Best Practices For A Robust Cleaning Validation PDF

Best Practices for a Robust
Cleaning Validation
Beth Kroeger
Technical Services
Manager
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
3/
Cleaning Chemistry
Cleaning also depends on cleaning
conditions
Water Quality
Individual Performing Cleaning (esp. in manual
cleaning)
Surface being cleaned
Nature of Soil
4/
Identifying Risk in
Cleaning Validation
Need to know and
understand:
Process flow
Equipment
Process soils
Components of cleaning
Where to start?
5/
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
6/
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
7/
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
8/
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
9/
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
10/
Product Grouping Criteria

Build soil categories
Determine Worse Case
11/
Risk Ranking Specific

Soils
Parameter
Product
Difficulty to
clean - lab
study or
subjective
Toxicity
LD50 (oral rat)
Solubility g/100mL of
water
Risk Level
0
Very easy to
clean water
effective
2500
mg/kg
Very soluble
100% in
water
Risk Level 1
Easy to clean
and highly
mobile in
liquid state
> 2500
mg/kg and
1250 mg/kg
Freely
Soluble
99.9 % in
water
Risk Level 2
Risk Level 3
Moderately
easy to clean
some
viscosity
issues
Moderately
hard to clean
Thicker
products,
some
insoluble
ingredients
>1250 mg/kg
and 500
mg/kg
Soluble
99% in water
>500 mg/kg
and 250
mg/kg
Slightly
Soluble
>10% but
<90% in
water
Risk Level 4
Risk Level 5
Difficult to
clean oily
substance,
builder or
excipient
Very Difficult
to clean such
as denatured
protein,
dyes,
titanium
dioxide
>250 mg/kg
and 25
mg/kg
Very Slightly
Soluble <
10% in water
25 mg/kg
Practically
Insoluble
< 0.01% in
water
12/
Example (Dietary
Supplements)
Oral Dosage Form
Solubility (active)
Potency - RDA
(mg)
Toxicity
Oral LD50 (mg/kg)
Cleanability in
Alkaline
Detergent
Total RPN
(SPTC)
Calcium
Practically
insoluble
800-1200
6450
14
Chromium
Not specified
0.0500.200
100-400
80
Iron
Soluble
10-15
319
96
Magnesium
Slightly
soluble
270-400
4722
30
Potassium
soluble
Not
specified
7200
18
Selenium
Insoluble
0.200
4.8 -7.0
210
Zinc
Soluble
10-15
5000
24
13/
Residue limit selection (1)

Lowest limit among group
Product
Active
Limit
Maple
25
Honey
15
Peppermint
10
Sugar
30
If syrup is worst case (most difficult to clean),

then validate maple at a limit of 10 units
peppermint.
14/
Residue limit selection (2)

Most difficult to clean and most toxic
Product
Active
Limit
Maple
25
Honey
15
Peppermint
10
Sugar
30
3 PQ runs of syrup at a limit of 25 AND 3 PQ

runs of candy cane at a limit of 10
15/
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)
16/
Sources of Guidance for

Limits
US FDA, Guide to Inspections of Validation of
Cleaning Processes (1993)
Pharmaceutical Inspection Convention (PIC),
Recommendations onCleaning 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)
17/
Interesting Agreement.
All guidelines agree that they wont 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
18/
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 g/cm2
Spiking studies should determine the concentration at
which most active ingredients are visible,
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.
19/
Residue Limits
Possible uses of limit
Daily amount allowed (ADI or ADE) (g or mg)
Concentration in next product (g/mL or g/g)
Absolute amount in manufacturing vessel/train
(MAC or MACO maximum allowable carryover)
(mg)
Amount per surface area (g/cm2)
Amount per swab (g)
Concentration in swab extract solution (g/mL)
Concentration in rinse solution (g/mL)
20/
Residue Limits In
Laymans 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.
21/
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
22/
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.
23/
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
24/
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
25/
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
26/
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 g/g) > 10 ppm (10 g/g)

27/
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)
28/
MAC
Absolute amount in manufacturing vessels
For tablet example: concentration limit of
active in A in product B is 10.0 g/g.
Batch size is 200 kg
10.0 g/g x 200 kg x 1,000 g/kg = 2,000,000 g
29/
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
30/
Limit per surface area

Calculated by dividing absolute amount limit
by shared surface area
Example:
Absolute amount = 2,000,000 g
Surface area is 450,000 cm2
Limit per surface is:
2,000,000 g/ 450,000 cm2 = 4.4 g/ cm2
31/
Putting the Terms Together

Nature
Batch
Size x Dose (Next Product)
(Completed)
(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
32/
Limit per swab

Amount per swab depends on
Limit per surface (g/cm2)
Swabbed area cm2
Example:
Limit per surface = 4.4 (g/cm2)
Swabbed area = 25 cm2
4.4 g/cm2 x 25 cm2 = 110 g (active Product A)
33/
Limit in swab extract

Concentration in swab extract depends on
Limit per surface g/cm2
Swabbed area cm2
Amount of solvent for extraction g
Example:
Extracted in 20 g of solvent
4.4 g/cm2 x 25 cm2 = 5.5 g/g

20 g
34/
Leveraging sampling
Increase concentration by decreasing volume
for extraction.
If extracted into 20 g solvent:
110 g / 20 g = 5.5 g/g
110 g / 10 g = 11 g/g
110 g / 5 g = 22 g/g
35/
Leveraging sampling
Increase concentration by increasing
swabbed area:
If 25 cm2 is extracted into 20 g solvent:
110 g / 20 g = 5.5 g/g
440 g / 20 g = 22 g/g
440 g / 5 g = 88 g/g
36/
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)(5.610-4) 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
37/
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
38/
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
39/
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
40/
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)
41/
Calculation of ADE Value

Per ISPE BaselineGuide: 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 (MORs & PARs)
ADE limit alone may not be acceptable as

carryover, though considered safe
Flavor, smell, product quality, etc.
Default to visually clean
42/
Best Practices for successful

Cleaning Validation
A Manufacturing perspective..
A successful Cleaning Validation program isnt successful if it

doesnt work in Manufacturing!
43/

Cleaning Validation
Dont 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:
44/

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?
45/

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
46/

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
pH 7.0 0.5
PAR
Area of Success pH 7.0 1.0

Area of Knowledge pH 7.0 2.0
47/

Cleaning Validation
Clean Hold Time
Following cleaning, how long equipment remains
clean before reuse.
Not concerned with process residue; focus is on
controlled storage (bioburden proliferation)
Dirty Hold Time

How long dirty equipment can remain dirty prior
to cleaning
Generally, longer DHT increasingly difficult to
clean
Be aware of potential changes in active/excipient
physical or chemical properties
48/

Cleaning Validation
Clean hold times and Dirty hold times are
acceptable:
Work with Manufacturing to see whats optimal and
whats 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. Dont make
Manufacturing have to calculate delta time.
49/

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
50/

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).
51/

Cleaning Validation
Clear and concise procedures:
52/

Cleaning Validation
Clearly define all sample requirements:
Step taken
In what?
Volume
Storage conditions
How to label
53/
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.
54/
Why Perform a Lab-Scale Study

Run
Cleaner
Temperature
Concentration
Cleaner A
Ambient
1% v/v
Cleaner B
Ambient
1% v/v
Cleaner C
Ambient
1% v/v
Cleaner A
Ambient
5% v/v
Cleaner B
Ambient
5% v/v
Cleaner C
Ambient
5% v/v
Cleaner A
45C
1% v/v
Cleaner B
45C
1% v/v
Cleaner C
45C
1% v/v
10
Cleaner A
45C
5% v/v
11
Cleaner B
45C
5% v/v
12
Cleaner C
45C
5% v/v
13
Cleaner A
60C
1% v/v
14
Cleaner B
60C
1% v/v
15
Cleaner C
60C
1% v/v
16
Cleaner A
60C
5% v/v
15 min
30 min
45 min
60 min
55/
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
56/
Where to start:
Cleaning Agent Selection
Alkaline Cleaners
Organic acids
Tableting excipients
Proteins/Fermentation
residues
Oils/Waxes/Fats
Grease
Polysaccharides
Acidic Cleaners
Particulates
Alkaline Salts:
Bicarbonates,
carbonates
Metal Oxides
Hard water scale
57/
Performing a Lab-Scale Cleaning

Study
Coat coupon with 1-2 gms of soil
Emulate process conditions and dirty hold
time
58/
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
1%
60
15
1%
80
15
2%
60
15
2%
80
15
1%
60
30
1%
80
30
Temperature
Concentration
59/
Acceptance Criteria
Soiled Coupon
Visual Failure
Water Break Free

Failure
60/
Advantages of Lab-Scale
Cleaning Study
Fails TOC/HPLC
Passes Acceptance Criteria
61
61/
Cleaning Study
Residue build-up over time
62/
Cleaning Study
Same coupon,
different angle.
Residue visible
in first angle, not
in second.
Same coupon,
different angle.
Residue visible
on both angles,
15 coating and
cleaning cycles.
63/
Cleaning Study
Same coupon,
different angle.
Both coupons wet
Same coupon,
different angle.
Both coupons dry
64/
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., ONeill, J.C. and Hartman J.L. (2007) Materials of construction based on recovery data
for cleaning validation. Pharmaceutical Technology, Oct., pp. 103116.
LeBlanc, D.A. (2000) Validated Cleaning Technologies for Pharmaceutical Manufacturing. USA:
Interpharm Press.
Verghese, G. and Lopolito, P. (2007) Process Analytical Technology and Cleaning. Contamination
Control, Fall 2007, pp. 2226.
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
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).
Thank you for your

attention!
beth_kroeger@steris.com
65/

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Best Practices for a Robust

Best Practices for a successful cleaning

Parameters and attributes

Critical Quality Attributes

Same materials of construction

Must have same cleaning process

Alternatives - Validate separately largest /smallest sizes

Is there justification to look for one residue as

Product Grouping Criteria

Risk Ranking Specific

Residue limit selection (1)

If syrup is worst case (most difficult to clean),

Residue limit selection (2)

3 PQ runs of syrup at a limit of 25 AND 3 PQ

Grouping for a Contract

Sources of Guidance for

WHO Technical Report No. 937: WHO

Need to determine how much that will represent in the

Toxicity or LD50 (with appropriate safety factor)

Daily amount allowed

Minimum daily dose of active is:

Daily amount allowed:

Safety Factor Term

Safety Factor Term

*Note: Significant rationale must be given if safety

Does not depend on the Nature or Level of

Maximum daily dose of Product B is:

Concentration in next product:

NOTE: (25 g/g) > 10 ppm (10 g/g)

Limit per surface area

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

Putting the Terms Together

Limit per swab

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

Limit in swab extract

4.4 g/cm2 x 25 cm2 = 5.5 g/g

Limits for Cleaning Agents

The ADI or NOEL would take the nature place in

Doursman and Stara, J. Regulatory Toxicology and Pharmacology, 3, 224-238, 1983

Things to Avoid in Setting

Calculating the Safety

NOTE: Safety factor is already included in the ADE as

Calculation of ADE Value

Calculation of ADE Value

ADE limit alone may not be acceptable as

Best Practices for successful

A successful Cleaning Validation program isnt successful if it

Best Practices for successful

Best Practices for successful

Consider where can contamination occur?

Best Practices for successful

The information and knowledge gained from

Best Practices for successful

Area of Success pH 7.0 1.0

Best Practices for successful

Dirty Hold Time

Best Practices for successful

Take time out past 24 hours and set validated

Best Practices for successful

Best Practices for successful

Best Practices for successful

Best Practices for successful

Why Perform a Lab-Scale Study