Cleaning Process

Development
Tulus Tritjamono
Ass. Director
PT. INFION
20 Aug 2015
 Cleaning Validation
Cleaning validation lifecycle
Residue
Identification

Equipment Design &

Change Management
Process Attribute

Product Grouping/ Monitoring, Product review &

Equipment Grouping Revalidation

Cleaning process Protocol development,

Characterization - Excecution & Report
Cycle Development

Limit Determination Cleaning Assessment

Sampling Techniques
Test Methods &
Recovery Studies
 Cleaning
Process Development
Equipment Design
Equipment Characterization
Classification of Product
Cleaning Agent Selection
Cleaning process development
Sampling method
Cleaning process
 Equipment Design
Adequate (GMP) design/structural complexity and
configuration
Material and Surface
Non-Reactive and cleanability
Compatibility with detergents
Cleanability must be a key criterion in the selection and
design of the equipment.
Any surfaces that which have porous properties will require that
during cleaning validation the adequate product removal is ensured to
minimize the potential of cross-contamination.
Interior corners are preferably curved
Process piping and components must be sloped to drain as to not
allow for pooling of material.
 Pipework design

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Pipework design
Pipework Design
Equipment Design (1)
Equipment Design (2)

The transfer pipe can be

dismantled from the main
equipment to facilitate the cleaning
process
 Difficult to clean areas

For Example :
Trays, especially the underside of the
trays
Shelf hoses, especially older braided
hoses
Shelf hose manifold connections
Instrument and relief valve connections
Probe connections and lead throughs
Bellows
Shelf stack mechanisms
Threads
Static gaskets
Condenser coil clamps
View ports

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 Critical Area

Dead Leg difficult to clean

Complexity and delicacy of equipment
 Critical Area
Difficult to
clean area are
washing
manually
Dismounting
Filter before
rinsing
 Critical Area

After pre-wash:
Inspect visually on
critical point
Continue with Jet
Spray Washing
Critical Area FBD
 Difficult areas to clean
Structural Complexity: Pipework design in CIP
Instrument Tee for CIP: L/D < 1.5

Adequate Turbulence (flow rate) for CIP

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 Difficult areas to clean

Branch Piping Orientation

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 Mixing Tank
SPRAY BALL

AGITATOR
Spray ball
Critical Area
 Silicone Tubing
Chemical Resistance properties
Chemical absorption/ adsorption
Recommended operating temperature
Withstands Repeated CIP and SIP.
Complies with Regulatory Guidelines (USP
class VI) non-toxic, non-hemolytic and non-
pyrogenic
Silicone Tubing
Silicone tubing conection
 Equipment influences on cleaning
Equipment Type Major, Minor,
Dedicated, Non-Dedicated
Role in the Process Upstream,
Downstream
Materials of Construction
Surface Finish
Geometry / Complexity

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 Equipment Considerations

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 Equipment Considerations

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 Equipment Considerations

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 Equipment Considerations

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 Equipment Design Survey

Survey the equipment

Identify weaknesses in the design
Identify risks associated with the weaknesses
Mitigate as possible

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 Example Design Risk Assessment Parameters
Characteristic High Rating Low Rating Possible Mitigations /Actions for High Ratings
Positive Slope /Free Non-free draining Free draining Reengineering
Draining
Forced flow and forced drying
Non-additive /Non- MOC not appropriate for MOC appropriate Reengineering
reactive /Non-absorptive easy cleaning
Materials Of Special considerations for cleaning action /
Construction (MOC) chemistry

Enhanced inspection /testing to confirm cleanliness

Smooth, polished Finish was not designed to Finish is smooth, Refinishing surfaces
finishes be smooth or finish has polished and intact
significant damage Enhanced cleaning action / chemistry

Enhanced inspection / testing to confirm cleanliness

Coved Corners Not coved and critical Coved or non-critical Tool selection for cleaning
product contact surface
Special instructions during cleaning
Joints Not sealed or sealant Sealed with the correct Replace sealant
inappropriate to rigors of material or not critical
cleaning to product /cleaning Use different chemistry or tool for that location
contact
More frequent PM and replacement
Dead leg survey Dead legs are present or No dead legs or poor Reengineering
orientations that would orientations
hold up product and fluids Disassembly for cleaning or disassembly after CIP
for inspection and additional off-line cleaning

29
 Results of Design Assessment

Product Risk

Equipment Design Risk

High Low
High Reengineering to Reengineering is still
mitigate is your best best, but procedural
course of action improvements may
suffice

Low Equipment is not likely to No Action Necessary

be a problem, but take
care in your cleaning
program design

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 Equipment Characterization Process
Initiate the Assessment
Identify product contact materials of construction for
processing equipment and their locations
Use drawings, vendor certifications, on-site inspections
Identify the approximate percentage of surface area
each contact material comprises (can approximate)
Calculate the product contact surface area for the total
piece of equipment
List the cleaning SOPs and cleaning agents in use for
the equipment
Discuss with your operations personnel to establish
hard to clean locations
 Equipment Characterization Process
Assessment cont
Repeat the review for any potential equivalent equipment
Review for equivalency should include:
Make / Model / Geometry / Features
Scale / Size / Capacity
Materials of Construction / Surface Finish
Installation and Operational Qualification Equivalence
Same Position / Role in the Process
Equivalency will also be determined based on:
Cleaned with same procedure
Cleaned with identical cleaning agent
Overlap in products produced on those pieces
Grouping / bracketing equipment can then be used to
determine the number of cleaning validation trials and how
they are organized

Asia Pacific Consultants Cleaning Validation November 2012 Session 2 Slide 32

 Equipment Characterization Process
Identify sampling locations and sampling techniques
Sampling locations should be selected based on:
Hard to clean locations or complex geometries identified hot
spots
Locations that might disproportionately contribute residue to
the next process (e.g., filling needles, discharge valves, punch
and dies, chromatography skid fraction collection valves and
piping, etc.) identified critical sites
Materials of construction or surface finishes with an affinity for
the residue
Role in process that is likely to lead to build-up or difficult to
clean residue
Number of sampling locations should be based on:
Number of locations that fit the descriptions above
Overall size of the equipment
 Equipment Characterization Process
Documenting Sampling Site Selection
Documenting decisions aids in ensuring that sampling
sites are effectively rationalized and eliminates some of
the subjectivity
Rankings can be scaled as H, M, L or given a number scale
Methods for identifying sampling locations include:
Holding discussions with operators to identify difficult to
clean locations
Witnessing cleaning procedures to identify problem areas
Conducting screening studies (e.g. Riboflavin testing)
Sampling Critical Site Hot Spot Affinity to MOC or Role in Process Likely Ranking
Location surface finish to Lead to Residue
 Equipment Grouping
Equipment that is similar in design and
function may be appropriately grouped
The cleaning method may be validated on the
largest and smallest scale equipment i.e. bins
or holding tanks.
Key to grouping:
The equipment should have the same cleaning
procedure.

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 Equipment Grouping
Granulation Equipment, Bin Container
Sieving & Mill equipment
Bag Filter
Coating Machine & Accessories
Tablet Press Punches & Dies
Parts of Primary Packaging Machine
Liquid Filling
Mixing: Semi solid, Liquid oral/ injectie

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 Equipment Grouping
Granulation Equipment, Bin Container
Sieving & Mill equipment
Bag Filter
Coating Machine & Accessories
Tablet Press Punches & Dies
Parts of Primary Packaging Machine
Characteristics of the Products
 Characteristics of the Products
Understand Chemical Characteristics of the
Product(s)
Product matrix
Type of active molecule
Excipients/Process related components
Product matrix is a critical element for:
Cleaning process design
For the determination of detergent type
 Characteristics of the Products
Physicochemical characteristics
Solubility with medium (e.g., water, organic
solvent)
Reactivity is a critical element for the
determination of process parameters
Degree of a reaction with a detergent or medium at
different conditions.
Degradants
Chemical state :Liquid, Semi-solid, Solid
 Characteristics of the Products
Toxicity/Pharmacological potency
Critical for acceptance criteria
Potent products and/ or component
degradants after reaction with a detergent
Critical for acceptance criteria
 Characteristics of the Products
Anti-acid group
Al Hydroxide and Mg Hydroxide
Magaldrate, Sucralfat
Product that contain ethocel/ methocel and
eudragite as excepient.
Product that contain certolake coloring
agent
Corticosteroid
Regular group
Cleaning Agent Selection
Detergents embedded in System
Focus on Detergents
 The main factors in cleaning

Consider time for cleaning

vs. multiple use of Action
Spray pressure
equipment (CIP,Washer)

Economical impact,
increase productivity
Time
Detergents
3 10 min
Alkaline
Acid
Temperature Neutral
(60oC 80 oC) Enzymatic
 Cleaning Task - Type of Residue?
Using water alone is O.K. if it works e.g.
parenteral
No need to prove absence of detergents
Depending on the type of residue, water alone is
not effective enough e.g. oily residue
Severe drawbacks by using organic solvents
(health and safety at work, solubility, disposal
etc.)
Limited spectrum of activity for commodities
such as NaOH, KOH or H3PO4 e.g. residue at
biotech production
 Type of Contamination ?
In > 80% of all cases the residue is of organic
nature An alkaline process will work best
Mineral salts, acid soluble residue etc. require
an acidic cleaning process
A neutral cleaning process can be considered e.g.
in case of very sensitive materials (anodized
aluminum used for formatting parts)
Enzymatic cleaning Not seen very often in
practice
Type of Substrate? Compatibility
 Classification of Detergents
Most common detergents
Alkaline Detergents
Acid Detergents/Neutralizer
Neutral Detergents
Additives booster
Surfactant Additives
Oxidizers
Special Products
Enzymatic Detergents
Corrosion inhibitors e.g. for reprocessing of tablet
tooling
 Cleaning Agent Selection
Selection of a Cleaning Agent
Depending on the particular type of the chemicals
(soils) which should be removed, considering:
Chemical/Physical nature of the molecule (soil) which
should be removed
Reactivity,
Physicochemical characteristics of the molecule,
Chemical state of the soil : Solid or Liquid
 Cleaning Agent Selection
Application parameters for the cleaning
agents
Type of the cleaning agent
Depending on the type of the soils which should be
removed.
Concentration
Effectiveness
EH&S consideration
Temperature
Contact time
 Cleaning Agent Selection
Alkaline detergents Acidic detergents

Alcohols Amines, alkaloids

Aminoacids Aldehydes, Amilines
Diols, triols Carbonates & Bicarbs
N-heterocyclics Ethers, Ketones
Organic acids N-heterocyclics
Acid salts Insoluble hydroxides
Phosphates Metal Oxides/ hydroxides
Polysaccharides Pyridines
Proteins, fermentation Pyrolidines
Oils, fats, greases
Steroids
Sugar
Detergent Selection

Mild alkaline
Cleaning Process Development
 Selection of Cleaning Process
Cleaning Method
Soaking
Manual cleaning
Ultrasonic cleaning
CIP / WIP/ COP
Machine washer
 Type of Cleaning
Clean-In-Place (CIP)
Stationary equipment
Wash-In-Place (WIP)
Requires dismantling and some manual cleaning
Tablet press
Clean-Out-of-Place (COP)
Transportation to and from wash room
Cross contamination potential
Hold dirty / hold clean
CIP & COP
 Manual Cleaning
Disadvantages of Manual
Manual cleaning is done : cleaning
Fragile items : thermal Safety concern for operators
related to water temperature,
sensitive, thin glass chemicals
Hard to clean Repeatability of process
Part which cannot be Process is slower impact on
throughput especially on large
soaked in water ( Stopper volume.
bowl). How to monitor critical
parameters of cleaning
process?
Induced cost: higher
comsumption of utilities,
chemicals.
 Clean-In-Place
CIP Equipment When CIP method use?
Operator do not need to
dismantle mechanical
equipment for manual or
automated washing purpose
Saves time. No dismantling
and reassembling operations.
Convenient for large and bulky
containers / drum/ vessel.
Suitable if soils to be removed
are easy ones. i.e. not sticky/
dried types and critical areas
of parts to be processed are
easily accessible
Disadvantages of CIP method?
Some parts cannot be processed. Eg.
Guiding rails, stopper bowls, filter
housings, tool from preparation area.
Utilities consumption is much
substantial that with automated
washer ( water, chemicals)
CIP systems can be of complex design
and lead to substantial installation
costs.
No detection of potential biobarden
as CIP does not allow for visual
inspection nor access to all parts
areas.
CIP bottle filling machine
Cleaning Process Development.. 1
Selection of Cleaning Process
Automated vs. Manual
Automated CIP and/or COP
Readily validatable
Consistency and reproducibility
Better process control
Manual
Inconsistency
Hard to validate, but not Impossible
Cleaning Process Development..2
Consider:
Previous validation data if available
Historical cleaning data (trending)
Complexity and delicacy of manufacturing
equipment
Level of facility automation
Cleaning cycle development
CIP or COP design and capacity
Nature of soils
Cleaning Process Development..3
Critical parameters
Interval time between the end of equipment
use and cleaning
Temperature
Pressure
Volume
Process time
 Sequence Development..1
Pre-Wash: piping and equipment to be
cleaned by pressure washing
End point
Total volume or time
On-line turbidity, conductivity or return flow
Must be drained
Detergent washing
Acid or alkali depending on the type of soil
Continuous feed or recycle
Endpoint
Volume or time
Must be drained
 Sequence development..2
Post Wash and drains
To remove residue after pre-rinse and
detergent washing
Continuous flow and drain
Usually not heated
Neutralization wash and drain
Endpoint total volume and/or elapse time
Final rinse and drain
Endpoint total volume and/or elapse time,
pH, conductivity, TOC
 Cleaning Process Development
Parameter and range determination
Factoring experimental design (example)

pH

5.5 6.0 6.5

30 10
Temp 40 20 Conc
(%)
(C) 50 30

10 20 30
Time (min)
 Cleaning Process Development
Study approach
Coupon study
Same materials as manufacturing equipment
Equivalent surface treatment
Experimental run
Worst case approach
Residues to be cleaned
Equipment surface
Appropriate sampling and analytical methods
 Cleaning Process Development
Sampling
Direct surface sampling
Swabs
Rinse water sample
Visual inspection
Analytical Methods
Depending on the types of analytes
Type of analytical methods
Specific or non-Specific
Selection of methods based on the nature of the analytes
 Sampling Method (1)
Swab Sampling, Rinse Sampling, Placebo Sampling
Swab Sampling :
Advantages:
Can focus on worst case location
Mechanical means of removing substances
Issues:
Swabbing is a manual procedure
Inability to access some area of sampling site
Assumes uniformity of contamination surfaces
Must extrapolate sample area to whole surface
Sampling location:
Functional locations: blades, tank wall, fitting
Most difficult to clean locations: prior experience
 Swab
Swab on the critical area
Swab
 Sampling Method (2)
Rinse Sampling
Using solvent to contact all surfaces of sampled item to quantitatively
remove target residue
Solvent can be water, water with pH adjusted or organic solvent
Must contact all surfaces
Residue measured in collected sample
Advantages:
Sample inaccessible location
Provides overall picture
Use of different solution from process rinse
Issues:
Solubility of residue in rinse solution
Dilution effect
Unreliable, inconsistent recovery
 Rinse Sampling
Two Types:
Separate sampling rinse:
Done after process rinse is complete
Rinse solution may be different from process rinse
Sample of the final process rinse:
Sample is taken from final process rinse
Reputation of rinse sampling:
Bad name because of misuse assumption that if rinse water meets
compendial spec., that equipment was clean
Failure to demonstrate removal of residue by rinse solution (recovery
study)
 Standard Operating Procedure
List parts or surfaces to be cleaned.
List materials to be used for cleaning.
List any requirements for handling prior to cleaning.
Provide directions for making up the detergent
solution following the manufacturers instructions.
Provide manual cleaning instructions .
Describe drying procedure.
List any post cleaning handling procedures
Cleaning Process
Manual Cleaning with Jet Washer
WIP High Share Mixer

WIP System
 Cleaning Process High Share Mixer
Pre-Wash
Volume or time
Drain
Turbidity
Wash with
Detergent
Vol / time
Conc detergent
Manual Cleaning
and Jet Washer
Visual inspection
Rinse with
Potable Water Drying
Volume or time Temp / Time
Detergent Residue
Rinse with Flash with
Purified Water Pharma Comp Air
Vol & Time
Swab TOC
WIP HMG
WIP Fluid Bed Dryer

WIP System
 Pre-rinse Cleaning Process Fluid Bed Dryer
Volume or time
Turbidity
Filter
Dismounting

Rinse with
Detergent
Vol / time
Conc detergent

Manual Cleaning
and Jet Washer
Visual inspection
Rinse with
Potable Water
Volume or time
Detergent Residue
Rinse with
Drying
Purified Water
Temp or time
Vol & Time
SwabTOC
 Cleaning Instruction for Exhaust Air Filter
CLEANING INSTRUCTIONS for all kinds of exhaust air filters
The following important points must be observed:
1. Remove carbine hooks, tightening straps, etc. from the filter.
2. Put the filter into the washing maschine and wash it with the
washing powder shown below:
3. Washing powder for polyamide (PA) 1...2 g/l alkaline washing
powder
4. Washing powder for polyester (PES) 1...2 g/l non---alkaline washing
powder or A 1% cleaning solution with a pH value < 12,5
5. Washing temperature: max. 40 C
6. Either hang the filter up to dry or dry it in the fluid bed
machine or other mechanical dryer.
7. Drying temperature: max. 60 C
Filter Dismounting
 Cleaning Process of Bag Filter
Cleaning Process of Bag filter using washing machine and drying machine
 Cleaning Process Bag Filter
Filter
Dismounting

Put into the

Washing Machine
Vol / time
Conc detergent
Wash with the
detergent
10 menit
Rinse with
Potable Water Drying
10 menit
Detergent Residue Temp or time
Rinse with Put into the
Purified Water 10 menit Drying machine
Rinse TOC
Punches & Dies

Cleaning of Punches & Dies using

ultrasonic washer
 Punches & Dies
P&D
Dismounting

Put in
P&D Holder

Ultrasonic Bath
With Potable Water
+Detergent
P&D Storage
Vol / time
Conc detergent

Rinse with Food Grease

Potable Water Applied
Detergent residue

Rinse with
Drying
Purified Water
RinseTOC
 Bracketting
Reducing the effort cleaning validation by scientific rationale
Grouping the substances:
The same equipment train
The same cleaning procedure
Select worst case situation for each group

E CLEANING PROCEDURE
Q 1 2 3 4 Company ABC :
U
I
I A, B, C, A2, B2, Z CC, DE SU, VL
D, E, F AT, AN TV, JX
4 equipment train with 4
P
cleaning procedure & 78
M
E II G, H, I KL, AB, Z KK, CD YG, LL products
N J, K, L TL, BD RT, AN CN, ZS
By bracketting and worst case
T situation --> minimum 16
III M. N, O WS, TT CT, MK TG, Z2 products should be validated
T
P, Q, R EF, AM KT K3, HT
instead of 78 products
R
A
IV A1, B1, S QS, VC MX B5
I
N T, U, V ND, TL KD G1, KR