PP - Steris

Nordic ISPE
20 Apr 2016
Presented by:
Beth Kroeger
Technical Services Manager
STERIS Corporation
beth_kroeger@steris.com
1/
Agenda
• Lab Studies for Cycle Development

• Residue Selection
• Equipment considerations and design issues
Copyright © 2014 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation 2/
Why Cleaning process is
important
• Inspectional focus:
– “Typical” Regulatory Observations
“You have not established an

“There is not sufficient
adequate rationale, including
documentation to determine
determining whether this
the effectiveness of your
product is the most difficult
cleaning agent used”.
product to clean”.
“For example, your firm does

not have data to demonstrate
your cleaning processes for
non-dedicated manufacturing
equipment and utensils are
adequate”.
Is this clean??
Cycle Development:
Where to start?
• Need to know and understand:
– Process flow
– Equipment
– Process soils
– Components of cleaning
Cycle Development:
Where to start?
• Meet with your team or “Customer”
– Discuss process residue details
• Aqueous, oil based, suspension, solids, powders, etc
– Equipment surface MOC
– Available cleaning methodology options
– Process temperature and process details
– Decontamination step?
– Dirty hold time
– Restrictions?
• Schedules, waste, limitations
Parameters and attributes
of cleaning processes
• Critical Performance Parameters (CPPs)
– Process times (includes Dirty-hold)
– Turbulence or flow
– Cleaning agent concentration
– Temperature
• Critical Quality Attributes
– Visual Inspection
– Analytical residue limits (HPLC or TOC)
– Microbial (Bioburden/Endotoxin)
– Conductivity/pH
Cleaning parameters
(CPPs)
• Why parameters important?
– Defining cleaning system
– Modeling lab study
– Selecting worst case
Lab-Scale cleaning study
• Optimize cleaning parameters using
beaker/coupon study
– Soiling is expensive large scale
– May not be feasible due to availability of
equipment
– Quantitative measurement of residue removal
easier at small scale
– Matrix approach: Run multiple conditions at the
same time.
Why Perform a Lab-Scale Study
Run Cleaner Temperature Concentration 15 min
30 min
1 Cleaner A Ambient 1% v/v
45 min
2 Cleaner B Ambient 1% v/v
60 min
3 Cleaner C Ambient 1% v/v
4 Cleaner A Ambient 5% v/v
5 Cleaner B Ambient 5% v/v
6 Cleaner C Ambient 5% v/v
7 Cleaner A 45°C 1% v/v
8 Cleaner B 45°C 1% v/v
9 Cleaner C 45°C 1% v/v

Perform a Lab-Scale
cleaning study
• Parameters: TACT
• Criteria
– Visually clean
– Water Break-free
– Gravimetric Assessment
• Acceptance criteria: ± 0.0001 grams
– Scale accuracy ± 0.00005 grams
• Coupon blank weight, amount of residue spiked on
coupons.
• Amount of residue remaining after cleaning assessment
Perform a Lab-Scale cleaning
study
• Water break test method
– ASTM: A380: Standard
Practice for Cleaning,
Descaling and Passivation…
– Test for the presence of
hydrophobic contaminants on
a cleaned surface.
• Contaminated area has lower
surface tension than water
causing water to bead up at that
location
• Only for items that can be dipped
• Test is rapid and non-destructive
Where to start:
Cleaning Agent Selection
Alkaline Cleaners Acidic Cleaners

• Organic acids • Particulates
• Tableting excipients • Alkaline Salts:
• Proteins/Fermentation Bicarbonates,
residues carbonates
• Oils/Waxes/Fats • Metal Oxides
• Grease • Hard water scale
• Polysaccharides
Coupon Preparation
• Multiple MOC and surface finish designations
can be evaluated.
• Prep residue in manner that is representative
of expected worse case conditions in
manufacturing
– Amount of residue to apply
– Exposure to heat
– DHT
Performing a Lab-Scale Cleaning
Study
• Use 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 Temperature
1% 60 15
1% 80 15
Concentration
2% 60 15
2% 80 15
1% 60 30
1% 80 30
Performing a Lab-Scale
Cleaning Study
• Agitated immersion
– Evaluates the “chemistry” of the
cleaning conditions under low
agitation conditions
– Used to evaluate impact of the
cleaning solution, concentration
and temperature on the rate of
cleaning.
– Outcome is the optimal
conditions for removing residue
Acceptance Criteria
Soiled Coupon Visual Failure Water Break Free

Failure
Advantages of Lab-Scale
Cleaning Study
Fails TOC/HPLC Passes Acceptance Criteria
Copyright © 2014 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation 18 18/
Cleaning Study
• Residue build-up over time
Cleaning Study
Same coupon,
Same coupon, different angle.
different angle.
Residue visible
Residue visible on both angles,
in first angle, not 15 coating and
in second. cleaning cycles.
Cleaning Study
Same coupon,
different angle. Same coupon,
different angle.
Both coupons wet
Both coupons dry
Agenda

Residue Selection
• 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
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
Residue Properties as Basis
for Cleaning
• Example: Antibiotic suspension containing API
– Original cleaning method: Water, PW, dry
• No documented cleaning validation for many years
• API and unknown peaks on original cleaning validation
attempts
• API insoluble
– Second method: Alkaline detergent, water, PW, dry
• Unknown peaks again
• API insoluble
– Final method: Acid detergent, Alkaline detergent,
water, PW, dry
• No residues or unknown peaks detected
• Unknown peaks determined to be flavors
• API dissolves
pH solubility profile, pH 1 – 12
Note of caution…..
Determination of most
difficult to clean
• Basis for cleaning program:
– Water Solubility – USP Tables
• Is it adequate: NO
– Understand the effect of pH and solubility in
cleaning agent
– Determine solubility at range pH 1-12

– Understand solubility at pH of cleaning detergent
Agenda

Equipment Surface and Design
• What the regs say:
– § 211.63: Appropriate design, easy to
clean
– § 211.65: Surfaces not reactive, additive
or absorptive
• No defects
• Smooth surface
– § 211.67: cleaned to prevent
malfunctions or contaminations
• No corrosion
• Standards and guidelines
– ASME BPE (Bioprocessing Equipment)
• Discusses equipment design
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
Spray Devices
• Spray balls may provide adequate coverage
but not uniform impingement at all locations
– Use agitated immersion, cascading flow and
impingement
– Static spray balls rely high volume, low flow
cascading cleaning action
Spray Devices
• Operating parameters
– Pressure: 3 – 8 bar dynamic
– Flowrate: ASME® BPE standard targets:
• Static spray device flow:
– 31 Liter per minute/meter of circumference
(lpm/m) (2.5 gpm/ft of circumference)
– Results in turbulent sheeting action for tanks with
180°up spray ball
• Lower flow rate may be used when static or dynamic
spray devices are used with 360° spray pattern
• Rotary spray device flow:
– 26 lpm/meter of circumference (2.1 gpm/ft)
Spray Devices
lpm lpm
Calculated CIP flowrate (gpm) = π*d*desired flowrate per ft of circumference
Spray Device Selection
• Spray Device Selection
– Static balls vs. dynamic devices
• Impingement , time, drainability, reliability, maintenance, cost
– Throw length:
• Pressure, flow rate, effective diameter
– Potential for clogging
– Potential for re-deposition
Equipment Surface and Design
• Circuits and transfer panels

– Multiple paths
• Rotate for short periods multiple
times?
• Each path once for longer duration?
• Consider lab study results and how
impacted
– Consider what is transferred
and added if using induction
ports
• Separate coupon study for raw
materials vs. blend?
CIP Pipe Design Criteria
• Piping sloped to drain points with proper

support to maintain alignment
• Number and length of dead legs minimized
• Dead legs oriented to be easily cleanable
• Welded joints for permanent pipes
• Sanitary joints for semi-permanent
connections
• Flush self positioning gaskets
Equipment Surface & Design
• Go to the manufacturing area and look at the

equipment, not just the P&ID…..
– Look for possible problems areas BEFORE you
start.
• Corners, crevices, deadlegs, valves, seals,
• Sample locations
– Consider where can contamination occur?
– Where can problems be fixed by re-engineering?
– What portions of the process can be cleaned in
place?
– Do sections need to be removed for cleaning?
COP or use of jumpers/manifolds?
Cleaning and Cleaning Validation, Volume 1, by Paul Pluta; Chapter 8, “Cleaning Engineering and Equipment Design” by
George Verghese and Paul Lopolito; PDA, Davis healthcare International Publishing, LLC ©2010
Thank you for your attention
Nordic ISPE
20 Apr 2016
Presented by:
Beth Kroeger
Technical Services Manager
STERIS Corporation
beth_kroeger@steris.com
38/

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Nordic ISPE

• Lab Studies for Cycle Development

“You have not established an

“For example, your firm does

4 Cleaner A Ambient 5% v/v

5 Cleaner B Ambient 5% v/v

6 Cleaner C Ambient 5% v/v

7 Cleaner A 45°C 1% v/v

8 Cleaner B 45°C 1% v/v

9 Cleaner C 45°C 1% v/v

10 Cleaner A 45°C 5% v/v

11 Cleaner B 45°C 5% v/v

12 Cleaner C 45°C 5% v/v

13 Cleaner A 60°C 1% v/v

14 Cleaner B 60°C 1% v/v

15 Cleaner C 60°C 1% v/v

16 Cleaner A 60°C 5% v/v

Alkaline Cleaners Acidic Cleaners

Concentration Temperature °C Time Temperature

Soiled Coupon Visual Failure Water Break Free

Fails TOC/HPLC Passes Acceptance Criteria

• Lab Studies for Cycle Development

• Potential Residues for consideration:

– Determine solubility at range pH 1-12

• Lab Studies for Cycle Development

Calculated CIP flowrate (gpm) = π*d*desired flowrate per ft of circumference

• Circuits and transfer panels

• Piping sloped to drain points with proper

• Go to the manufacturing area and look at the

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Calculated CIP flowrate (gpm) = πddesired flowrate per ft of circumference