing, Volume 3, PDA/DHI Publishing (2014)
14
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Designing a Cleaning Process –

Where to Start ?
• Need to know and understand:
Process flow Process Process soils Components

Equipment of cleaning
15
Cleaning Methods
• Static immersion
• Agitated immersion
• Solvent reflux
• Automated parts washer
• Ultrasonic
• High pressure water jet
• Manual
• Sink scrub (brush)
• Wipe
• High pressure spray
• Foamers
• Clean-in-Place (CIP)
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Typical CIP Cycle Function
Pre-rinse  Removal of soluble and gross

residues
 Removal of soluble and dried
Alkaline
residues with cleaner, heat
cleaning
and/or wetting
 Removal of the suspended or

Water rinse
solubilized soiled and the
alkaline cleaner
 Removal of acid-soluble
Acid rinse
/inorganic soils and
neutralization of alkali residues
 Removal of all cleaner
Final rinse
residue and product residue
 Facilitate draining on low-

Air dry surface draining
17
Equipment Surface & Design
• Dead Leg in piping and process connections

– an area of entrapment in vessel or piping run that could lead to
contamination of the product.
– Dead leg Orientation: pitched to drain
– There is evidence that an L/D of 2 or less may prevent the branch from
the dead leg (Ref: ASME BPE-2019)
CIP Solution
L/D < 2
Good Turbulence Intermediat No Turbulence

Good Mixing e Poor Mixing
Good Cleaning Turbulence Poor Cleaning
and Mixing Ref: Handbook, Cleaning in place; A guide to
cleaning technology in the food processing
industry
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Equipment Surface & Design
• Coverage
– Shadow areas
– Riboflavin Testing
• Riboflavin Procedure:
– Coat with riboflavin (0.2 g/L)
– Observe with UV light while wet
– Dry and then short rinse cycle with water
– Observe with UV light while wet
– If poor coverage, make changes and repeat until 100% coverage
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Cleaning Design Space
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Design Space (ICH Q8 R2)

• The multidimensional combination and interaction of input
variables (e.g., material attributes) and process parameters that
have been demonstrated to provide assurance of quality.
Product design
Continuous Improvement
21
Process Knowledge
Key inputs and data are Consideration must be given to

analyzed and evaluated
- Product knowledge - Soil type

- Process knowledge - Process method, time, solubility, etc
- Regulations - Equipment design & configuration
- Quality Attributes - Utility impact, environmental, heat,
- Critical Processing pressure, etc
Parameters
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Design Space
Critical Process Parameters Critical Quality Attributes (CQA’s)

(CPP’s)
- Temperature - Visual Inspection

- Cleaning action (manual) - Analytical Residue Limits
- Cleaning agent - Microbial Limits
- Cleaning agent - Drainability / Drying / Air Blows
concentration
- Clean Hold Time (CHT)
- Time
- Conductivity / pH
- Dirty Hold Time (DHT)
23
Cleaning Design Space

• Cleaning process:
Products Critical Acceptable Values
Parameters of Parameters
Product A • Temperature 50°C, 10mins, 2%
• Cleaning agent alkaline cleaner
Product B • Concentration 50°C, 20mins, 2%
• Time alkaline cleaner
• Pre-requisite for Equipment &

Product grouping:
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Soil Characterization
25
Soil Characterization
Purpose: To understand characteristic of
soil
• Solubility in water/cleaning agent (pH ?)
• Toxicity, concentrations
• Excipients, degradants
• Verify suitability of current cleaning
methods / parameters
• Cleanability
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pH solubility profile, pH 1 – 12
27
Residues and Soils

• Actives, excipients, process materials, bioburden,
endotoxin
• Amounts of soils on surfaces
• Nature of soils on surfaces
– Freshly deposited Same soil, different process temperature
– Dried on during process
– Dried on during dirty hold time
– Baked on during process
– Compacted
~55% protein, 35% minerals, 6% fat~17% protein, 75% minerals, 6% fat
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Type of Soils
Potential Residues for consideration:
• API (Drug substance)
• Excipients / Colorants / Dyes / Fragrances / Flavors
• Preservatives
• Degradants / Impurities
• Starting materials / Processing aids
• Mother liquors / Solvents
• Lubricants / antifoams - silicates
• Bioburden
• Mycoplasma / Prions / Viral particles
• Endotoxin
29
How Do We Choose ?
Which materials represent the greatest risk to the next
process?
• High potency; high toxicity; allergenic
• Creates condition that is unacceptable to consumer (e.g.
off-color, abnormal fragrance, particulates)
• Hardest to clean / remove.
Is there justification to look for one residue as a “worst
case” when compared to other selected residues?
• Cleanability
• Toxicity
• Solubility
Based on risk assessment, perform qualification on
most difficult to clean products & product with the
lowest limit
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7/16/2020
Example (Dietary Supplements)
Cleanability in
Potency ‐ RDA Toxicity Total RPN
Oral Dosage Form Solubility (active) Alkaline
(mg) Oral LD50 (mg/kg) (S×P×T×C)
Detergent
Practically
Calcium 7
insoluble
1 800‐1200 1 6450 2 14
0.050‐
Chromium 4 Not specified 5
0.200
2 100‐400 2 80
Iron 3 Soluble 4 10‐15 2 319 4 96

Slightly
Magnesium 5
soluble
3 270‐400 1 4722 2 30
Not
Potassium 3 soluble 3
specified
1 7200 2 18
Selenium 7 Insoluble 5 0.200 3 4.8 ‐7.0 2 210
Zinc 3 Soluble 4 10‐15 1 5000 2 24
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Oral Solid Dosage
32
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Warning Letter
5. A summary of updates to your cleaning validation
protocol to better incorporate conditions identified as worst
case. This should include but not be limited to evaluating
drugs that are of highest toxicity, drugs that are lowest
solubility in their cleaning solvents, drugs that have
characteristics that make them difficult to clean, and
swabbing of various equipment locations that are most
difficult to clean.
Warning Letter 320-19-44 (Sep 2019)
33
Cleaning Mechanisms & Critical

Cleaning Parameters
34
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Cleaning Agent Options
Water
Commodity Chemicals
Formulated Cleaners
Organic Solvents
35
Cleaning Agent Options &

Cleaning Mechanisms
Water • Solubility
Commodity • Solubility
Chemicals • Hydrolysis
• Solubility Emulsification
Formulated • Hydrolysis Dispersion
Chemistry • Wetting Chelation
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Cleaning Agent –
Formulated Detergent e.g. CIP100
Components Function
Water
- Reverse Osmosis
- De-Ionized Solvent - Dissolve
- Purified Water
- Water For Injection
Bases Alkalinity source, hydrolysis

Chelants Tie up calcium, iron
Dispersants Suspend solids
Oxidants Oxidize, kill microbes
Surfactants Wet, solubilize, emulsify, disperse
37
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7/16/2020
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39
Direct Impingement
by Spray Ball/
Spindle
Cascading Flow
CIP SKID
Agitated Immersion
40
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Action
• Physical Removal: related to force on surface
• Helps to dislodge residues
• Limited in static spray balls
– Distribution device, not an impingement device
Static Spray Ball Rotary Spray Head Rotary Jet Head
41
Direct
Impingement
by Spray Arm
Cascading Flow
Direct Impingement by
Spray Ball/Spindle
42
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Critical Cleaning Parameters
Concentration has inverse relationship with

time and temperature
Higher generally better
43
Selecting Cleaning Agents –

Issues to Consider
• Effective cleaning, broad spectrum
• Consistency, lot traceability, availability,
• Stability
• Analytical methods availability
• Low foaming for spray applications
• Low toxicity, safety, environmentally acceptable
• Substrate compatibility
• Free rinsing
• Technical support
• Other requirement, halal certification
44
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Rinsability
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
45
Rinsability
Percent residue removal
120
100.0
95.0
10090.0
85.0
80.0
75.0
TOC
8070.0 Sodium (IC)
65.0
60.0 Potassium (IC)
%Removed
Titration
6055.0
50.0 Organic Acid
45.0 Chelant
40.0
4035.0
30.0
25.0 Analyzable Surfactant
2020.0
15.0
10.0 TOC
5.0
0 0.0
0 1 2 3 4 5
15
30
45
Rinse Time, seconds
Measurement of Organic and Inorganic Residues Recovered from

Surfaces, Journal of Validation Technology, Volume 6, Number 1,
November 1999.
46
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Formulated Chemistries
• Why use formulated cleaner?
– Free-rinsing: less water usage; less total process time
120
Rinse Comparison using Titration Data
98.6
Weight percent removed during rinse

100
80.6
80
60
CIP100
NaOH
40
18.4
20
1.3 0.1 0.8 0 0 0 0.1

0
Rinse 1 Rinse 2 Rinse 3 Rinse 4 Final
Number of Rinses in 110 g purified water
Information from Lab Report No. 3268
47
Cleaning Performance
Soil and Surface & Cleaning Factors

Residue Equipment Design
Wet Material of Cleaning agent
Dry construction Cleaner concentration
Baked Irregularities Time (wash, rinse, etc.)
Steamed Roughness Temperature (wash,
Compressed Flow rates rinse, etc.)
Dirty hold time Coverage Water quality
Composition Drainability Action
Amount Minimize dead legs Rinsing
Orientation of dead
legs
Valve selection
Insert selection
48
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Optimization of Cleaning Parameters
49
Lab Evaluation
Process And Cleaner Evaluation

(PACE)
T – Temperature
C - Chemistry
C - Concentration
Visual Check
T - Time
Waterbreak Free Test
Gravimetric Test
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Acceptance Criteria
•Soiled Coupon Visual Failure •Water Break

Free Failure
51
Acceptance Criteria
• Visual Inspection
• Water-break Free (WBF)
• Gravimetric (± 0.1 mg)
52
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Advantages of Lab Scale Study
Same coupon, Same coupon,

different angle. different angle.
Both coupons Both coupons

wet dry
53
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
Temperature
1% 80 15
2% 60 15
2% 80 15 Concentration
1% 60 30
1% 80 30
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CASE Study
Cell culture medium
Agitated Immersion 1
TIME/ VISUAL WATER

CLEANER CONC.
TEMPERATURE OBSERVATION BREAK-FREE
Sodium
0.5% v/v 60 min/ 60°C Light residue No
Hydroxide
Sodium
5% v/v 60 min/ 60°C Light residue No
Hydroxide
Acid detergent 1% v/v 60 min/ 60°C Light residue No
Alkaline
1% v/v 10 min/ 60°C Visually clean Yes
detergent
Alkaline
0.5% v/v 10 min/ 60°C Visually clean Yes
detergent
55
Formulated Chemistries
• Harvest material, air-dried
– Proteins, salts, Antifoam, Tropolone, MHX
Water
Visual
Cleaner Conc. Time/Temp Break
Observation
Free
Sodium
5% v/v 90 min/ 60°C Visually Clean Yes
Hydroxide
CIP 100 0.5% v/v 10 min/ 60°C Visually clean Yes
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Examples of Challenging soil
• Titanium dioxide
 Alkaline cleaner + Booster/Additive
• Enteric coating
 Alkaline / acidic cleaner
• Opadry
 Alkaline cleaner
 Spray wash
 Pre-soaked followed by manual scrub
• Paraffin Waxes
 Alkaline cleaner + Booster/Additive
57
When to Perform Lab Scale

Evaluation ?
• A cleaning protocol is being developed for a new
product or process
• The current cleaning process is being upgraded or
improved
• To “trouble-shoot” problems in a current cleaning
process
• Establish a “worst-case” product in a group of
products
– Cleanability
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Agenda – Part 2
• Analytical methods and Acceptance

limits
• Scale-up of cleaning process and
considerations for equipment train
• Strategies to overcome common
cleaning challenges
59
Analytical Methods and Acceptance

Limits
60
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CPPs and CQAs

Critical Performance Parameters (CPPs)
• Cleaning temperature
• Turbulence or flow (action)
• Cleaning agent concentration
• Process times (includes Dirty-hold)
Critical Quality Attributes (CQAs)
• Visual Inspection
• Analytical residue limits (HPLC or TOC)
• Microbial (Bioburden/Endotoxin)
• Conductivity/pH

Copyright © 2014 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation
61
Swab Sampling
Swab pattern directions
Non-flat surfaces
Flat surfaces
Flip Swab
Flip Swab
Connecting Pharmaceutical Knowledge ispe.org62
62
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Swab / Rinse Recovery Studies

The goal is to demonstrate reproducibility and the
effectiveness of the method :
Recovery testing:
 Spike coupon with known amount

 Remove in swab or simulated rinse procedure
 For swab, desorption
 Analyze sample
Case 1 Case 2
Pipette with
rinse solution Spike
bottom of
SS beaker
directly
spiked
coupon
Recovery factor to be applied to
Clean collection Lab shaker
vessel • Acceptance limit, or
 > 90% excellent with no recovery factor • Actual result
 > 70 - 90% is good with recovery factor
 > 50 - 70% may be okay with recovery factor
 < 50% is questionable
 If recovery > 100%, default to 100%
63
Acceptance Criteria (CQA)

Visually clean, depends on:
 Lighting
 Viewing angle
 Viewing distance
 Contrast of residue and surface
 Inspector’s eyesight
Dry or wet surface ?
Bioburden limit: Endotoxin limit:

Rinse sampling:  Typically measured in the final rinse
 WFI: 10CFU/100mL  Rinse sampling: 0.25 EU/mL
 PW : 100CFU/1mL
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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
NOAEL  Weight Adjustment
PDE (mg/day)
F1F2F3F 4 F5
65
Cleaning program strategy for acceptance criteria setting

Visually clean
+
Cleaning strategy Lowest MACO
Worst case active residue

=
Lowest MACO
Active residue proprietary

Therapeutic Portfolio
Toxicological
management Health
daily dose based based
Minimum therapeutic Minimum dose with kill Minimum dose with
dose that give a of 50% population toxicological and
pharmacological effect  (LD50) pharmacokinetic
1/1000th  NOAEL limit (NOAEL)  PDE/ADE
limit
MACO= TDD*MBS MACO= NOAEL *MBS MACO= PDE *MBS
TDDN * SF TDDN*SF TDDN
1/1000th LD50* BW NOAEL * BW
SF F1*F2*F3*F4*F5
Setting acceptance criteria (MACO)
Identify active residue

Extrinsic source of active residues:
Active and/or cleaner residue, material degradation, leachable/extractible
Intrinsic source of active residues:
Connecting Pharmaceutical ispe.org
Knowledge
Product intrinsic impurity
66
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Case Study: Application of PDE Limit
• Cleaning of Product A in a vessel

• Next product manufactured (Product B) in
the same vessel are as follows:
- Batch size: 50kg (50L)
- Surface area of vessel: 500,000 cm2
- Maximum daily dose : 5 mL (Liquid injectable)
67
Health-based PDE value for Product A is 5mg/day

Maximum Allowable Carryover, MAC (µg) =
PDE: (mg/day)
MBS: Minimum batch size of next product
manufactured in same equipment
TDDN: Maximum daily dose of next product
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, µ ,
Maximum Allowable Carryover, MAC (µg) =
MAC (µg) = 50,000,000 µg
Limit / Surface Area (µg/cm2) = MAC (µg) / Total Surface Area (cm2)
= 50,000,000 µg / 500,000 cm2
= 100 µg/cm2
Limit / swab (µg Product A): = Limit / surface area (µg/cm2) X Area
Swabbed (cm2)
= 100 µg/cm2 x 25 cm2
= 2,500 µg
69

Each swab is desorbed in 25mL of WFI
Limit per swab (ppb Product A)
= [Limit per swab (µg Product A) / 25mL] x 1000mL
= [2,500 µg / 25 mL] x 1000mL
= 100,000 ppb
= 100 ppm
TOC method
Limit per swab (ppb TOC) = Limit per swab (ppb Product A) x 0.1
[Carbon content is 10%]
= 100 ppm x 0.1
= 10 ppm
The TOC swab limit based on swab area of 25 cm2 is 10 ppm.
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Process Capability and Limits

Q6. How can limits for cleaning purposes be established?
A: Although the EMA guideline (EMA/CHMP/CVMP/SWP/169430/2012)
may be used to justify cleaning limits (as per Introduction paragraph 3),
it is not intended to be used to set cleaning limits at the level of the
calculated HBEL.
The STV should be used with the process capability of the

cleaning process to establish the alert and action levels:
STV “A”
Residue Level
Action Limit
Process Capability (Cpk)
Process Control Limit
Individual Data Points
71
Scale-up of cleaning process and

considerations for equipment train
72
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Scale up and Fine Tune

• Choose one worst case tank / equipment
• Worst case is based on
– Distance of CIP skids from tank /
equipment
– Complexity of CIP circuits (no. of
turns, etc) or equipment
• Use actual soil/placebo/mock soil (with
justification)
• Dirty Hold Time
• Rinse and Swab sampling
• Critical Quality Attributes
– Visual Inspection
– Analytical residue limits (HPLC, TOC,
etc.)
– Microbial (Bioburden/Endotoxin)
– Conductivity/pH
• Verify if acceptance criteria are met
• Optimize the cleaning parameters
73
Cleaning Cycle Development – Parts Washer
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Equipment / Product Grouping

Equipment Product
Grouping Grouping
Same Similar product

equipment type type
Same cleaning Same

procedure equipment train
Identical
equipment of Same cleaning
same sizes / procedure
different sizes
75
Strategy Approach - Example

Equipments
Cleaning SOP 1
Equipments group Cleaning SOP 2
Cleaning SOP 3
Product 1
Equipments group
Product 2
Cleaning SOP 1
Product 3
Determine MACO Determine worst case

worst case product to clean
3 runs?
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Equipment Train
• Maximum Allowable Carryover (MAC)

• Sum of all residues on each piece of shared equipment
• Apportion the total MAC to various pieces of shared
equipment
Example:
• Vessels A and B have surface acceptance limit of
8µg/cm2, it can be split into 3µg/cm2 for vessel A,
and 5µg/cm2 for vessel B
77
Equipment Shared Surfaces

• Shared surface area between 2 products is key
– The larger the surface area, the lower the limit
• Product A to product B
– Made on same equipment
– Product contact shared surface area
– Made on some common equipment
– Use the relevant product contact surface area
Product Equipment W Equipment X Equipment Y Equipment Z

A √ √ √
B √ √ √
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Strategies to Overcome Cleaning

Challenges
79
Common Cleaning Challenges for Pharmaceutical

and Biopharmaceutical Facilities
Air Liquid Derouging &

Slip Agents
Interface Passivation
Microbial
Micro-Pitting
Contamination
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Cleaning Challenge #1
SLIP AGENTS
81
Slip Agents
Raw material impurities
• Hydrocarbons (Steramide, Erucamide, Oleamide)
– Mold release agents used in processing of bags & and
equipment
– Prevents caking of powders
– Found on bags used for storage and transport
• Polymers (Teflon, Nylon, PTFE, Silicone, etc.)
– Equipment used in raw material manufacturing
– Bags or containers used for raw material storage
– Impurities from source material
• Mineral Silicates (Silica, Talc, Kaolin)
• Lubricants
• Valves, gaskets and tubing – (source for siloxanes)
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Erucamide, stearamide, and oleamide

• 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
• Stable molecules
– In highly acidic or basic conditions, terminal amide group can deamidate to
form the parent fatty acid. The conversion of the fatty acid does not change
the solubility in water.
– rest of molecule is aliphatic and remains intact under these conditions, with
no production of smaller soluble fragments.
• Buffers used are aqueous and don’t solubilize these slip

agents
83
Case Study – Slip Agents
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AIR LIQUID INTERFACE (ALI)
85
Case Study – Air Liquid Interface
Air Liquid
Interface (ALI) Air
Product
Cleaning air-liquid interface

-Increase temperature of cleaning (70-80oC)
-Increase cleaning agent concentration (3-5% v/v) –
e.g CIP100
-Use of an oxidizing agent to improve cleaning
(e.g Proklenz Booster)
-Increase impingement by rotating spray devices
focused on the air-liquid interface
-Increase the time of the initial pre-rinse
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Biotech – Air Liquid Interface
87
Biotech – Air Liquid Interface

MAB MFG using attached mammalian cells in MA, USA
Soil Cleaner Conc. Method Temp Time
Media CIP 100 1% v/v AI 60 C 15 min.
Cytopore 2 CIP 100 1% v/v AI 80 C 15 min.
Cell Culture CIP 100 1% v/v AI 60 C 30 min
A/L Residue CIP 100 4% v/v SW 80 C 1-4 hrs*
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DEROUGING & PASSIVATION
89
Types of Rouge
• Type 1
– Oxidized metal particles generated from external
sources by erosion or corrosion
– Easier to remove, can often be wiped off
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Types of Rouge
• Type 2
– Rouge formed from in situ oxidation of stainless
steel
– Tightly adhered, could have underlying damage.
91
Types of Rouge
• Type 3
– Black oxide rouge generated from high
temperature or steam
– Non-reactive, behaves like a passive layer
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Causes of Rouge
 Inappropriate MOC. 316L is the best option

Surface finishing / Damaged surface
 Corrosive contaminant / environment:
Chloride , Sulfide
 Steam
High temperature
 Residue
 Inadequate cleaning procedure:
Remove effeciently residues
Optimal frequency of sanitization
 Lack of periodic Maintenance
93
Conventional Method
Derouging Cycle Conventional Method of

Derouging
Pre-Cleaning Using NaoH – 60min
Rinse 2 Rinse x 30min – 60min
Derouge Using Nitric Acid – 120min
Rinse 2 Rinse x 30min – 60min
Passivate Using Citric Acid – 60min
Final Rinse 3 Rinse x 30min – 90min
Total 450 min (7.5 hour)
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Importance of Pre-Cleaning
Organic
Residue
Organic residues covering the
Stainless Steel rouge. Derouging will be ineffective
Formulated Alkaline Detergent

Step The use of a formulated alkaline
#1 to remove the organic soil to
Stainless Steel uncover the rouge
The use of an alkaline to

Stainless Steel remove the organic soil to
uncover the rouge
Step Formuated Acidic Detergent The use of an acidic cleaner to

#2 remove rouge and passivate at
Stainless Steel the same time
The shiny surface of SS restored

Passivated Stainless Steel and passivated
95
New Trending Method

Conventional Method of STERIS Method of
Derouging Cycle
Derouging Derouging
Using Formulated Alkaline

Pre-Cleaning Using NaoH – 60min
Detergent CIP100 – 30min
Rinse 2 Rinse x 30min – 60min 2 Rinse x 30min – 60min
Using Formulated Acidic

Derouge Using Nitric Acid – 120min Detergent CIP200 to derouge
and passivate – 60min
Rinse 2 Rinse x 30min – 60min Not needed
Passivate Using Citric Acid – 60min Not needed
Final Rinse 3 Rinse x 30min – 90min 2 Rinse x 30min – 60min
Total 450 min (7.5 hour) 210min (3.5hr)

*system that has average rouge in system
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Case Study # 1
Rouge Remediation :
•15 – 20% Acidic based
detergent CIP200 at 70°C
for 3 – 4 hours.
Preventive Maintenance
•Now performed annually
•5 – 10% Acidic based
detergent CIP200 at 70°C
for 1 hour.
97
Case Study # 2
– Multi-Effect Water Still Generator
ProKlenz Two CIP 200
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Case Study # 3
Cleaning process: 5% Alkaline Cleaner CIP100@ 60°C for 2 hours

Derouging process: 25% Acid Cleaner CI200 re-circulating in the
process vessels and piping circuits @ 70-80°C for 9.5 hours.
99
Case Study
#4 -
Mannual
Derouging
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Case Study # 5 - Before
101
Case Study # 5 - After
Descaling 5% Acidic Detergent CIP200 (Formulated)

@60DegC, 1 hour
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Case Study # 6
103
Corrosion in Buffer Tanks
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Chlorides
• 300 Series Stainless Steel alloys are prone to
corrosion in the presence of chlorides
• Pitting corrosion is an electrochemical
oxidation-reduction process, which occurs in
the absence of the passive layer
105
105
Micro-Pitting
• Pitting corrosion is the localized corrosion of a
metal surface confined to a point or small
area.
• Pitting is one of the most damaging forms of
corrosion.
Connecting Pharmaceutical Knowledge 106

ispe.org
106
53
7/16/2020
Micro-Pitting

ispe.org
107
Passivation
Over time, chromium oxide layer will
Chromium react with air to form deplete and stainless steel is prone to
chromium oxide – a passive protective attack by chemicals and corrosive
layer product, causing rouge
CrO CrO CrO CrO CrO

1 CrO Fe C 2 CrO Fe C
Stainless Steel is made from different
components includiung iron, carbon,
chromium
Passive Protective Layer Chromium

Oxide restored
Acidic Detergent
O2 CrO O2 O2 CrO
CrO CrO CrO
Cr
3 Cr
CrO Fe C Cr
CrO Fe C
Exposing stainless steel to CIP200
4 acidic detergent helps to remove the
rouge and bring the chromium to the
surface, reacting with oxygen to form
chromium oxide, the protective later
again
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Koslow Test Kit – Field tool
Millivolts Indication (Light Color)

+1000 to -199 High Non-Passive Range (RED)
-200 to -400 Passive Range (GREEN)
-401 to -1000 Low Non-Passive Range (RED)

ispe.org
109
Case Study # 6 – Media Prep Tank
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Connecting Pharmaceutical Knowledge 111 ispe.org
111
Microbial Contamination Control
– Biofilm
112
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Biofilm Definition
 Biofilm is generally composed of multiple microorganism
encased in matrix extracellular polymetric susbstance
(EPS):
Conceptual drawing: Biofilm generation
 EPS increase the Microorganism resistance and ability

to survive in rude environment
113
BIOFILM GENERATION
Source: Montana State University Center for Biofilm Engineering
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Factors influencing biofilm

generation
115
Revolutionary Breakthrough : Biofilm Removal

ProKlenz One
• Biofilm removal label claim in US
• Biofilm removal at a 5% concentration on a pre-
cleaned, non-porous, nonfood contact surface at
60°C for a contact time of 10 minutes
• This performance claim demonstrates the efficacy of
ProKlenz ONE as both a cleaner and disinfectant
• “To prevent the formation of biofilms, sterilization

or disinfection or regeneration of water systems
should be carried out according to a
predetermined schedule and also when
microbial counts exceed action and alert limits.”
Annex 1 Draft
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Biofilm Remediation
I. Biofilm remediation will always use a combine strategy:
1. Use of alkaline cleaning chemistry to penetrate/denature EPS
 5% CIP100 at 60°C for 3 hours
2. Derouging & passivation, if required
 Acid cleaning and passivation using 15% acidic cleaner at 80 °C for 5
hours – CIP 200
3. Use of the sporicidal chemistry to sanitize the system
 Sanitization using sporicidal agent at 25 °C for 30 minutes, or
 Steam in place
II. Prevention of biofilm generation is a cycle process

 Engineering Design
 Optimal cleaning/sanitization frequency and procedure (TACT parameter)
 Optimal disinfection/sterilization frequency and procedure (TACT parameter)
 Appropriate cleaning detergent
 Routine trend analysis is also important
117
Robust Cleaning Process
• Physical-chemical proprieties • Periodic stainless-steel
• Cleaning methods/parameters maintenance

• Rouge remediation and preventive
• Residue profile
and carryover measures
• Product category
• Slip agent
• Air Liquid Interface • Engineering design (sanitary)
• Trending
• Effective cleaning and
sanitization process
•
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Equipment Cleaning Process

Development – Where and How to
Start ?
Richard Chai
Technical Service
Manager
STERIS Corporation
Richard_chai@steris.com
16 Oct 2018
Thank you !
119
60

FT - SM - ISPEIndonesiaAug2020 - 20200818 (Day 1)

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7/16/2020

Equipment Cleaning Process

• Lifecycle approach to Cleaning

Connecting Pharmaceutical Knowledge ispe.org

What is Cleaning Process

Soil Successful cleaning

Connecting Pharmaceutical Knowledge ispe.org

Connecting Pharmaceutical Knowledge ispe.org

• EU Guidelines for Good Manufacturing Practice

Connecting Pharmaceutical Knowledge ispe.org

Connecting Pharmaceutical Knowledge ispe.org

PIC/S PE 009-14 Part I (2018)

Connecting Pharmaceutical Knowledge ispe.org

Connecting Pharmaceutical Knowledge ispe.org

You are a contract manufacturer who makes several

Connecting Pharmaceutical Knowledge ispe.org

Lifecycle Approach to Cleaning Validation

Connecting Pharmaceutical Knowledge ispe.org

Lifecycle Approach to Cleaning

• Process defined through development & scale‐up activities

• Process designed evaluation on reproducibility

• Critical variables monitored

Connecting Pharmaceutical Knowledge ispe.org

Lifecycle Model – Stage 1

Cleaning Critical Cleaning Residue

Connecting Pharmaceutical Knowledge ispe.org

Lifecycle Model – Stage 1

Connecting Pharmaceutical Knowledge ispe.org

Designing a Cleaning Process –

• Need to know and understand:

Process flow Process Process soils Components

Connecting Pharmaceutical Knowledge ispe.org

Connecting Pharmaceutical Knowledge ispe.org

Typical CIP Cycle Function

Pre-rinse  Removal of soluble and gross

 Removal of the suspended or

 Facilitate draining on low-

Connecting Pharmaceutical Knowledge ispe.org

Equipment Surface & Design

• Dead Leg in piping and process connections

Good Turbulence Intermediat No Turbulence

Connecting Pharmaceutical Knowledge ispe.org

Equipment Surface & Design

Connecting Pharmaceutical Knowledge ispe.org

Cleaning Design Space

Connecting Pharmaceutical Knowledge ispe.org

Design Space (ICH Q8 R2)

Connecting Pharmaceutical Knowledge ispe.org

Key inputs and data are Consideration must be given to

- Product knowledge - Soil type

Connecting Pharmaceutical Knowledge ispe.org

Critical Process Parameters Critical Quality Attributes (CQA’s)

- Temperature - Visual Inspection

Connecting Pharmaceutical Knowledge ispe.org

Cleaning Design Space

• Pre-requisite for Equipment &

Connecting Pharmaceutical Knowledge ispe.org

Connecting Pharmaceutical Knowledge ispe.org

Connecting Pharmaceutical Knowledge ispe.org

Connecting Pharmaceutical Knowledge ispe.org

Residues and Soils

~55% protein, 35% minerals, 6% fat~17% protein, 75% minerals, 6% fat