Session1 Kroeger Beth Pres

Best Practices for a Robust
Cleaning Validation
Beth Kroeger
Technical Services
Specialist
STERIS Life Sciences
&
Amanda Deal
Senior Technical
Services Associate
STERIS Life Sciences
1/
Agenda
• Variables impacting the cleaning process

• Risk identification
– Equipment
– Residue evaluation
– Limits
• Best Practices for a successful cleaning
validation
• Performing a bench-scale cleaning process
development
Copyright © 2014 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation 2/
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
• Why parameters important?

– Defining cleaning system
– Modeling lab study
– Selecting worst case
Cleaning Chemistry –
Process parameters
• Cleaning also depends on cleaning
conditions…
– Water Quality – Which glass is cleaner?
Cleaning Chemistry –
Process parameters
conditions…
– Individual Performing Cleaning (especially in
manual cleaning)
Manual Cleaning Process
Variation
• Variation sources
– Different persons
– Different motivation
– Different physical strength
– Day shift, 2nd shift, 3rd shift, weekend differences
– On and on…..
Cleaning Chemistry

conditions…
– Surface being cleaned
Cleaning Chemistry

conditions…
– Nature of Soil
Cleaning Chemistry
conditions…
– Nature of Soil
• Slip agents: commonly used 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
Identifying Risk in
Cleaning Validation
• Need to know and
understand:
– Process flow
– Equipment
– Process soils
– Components of cleaning
• Where to start?
Performing a risk
assessment
• Risk based Scientific
Rationale are needed for
the following:
– Equipment Grouping
– Soil Selection
– Product Grouping
– Sampling method selection
– Sampling site selection
– Limit selection & calculation
– Analytical Approach
Equipment Grouping
Criteria
• Must be same type
– Size
• Same equipment of different sizes
– Example: 50L, 100L, 300L, 500L and 1000L tanks
– Same materials of construction
– Configuration
• Equivalent geometries/design risks
• Must have same cleaning process
– Cleaning agent
– TACT
– Frequency of cleaning
Equipment Grouping
Criteria
• Must have same manufacturing
process/soil characteristics
– Role/position in process
– Campaign length/dirty hold time
• Alternatives --
– Validate separately largest /smallest sizes
– Validate together testing extremes
Types 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
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
Product Grouping Criteria
• Build soil categories

• Determine “Worse Case”
Risk Ranking Specific
Soils
Risk Level
Parameter Risk Level 1 Risk Level 2 Risk Level 3 Risk Level 4 Risk Level 5
0
Moderately Very Difficult
Product Moderately hard to clean Difficult to to clean such
Easy to clean
Difficulty to Very easy to easy to clean – Thicker clean oily as denatured
•
clean - lab clean – water
and highly
mobile in
– some products, substance, protein,
study or effective viscosity some builder or dyes,
liquid state
subjective issues insoluble excipient titanium
ingredients dioxide
>1250 mg/kg >250 mg/kg
≥ 2500 > 2500 >500 mg/kg
Toxicity – and ≤ 500 and ≤ 25
mg/kg mg/kg and ≤ and ≤ 250 ≥ 25 mg/kg
LD50 (oral rat) mg/kg mg/kg
1250 mg/kg mg/kg
Slightly
Freely Practically
Solubility - Very soluble Soluble Very Slightly
Soluble Soluble Insoluble
g/100mL of 100% in >10% but Soluble <
99.9 % in 99% in water < 0.01% in
water water <90% in 10% in water
water water
water
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 1 800-1200 1 6450 2 14
insoluble
0.050-
Chromium 4 Not specified 5 2 100-400 2 80
0.200
Iron 3 Soluble 4 10-15 2 319 4 96
Slightly
Magnesium 5 3 270-400 1 4722 2 30
soluble
Not
Potassium 3 soluble 3 1 7200 2 18
specified
Selenium 7 Insoluble 5 0.200 3 4.8 -7.0 2 210
Zinc 3 Soluble 4 10-15 1 5000 2 24
Grouping for a Contract
Manufacturing Facility
• Facility may not know next product
• Want to avoid frequent re-validation of
cleaning processes. How?
– Develop cleaning matrix for products currently
produced in facility
– Identify worst case soil, and validate the cleaning
process
• When new products are introduced into facility, add it to
matrix and determine if re-validation is required.
• During original cleaning validation, adjust limits to be low
enough that the potential for re-validation is reduced
(based on historical manufacturing trends)
Sampling
• Sampling locations should be selected based

on:
– Hard to clean locations
– Locations that might disproportionately contribute
residue to the next product
– Materials of construction or surface finishes with
an affinity for the soil
– The role in the process that is likely to lead to
build-up or difficult to remove soils
• May use forced ranking to ID “Worst case”
swab locations.
Copyright © 2014 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation 23 23/
Example of Forced Ranking -
Bioreactor
Role in
Critical Site: Hot Spot Affinity to process Cleanability of
Sampling Potential large (historically MOC or likely to location/
Ranking
Location contaminant hard to Surface lead to coverage and
area clean) Finish difficult access
residue
Sidewall 1 1 1 1 1 5
Bottom Outlet
5 3 3 1 1 13
Valve
Dome Lid 1 1 1 1 5 9
Instrument
1 5 3 1 5 15
Port
Sampling Port 5 5 3 1 1 15
Agitator 1 1 1 1 3 7
1 = Low Risk
3 = Moderate Risk
5 = High Risk
Sources of Guidance for Limits
• US FDA, Guide to Inspections of Validation of
Cleaning Processes (1993)
• Pharmaceutical Inspection Convention (PIC),
Recommendations on…Cleaning Validation (2001)
• Canadian HPFB, Cleaning Validation Guidelines
(2001)
• EC Guide to Good Manufacturing Practice – Annex 15
(Paragraph 36) (2006) & GMP Part II (formerly
Appendix18) (2005)
• WHO Technical Report No. 937: WHO
Supplementary Guidelines on GMP (Annex 4):
Validation (2006)
• European Medicines Agency EMA/CHMP/CVMP/
SWP/169430/2012. Guideline on setting health
based exposure limits for use in risk identification…
November 2014 (effective June 2015)
Interesting Agreement….
• All guidelines agree that they won’t set limits
• Yet 4 of the 5 guidelines go on to list

“examples” of limits that are then commonly
employed – and that are frequently cited as
“requirements”
Background
• Limits timeline:
Fourman, G., and Mullin, M., ISPE Baseline® Guide:
“Determining Cleaning Validation Risk-Based Manufacture
Acceptance Limits for of Pharmaceutical
Pharmaceutical Manufacturing Products
Operations,” Pharmaceutical (Risk-MaPP), September,
Technology, April 1993 2010
1990 2000 2010

EMA: Guideline on setting
FDA Guidance: Guide to health based exposure limits
Inspections Validation of for use in risk identification in
Cleaning Processes, the manufacture of different
July1993 medicinal products in shared
facilities, November, 2014
Sources of Guidance for
Limits
• European Medicines Agency
EMA/CHMP/CVMP/ SWP/169430/2012.
– Guideline on setting health based exposure limits
for use in risk identification
– November 2014 (effective June 2015)
Residue Limits
• Fourmen and Mullen1 approach for active:

– Most stringent of dose calculation and 10 ppm (in
next product)
AND
– Visually clean
• Typical visual limits is 1 – 4 µg/cm2
• Spiking studies should determine the concentration at
which most active ingredients are visible,
1 Fourman, Gary L., and Michael V. Mullen, “Determining Cleaning Validation Acceptance Limits for
Pharmaceutical Manufacturing Operations,” Pharmaceutical Technology, Vol.17, No. 4, April, pages 54 -
60, 1993.
Residue Limits
• Possible uses of “limit”

– Daily amount allowed (ADI or ADE) (µg or mg)
– Concentration in next product (µg/mL or µg/g)
– Absolute amount in manufacturing vessel/train
(MAC or MACO – maximum allowable carryover)
(mg)
– Amount per surface area (µg/cm2)
– Amount per swab (µg)
– Concentration in swab extract solution (µg/mL)
– Concentration in rinse solution (µg/mL)
Residue Limits – In
Layman’s Terms….
• Need to determine how much of the product we just
cleaned will be administered to each patient taking the
next product.
But in order to make this number useful….
• Need to determine how much that will represent in the
next batch and translate that number to a value in terms
of how much that might represent on the surface to
measure.
• Need the residual amount to be “safe”, add safety factor.
Nature Term
• How much of the product we just cleaned

(Product A)
– May be expressed as one of the following:
• Toxicity or LD50 (with appropriate safety factor)
• Minimum Therapeutic Dosage
• Allergenic Level
• Minimum pharmacological effect level
• NOEL (No Observable Effect Level)
– Most Conservative Approach
Daily amount allowed –
Product A
• Assume tablet Product A:
50 mg active per tablet, 1 tablet per dose, 2-4
doses/day
• Minimum daily dose of active is:
50mg/tablet x 1 tablet/dose x 2 doses/day = 100
mg/day
• Daily amount allowed:
– Acceptable Daily Intake (ADI)
– Acceptable Daily Exposure (ADE)
– Based on Safety/toxicity evaluation
(Or) 0.001 of a minimum daily dose of an active.
Safety Factor Term
• We want the amount of residual soil to be

“safe”, therefore may add a safety factor
– Safety factor is any convenient number, usually a
factor of 10 (e.g. 100, 1000, 10000)
– Safety factor is optional in some cases (not
optional when using terms such as LD50)
– The greater the safety factor, the larger the
reduction in the limit
Safety Factor Term
(Continued)
• Common practice is to apply safety factors
uniformly within a plant
– Topical Products: 10 to 100*
– Oral Dosage Products: 100 to 1000*
– Parenteral/Opthalmic Products: 1,000 to 10,000
– Research/Investigational Products: 10,000 to
100,000
*Note: Significant rationale must be given if safety

factor is less than the industry-standard 1,000
Dose Term
• Amount that will be administered to each

patient taking the next product (Product B)
– The amount of the next product that may be
administered
– Always most conservative to over-estimate this
term
• Does not depend on the Nature or Level of
active in Product B.
• Product B is the Maximum daily dose
– Typically mass or volume
Concentration in next
product - Product B
• Assume Product B:
1,000 mg tablets, 1 tablet per dose, 2-4 doses per
day
• Maximum daily dose of Product B is:
1,000 mg/tablet x 1 tablet/dose x 4 doses/day =
4000 mg/day or 4 gm/day
• Concentration in next product:
(100 mg/day)(0.001 safety factor) = 0.025 mg/g
4 gm/day
NOTE: (25 µg/g) > 10 ppm (10 µg/g)

Batch Term
• How much of the soil will be present in the

next batch?
– May be expressed as batch size (L or kg) or in the
number of doses (1,000,000 tablets for example)
– Most conservative to work with smallest possible
batch size (worst case)
• (Larger batch sizes will “dilute” your residue which is safer)
MAC
• Absolute amount in manufacturing vessels

• For tablet example: concentration limit of
active in A in product B is 10.0 µg/g.
• Batch size is 200 kg
10.0 µg/g x 200 kg x 1,000 g/kg = 2,000,000 µg
Size Term
• How much of the soil may remain on the

surface?
– Size of the equipment
– May represent full shared or maximum surface
area of an equipment train
– Conservative approach is to over-estimate surface
area of shared equipment
Limit per surface area
• Calculated by dividing absolute amount limit

by shared surface area
• Example:
– Absolute amount = 2,000,000 µg
– Surface area is 450,000 cm2
– Limit per surface is:
2,000,000 µg/ 450,000 cm2 = 4.4 µg/ cm2
Putting the Terms Together
Nature  Batch (Completed) (Next Product)

1

Size x Dose (Next Product) Safety Factor
Where:
Nature = Pharmacology of the active ingredient from the product
just completed
Batch = Batch size or volume or number of units of the next
product
Size = Surface area of shared or maximum equipment train
Dose = Amount (total dose weight) to be given per patient (daily or
per regime of the next product)
Safety Factor = Optional or variable term depending on other
considerations in the limit
Limit per swab
• Amount per swab depends on

– Limit per surface (µg/cm2)
– Swabbed area (cm2)
• Example:
– Limit per surface = 4.4 (µg/cm2)
– Swabbed area = 25 cm2
4.4 µg/cm2 x 25 cm2 = 110 µg (active Product A)
Limit in swab extract
• Concentration in swab extract depends on

– Limit per surface (µg/cm2)
– Swabbed area (cm2)
– Amount of solvent for extraction (g)
• Example:
– Extracted in 20 g of solvent
4.4 µg/cm2 x 25 cm2 = 5.5 µg/g

20 g
Leveraging sampling
• Increase concentration by decreasing volume

for extraction.
– If extracted into 20 g solvent:
• 110 µg / 20 g = 5.5 µg/g
• 110 µg / 10 g = 11 µg/g
• 110 µg / 5 g = 22 µg/g
Leveraging sampling
• Increase concentration by increasing

swabbed area:
– If 25 cm2 is extracted into 20 g solvent:
• 110 µg / 20 g = 5.5 µg/g
• 440 µg / 20 g = 22 µg/g
• 440 µg / 5 g = 88 µg/g
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)

NOEL = LD50 (mg/kg)×(5.6×10-4) x 70 kg1
• The ADI or NOEL would take the “nature” place in

equation
1 Doursman and Stara, J. Regulatory Toxicology and Pharmacology, 3, 224-238, 1983
Things to Avoid in Setting
Limits
• Limits based on analytical assay
• Limits based on compendial water specs
• Limit unrelated to target residue
• Limits selected arbitrarily
• No documentation of rationale or risk ranking
for how selected
Recent Approaches –
ISPE Risk MaPP
• Risk based approach for determining the
ADE (acceptable daily exposure)
• Typically established by trained toxicologist
• Focuses limit on “how” the carryover might
cause harm
• Would be used in place of 1/1000th
therapeutic dose approach
Calculating the Safety
Threshold Value (STV)
(ISPE)
Batch Size
ADE  STV
Maximum DailyDose
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 ADE Value
NOAEL BW
ADE (mg/day) 
UFC  MF PK
• Where:
– ADE = Acceptable daily exposure
– NOAEL = No observed adverse effect level
– BW = Body weight
– UFc = Composite uncertainty factor
– MF = Modifying factor (professional judgment)
– PK = Pharmacokinetic adjustments (route to route
adjustments)
Calculation of ADE Value
• Per ISPE Baseline®Guide: Risk-Based MaPP

– ADE should not be seen as a “limit”
– Use as a reference point for determining level of risk
– Establish Process Control Limits based on PD
Studies
• Like limits set for temp/humidity/alert, etc
• Tighter inner control limits than OOS limits (MOR’s & PAR’s)
• ADE limit alone may not be acceptable as
carryover, though considered safe
– Flavor, smell, product quality, etc.
– Default to visually clean
“New” Approach: EMA
Guidance
• 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
– Desire to update the approach to validation –
requires a toxicological assessment of product
residues.
PDE Value
• Key part of this assessment is the PDE

– Permitted daily exposure (PDE) value represents
dose that is unlikely to cause an adverse effect if
an individual is exposed at this dose every day for
a lifetime
• Not new approach; used in ICH Q3(R4), Guideline for
Residual Solvents
– PDE determination carried out substance-specific
on basis of all available toxicological and
pharmacological data
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 species
– 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: CIP®100
detergent
• The traditional method…
LD 50  BW  M BS
M AC 
M F1 M F2 LDD
860 mg/kg  60 kg 10 kg

M AC   6,450 mg
800 mg 100,000
• Where:
» LD50 is 860 mg/kg (CIP 100 detergent)
» BW is body weight (60 kg)
» MBS = Minimum batch size (10 kg)
» LDD = Largest daily dose (800 mg)
Case Study: CIP 100 detergent
• EMA Method:
– NOAEL = 120mg/kg/day
– F1 = 10
– F2 = 10 As determined
– F3 = 3 by toxicologist
– F4 = 1
– F5 = 3
120 mg/kg/day  60 kg
PDE (mg/day)   8 mg/day
10 10  3 1 3
Case Study: CIP 100 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
Process Capability and Limits
• The STV should be used with the process

capability of the cleaning process to establish
the alert and action levels:
STV “A”
Area of knowledge
Action Limit
Residue Level
Process Capability (Cpk)

Alert Limit
Proven Acceptable Range (PAR)
Process Control Limit (MOR)
Individual Data Points
Best Practices for successful
Cleaning Validation
• A Manufacturing perspective…..
A successful Cleaning Validation program isn’t successful if it

doesn’t work in Manufacturing!
Cleaning Validation
• Don’t work in a vacuum.
– Involve every group that will be involved with
Validation
• Quality Assurance
• QC Chemistry and Micro
• Manufacturing: Usually will execute the PQ. (Most likely be
pulling samples and will disassemble equipment).
• Process Engineers: (Fix equipment after bullet point #2).
• Facilities and Engineer: May have to re-engineer and
involved in facility effluent.
• EH&S:
Cleaning Validation
• Come 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 Validation
• Work with Process Development,
Manufacturing and Technical Services to
establish Design Space.
– MOR: Manufacturing Operating Ranges
– PAR: Proven Acceptable Ranges.
• The information and knowledge gained from
pharmaceutical development studies and
manufacturing experience provide scientific
understanding to support the establishment of
the design space, specifications and
manufacturing controls
Cleaning Validation
• Design space: Defined in ICH Q8 as
– The multi-dimensional combination and interaction of input
variables (e.g. material attributes) and process parameters
that have been demonstrated to provide an assurance of
quality.
MOR
Area of
Control PAR
pH 7.0 ± 0.5
Area of Success pH 7.0 ± 1.0
Area of Knowledge pH 7.0 ± 2.0

Cleaning Validation
• Clean hold times and Dirty hold times are
acceptable:
– Work with Manufacturing to see what’s optimal and
what’s achievable.
• May be schedule driven. (not able to tie up for Validation)
• Dirty hold times >24 hours. 3 days optimal.
– Take time out past 24 hours and set validated
time-limit back to a whole day. Don’t make
Manufacturing have to calculate delta time.
Most Frequent form 483
observations – FY2014
Top 10 FDA form 483 observations
(21 CFR 211) for FY2014
160
140 145
120
100 109
94
80 87
72 72
60 64 63
54
51
40
20
0
22(d) 160(b) 192 100(a) 67(b) 113(b) 165(a) 67(a) 68(a) 110(a)
Information from FDA website: http://www.fda.gov/ICECI/Inspections/ucm424098.htm

Cleaning Process
Problems
• Cleaning procedure documentation
– Should be equivalent to manufacturing process
documentation
• Details (exact requirements)
• Times
• Personnel accountability
Cleaning procedure exercise
Cleaning Validation
• TWO WORDS: Experimental Protocol (or
significant pilot work)
– Confirms lab performance of cleaning agents
– Tests critical process parameters
– Tests engineering design and controls
– Determines rinse conditions and acceptance levels
(both active and cleaning agents) to ensure they
are achievable
– Test hold times
– Optimize conditions
– ID sampling locations
Cleaning Validation
• Clear and concise procedures:
– ID all pieces of equipment: use checklists, tables
or pictures for clarity. (tools may be equipment
specific and not have “universal” names).
Cleaning Validation
• Clear and concise procedures:
Cleaning Validation
• Clearly define all sample requirements:

– Step taken
– In what?
– Volume
– Storage conditions
– How to label
Information included in SOP
• Piece of equipment or system
• Frequency of visual inspections
• Department responsible for conducting the
visual inspection
• HOW to visually inspect
– Is extra light used? Scope? Camera??
• Follow-up actions defined
And Finally…..
Perform a 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
– “Laundry mat” 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
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
Performing a Lab-Scale Cleaning
Study
• Coat coupon with 1-2 gms of soil
• Emulate process conditions and dirty hold
time
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
Acceptance Criteria
Water Break Free

Soiled Coupon Visual Failure
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 82 82/
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
Best Practices for a Robust
Cleaning Validation
References & Additional Reading:
Fourman, G.L. and Mullen, M.V., “Determining Cleaning Validation Limits for Pharmaceutical
Manufacturing Operations,” Pharmaceutical Technology 17(4), 54-60 (1993).
FDA, 1993, Guide to inspections of validation of cleaning processes. Rockville, MD, USA: Food and
Drug Administration, Office of Regulatory Affairs.
Forsyth, R., O’Neill, J.C. and Hartman J.L. (2007) Materials of construction based on recovery data
for cleaning validation. Pharmaceutical Technology, Oct., pp. 103–116.
Thank you for your
LeBlanc, D.A. (2000) Validated Cleaning Technologies for Pharmaceutical Manufacturing. USA:
Interpharm Press. attention!
Verghese, G. and Lopolito, P. (2007) Process Analytical Technology and Cleaning. Contamination
Control, Fall 2007, pp. 22–26.
LeBlanc, Destin A. et al., Cleaning Technology for Pharmaceutical Manufacturing Pharmaceutical
Technology 17:7, 84-92 (1993).
Points to Consider for Cleaning Validation. PDA Technical Report No. 29. PDA. Bethesda, MD.March beth_kroeger@steris.com
30, 1998.
Forsyth, RJ. et al., Correlation of Visible-Residue Limits with Swab Results for leaning Validation.
Pharmaceutical Technology 30 (11), 90-100 (2006).
LeBlanc, Destin A., Issues in Setting Limits for Actives in Bulk Biotech Manufacture. Journal of
Validation Technology 15 (1), 71-76 (2009).
Pluta, P (editor). Cleaning and Cleaning Validation Volume I. PDA Books (2009). ISBN 1933722371.
Troy, F., Hold Time Studies: A Lost Parameter for Cleaning Validation. Journal of Validation
Technology 13 (3) 206-209 (2007).
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Best Practices for a Robust

• Variables impacting the cleaning process

• Why parameters important?

• Cleaning also depends on cleaning

• Cleaning also depends on cleaning

• Potential Residues for consideration:

• Build soil categories

Iron 3 Soluble 4 10-15 2 319 4 96

Selenium 7 Insoluble 5 0.200 3 4.8 -7.0 2 210

Zinc 3 Soluble 4 10-15 1 5000 2 24

• Sampling locations should be selected based

• All guidelines agree that they won’t set limits

• Yet 4 of the 5 guidelines go on to list

1990 2000 2010

• Fourmen and Mullen1 approach for active:

• Possible uses of “limit”

• How much of the product we just cleaned

• We want the amount of residual soil to be

*Note: Significant rationale must be given if safety

• Amount that will be administered to each

NOTE: (25 µg/g) > 10 ppm (10 µg/g)

• How much of the soil will be present in the

• Absolute amount in manufacturing vessels

10.0 µg/g x 200 kg x 1,000 g/kg = 2,000,000 µg

• How much of the soil may remain on the

• Calculated by dividing absolute amount limit

2,000,000 µg/ 450,000 cm2 = 4.4 µg/ cm2

Nature  Batch (Completed) (Next Product)

• Amount per swab depends on

4.4 µg/cm2 x 25 cm2 = 110 µg (active Product A)

• Concentration in swab extract depends on

4.4 µg/cm2 x 25 cm2 = 5.5 µg/g

• Increase concentration by decreasing volume

• Increase concentration by increasing

• No therapeutic index for cleaning agents

ADI = LD50 (mg/kg)× body weight (kg)

• The ADI or NOEL would take the “nature” place in

Minimum Therapeutic Dose  Batch Size 1

NOTE: Safety factor is already included in the ADE as

• Per ISPE Baseline®Guide: Risk-Based MaPP

• Key part of this assessment is the PDE

• Used to account for various uncertainties and

860 mg/kg  60 kg 10 kg

• EMA Method (Continued):

• The STV should be used with the process

Process Capability (Cpk)

Individual Data Points

A successful Cleaning Validation program isn’t successful if it

Area of Success pH 7.0 ± 1.0

Area of Knowledge pH 7.0 ± 2.0

Information from FDA website: http://www.fda.gov/ICECI/Inspections/ucm424098.htm

• Clearly define all sample requirements:

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