Managing Risk in Cleaning Validation

MANAGING RISK IN CLEANING
VALIDATION
Michael Gietl
Technical Service Specialist
STERIS Corporation
michael_gietl@steris.com
Copyright © 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
Agenda
• Regulatory background
• Risk identification
– Residues
– Sampling
– Analytical methods
– Microbial considerations
– Limits
• Grouping
• Risk Management Tools
Cleaning Validation Master Plan
Equipment Cleaning SOP Critical Process

Characterization Definition Parameters
Product Product
Characteristics Grouping
Equipment
Train Definition Cleaning Agent Residue
Use Matrix Selection
Sampling Method
Selection
Equipment Hard to Clean
Sampling Sites
Grouping Locations
Limits Methods
Definition Validation
Hold Time
Definition Recovery
Studies
Engineering Hard to Clean Worst Case
Runs Locations Definition
Protocol Definition, Execution, and Summary

Report
Why Clean?
• Possible Reasons
– My boss said I have to do it
– The FDA/EMEA won’t approve my product without it
– I need job security
– It might be fun (?)
• REAL Reasons
– Reduce possibility of product contamination
– Demonstrate cleaning process is consistent
– Demonstrate cleaning process removes residues and
environmental contaminants
– Provide equipment that can be safely reused
Cleaning Validation
• “Documented evidence that an approved

cleaning procedure will consistently reduce
active pharmaceutical ingredients (API), process
residues, cleaning agents and microbial residues
from product contact equipment surfaces to
acceptable levels for the processing of drug
products”
– Reference: FDA; Guide to Inspections Validation of

Cleaning Processes, 1993
Regulatory Requirements
• Worldwide GMPs
– EU Annex 15 (Paragraph 36) (2006) & GMP Part II
(formerly Appendix 18) (2005)
– US FDA, Guide to Inspections of Validation of
Cleaning Processes (1993)
– Pharmaceutical Inspection Convention (PIC/S),
Recommendations on…Cleaning Validation (2001)
– WHO Technical Report No. 937: WHO Supplementary
Guidelines on GMP (Annex 4): Validation (2006)
RISK IDENTIFICATION
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
– Bioburden
– Mycoplasma / Prions / Viral particles
– Endotoxin
Cleaning Chemistry
• Cleaning depends on process control…
Time
Action
Concentration / Chemistry
Temperature
• Cleaning also depends on cleaning conditions…
– Water Quality
– Individual Performing Cleaning (esp. in manual cleaning)
– Nature of Soil
– Surface being cleaned
• Coupon/beaker studies
Understanding Your Soils
• Which materials represent the greatest risk to

the next process
• Is there justification to look for one residue as a
“worst case” when compared to other selected
residues?
– Cleanability
– Toxicity
– Solubility
• In water?
– Stability
Sampling
• Sampling locations should be selected based

on:
– Hard to clean locations or complex geometries (hot
spots)
– 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
• Number of locations?
Sampling Methods
Parameter Swab Rinse Placebo
Physical Removal Good Poor Moderate
Technique Dependent Yes No No
Hard to reach locations Poor Good Good
Adaptable to irregular Moderate Good Moderate
surfaces
Controlled Area Yes No No
Non-Invasive No Yes Yes
Adaptable to on-line No Yes No
monitoring
Can use solvents Yes Yes No
Identify and Define Sampling
Methods
• Swabs – area to be used
• Rinse – define and qualify method
• Microbial – recovery?
• Blanks and controls – handling & methodology
• Sample locations
– ID
– Justification
– Risk rationale
Analytical Methods
• Analytical methods are preferred to be specific to

the analyte
• Non-specific methods may be used provided that
all analyte identified is attributed to the worst
case residue limit
• Analytical methods and sampling methods must
be demonstrated to be suitable through methods
validation in conjunction with the sampling
method / extraction system and through recovery
studies
Microbiological Residues
• Bioburden and endotoxin contaminants should

be considered when required to be limited in the
final product
• Important considerations
– Environmental conditions
• Guidance for limits taken from:
– Product Specifications
– Historical data
Residue Limits
• FDA Guide to Inspection of Cleaning Validation

(7/1993)
– Rationales should be logical, practical, achievable,
and verifiable
– Sensitivity of analytical methods is critical to
establishing valid limits
– Three examples given:
• 10 ppm
• 1/1000 of normal therapeutic dose
• Organoleptic levels (e.g. visually clean)
Residue Limits
• Fourmen and Mullen approach for active:

– Most stringent of dose calculation and 10 ppm (in next
product)
AND
– Visually clean
• PIC/S Approach:
– Most stringent of…
• Dose calculation in next product
• 10 ppm in next product
• Visually clean
Residue Limits
• Possible uses of “limit”

– Daily amount allowed (ADI or ADE)
– Concentration in next product
– Absolute amount in manufacturing vessel/train (MAC
or MACO – maximum allowable carryover)
– Amount per surface area
– Amount per swab
– Concentration in swab extract solution
– Concentration in rinse solution
Residue Limits
• Need to determine how much product we just
cleaned will be administered to each patient
taking the next product
– How much will that represent in the next batch?
– How much will that represent on the surface?
– Need the residual amount to be “safe”, add safety
factor
– Need to recognize variability in manufacturing
process that may change from lot to lot and
incorporate into the strategy
The Three Types of Limits
• Limits associated with the nature of the

substance being cleaned (pharmacological
properties)
• Limits associated with the percentage of
contamination (10 ppm, for example)
• Limits associated with the process by which the
material is manufactured, cleaned, or analyzed
(e.g. visibly clean)
Calculating Residue Limits
• Limit in subsequent product (L1)
Minimum Daily Dose of Active in Product A 1

L1 = ×
Maximum Daily Dose of Product B 1,000
• Safety factor (in this case) is 1,000
Minimum Daily Dose of Active
in Product A
• 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)
• Therapeutic Dosage
• Allergenic Level
• Minimum pharmacological effect level
• NOEL (No Observable Effect Level)
– Most Conservative Approach
Maximum Daily Dose of
Product B
• 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
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)
• One option 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
(Hall, W.A. 1997. Cleaning for bulk pharmaceuticals chemicals. In Validation of
bulk pharmaceutical chemicals)
*Note: Significant rationale must be given if safety factor

is less than the industry-standard 1,000
• Limit per Surface Area (L2)
(L1)(Batch size of subsequent product)(1,000)

L2 =
shared equipment surface area
• In this case, 1,000 is a conversion factor to
account for ppm and to convert kg to µg
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)
Surface Area 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 in the analyzed sample

(L2)(swabbed surface area)
L3 =
amount desorption solvent
• Recovery factor from swab recovery studies may

be employed here, or apply to analytical result
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 x 1/Safety Factor

NOEL = LD50 (mg/kg)×(5.6×10-4) x 60 kg1
1 Doursman and Stara, J. Regulatory Toxicology and Pharmacology, 3, 224-238, 1983
Other Considerations
• Route of administration
– Topical, oral, parenteral, etc.
• Type of patient likely to receive product
– Adult vs. Child
• Position / role of equipment in process
– Conservative strategies moves one toward a purer
product as the product is processed to a finished
dosage (e.g. UF/DF skids, fillers)
Visually Clean
• Visually clean can be sole acceptance criteria

provided:
– All critical surfaces (especially those most difficult to
clean) can be visually examined
– The lowest level of surface residue of the target
residue which is consistently judged dirty has been
established and documented
– The surface acceptance criterion (in µg/cm2) of the
target residue has been calculated, and is above the
level of surface residue at which a surface is judged
visually dirty (visual limit)
Visually Clean
• Generally not enough to compare calculated

limit to level typically referenced (~4 µg/cm2)
– Level should be determined experimentally
• Requires consideration of:
– Distance of observer from surface
– Level of lighting
– Angle of lighting
Things to Avoid in Setting
Limits
• Limits based on analytical assay
– LOQ (maybe?)
– LOD (never!)
• Limits based on compendial water specs
• Limit unrelated to target residue
• Limits selected arbitrarily
• No documentation of rationale or risk ranking for
how selected
Clean Hold Time (CHT) and
Dirty Hold Time (DHT)
• 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 à increasingly difficult to clean
– Be aware of potential changes in active/excipient
physicial or chemical properties
RISK ASSESSMENT
Product Grouping (Matrixing)
• Develop overall approach to cleaning validation

for current products and provide framework for
future development of cleaning program
– Potency: potency of products based on normal daily
dose of products
• Example: Normal Daily Dose Potency Factor
< 5mg 5
5 – 199 mg 4
200 – 400 mg 3
400 – 600 mg 2
600 – 800 mg 1
Product Grouping (2)
• Toxicity: Generally reflects rank of groups in

terms of potency.
– Example:
Product Grouping Toxicity Factor
Prescription Products 3
OTC Products 2
Dietary supplements 1
• Solubility: Solubility of active in water/solvent/
cleaning agent being used to clean equipment
• Example:
Solubility (From USP) Solubility Factor

Very Soluble 1
Freely Soluble 2
Soluble 3
Sparingly Soluble 4
Slightly Soluble 5
V. Slightly Soluble 6
Practically Insoluble 7
• Cleanability: Represents situation where product

may be difficult to clean or high risk to clean
because of issues due to the nature of product
(other than potency, toxicity, and solubility)
• Examples: Coated tablets, extended release
products, etc.
Product Grouping
Cleanability Factor Description Example
1 Easiest to clean Very soluble tablets;
product does not stick to
surfaces
2 Average cleaning time/ Uncoated tablets,

effort capsules
3 More difficult to clean Coated tablets

4 Very difficult to clean Insoluble actives in
ointments/creams
5 Most difficult to clean Dyes that stain

equipment, strong odors
Example (Dietary Supplements)
Cleanability in
Potency -‐ RDA Toxicity Alkaline Total RPN
Oral Dosage Form Solubility (ac5ve) (mg) Oral LD50 (mg/kg) Detergent (S×P×T×C)
Prac5cally
Calcium 7 insoluble 1 800-‐1200 1 6450 2 14
0.050-‐0.2
Chromium 4 Not speciﬁed 5 00 2 100-‐400 2 80
Iron 3 Soluble 4 10-‐15 2 319 4 96

Slightly
Magnesium 5 soluble 3 270-‐400 1 TD Lo 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
Equipment Grouping
• Similar equipment design
– Materials of construction
– Equivalent geometries/design risks
– Equivalent “hot spots” and critical sites (sampling
sites)
• Similar manufacturing process
– Role/position in process
– Campaign length/dirty hold time
• Identical cleaning process
– Cleaning agent
– TACT
– Frequency of cleaning
EXAMPLE: DETERMINING
WORST-CASE LOCATIONS IN
FERMENTOR
1 baffle
2 Spray balls
Instrument
ports (pH, DO,
etc)
1. Coverage testing
(riboflavin testing)
2. Instrument/sample
port(s)
3. Air-liquid interface
4. Representative
surface
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.
• 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. 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 30, 1998.
• Forsyth, RJ. et al., Correlation of Visible-Residue Limits with Swab Results for
leaning Validation. Pharmaceutical Technology 30 (11), 90-100 (2006).
References & Additional
Reading (2)
• 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).
• Rathore, N. et al., Bench-Scale Characterization of Cleaning Process Design Space
for Biopharmaceuticals. BioPharm International 22 (3), 32-44 (2009).
• Kendrick, K. et al., Analysis of Degradation Properties of Biopharmaceutical Active
Ingredients as Caused by Various Process Cleaning Agents and Temperature.
Journal of Validation Technology 15 (3), 69-77 (2009).
• *Note: This is not a complete listing, just a guidance to literature the speaker has
found to be interesting/beneficial.
Questions?
THANK YOU!

Managing Risk in Cleaning Validation

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MANAGING RISK IN CLEANING

Equipment Cleaning SOP Critical Process

Protocol Definition, Execution, and Summary

• “Documented evidence that an approved

– Reference: FDA; Guide to Inspections Validation of

• Potential Residues for consideration:

• Which materials represent the greatest risk to

• Sampling locations should be selected based

• Analytical methods are preferred to be specific to

• Bioburden and endotoxin contaminants should

• FDA Guide to Inspection of Cleaning Validation

• Fourmen and Mullen approach for active:

• Possible uses of “limit”

• Limits associated with the nature of the

• Limit in subsequent product (L1)

Minimum Daily Dose of Active in Product A 1

• Safety factor (in this case) is 1,000

• We want the amount of residual soil to be “safe”,

*Note: Significant rationale must be given if safety factor

• Limit per Surface Area (L2)

(L1)(Batch size of subsequent product)(1,000)

• How much of the soil will be present in the next

• How much of the soil may remain on the

• Limit in the analyzed sample

• Recovery factor from swab recovery studies may

• No therapeutic index for cleaning agents

ADI = LD50 (mg/kg)× body weight x 1/Safety Factor

• Visually clean can be sole acceptance criteria

• Generally not enough to compare calculated

• Develop overall approach to cleaning validation

• Toxicity: Generally reflects rank of groups in

Solubility (From USP) Solubility Factor

• Cleanability: Represents situation where product

2 Average cleaning time/ Uncoated tablets,

3 More difficult to clean Coated tablets

5 Most difficult to clean Dyes that stain

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

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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