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Managing Risk Cleaning Validasi
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Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
MANAGING RISK IN CLEANING
VALIDATION
Michael Gietl
Technical Service Specialist
STERIS Corporation
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
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
Cleaning Validation Master Plan
Equipment
Characterization
Equipment
Train Definition
Equipment
Grouping
Cleaning SOP
Definition
Cleaning Agent
Use Matrix
Critical Process
Parameters
Product
Grouping
Product
Characteristics
Sampling Method
SelectionHard to Clean
Locations
Residue
Selection
Methods
Validation
Sampling Sites
Limits
Definition
Recovery
StudiesWorst Case
Definition
Hold Time
Definition
Hard to Clean
Locations
Engineering
Runs
Protocol Definition, Execution, and Summary
Report
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
Why Clean?
Possible Reasons
My boss said I have to do it
The FDA/EMEA wont 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
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
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
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
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 onCleaning Validation (2001)
WHO Technical Report No. 937: WHO Supplementary Guidelines on GMP (Annex 4): Validation (2006)
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
RISK IDENTIFICATION
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
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
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
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
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
Cleaning Chemistry
Laboratory experiments and engineering studies will help to establish the following criteria:
Time
Action
Clean in Place (CIP)
Washer (COP)
Manual
Chemistry / concentration
Temperature
Coupon/beaker studies
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
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
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
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?
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
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
surfaces
Moderate Good Moderate
Controlled Area Yes No No
Non-Invasive No Yes Yes
Adaptable to on-line
monitoring
No Yes No
Can use solvents Yes Yes No
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
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
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
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
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
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
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
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)
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
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
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
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
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
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
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
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)
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
Calculating Residue Limits
Limit in subsequent product (L1)
Safety factor (in this case) is 1,000
000,1
1
BProduct of DoseDaily Maximum
AProduct in Active of DoseDaily MinimumL1
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
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
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
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
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
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
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
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
*Note: Significant rationale must be given if safety factor
is less than the industry-standard 1,000
(Hall, W.A. 1997. Cleaning for bulk pharmaceuticals chemicals. In Validation of
bulk pharmaceutical chemicals)
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
Calculating Residue Limits
Limit per Surface Area (L2)
In this case, 1,000 is a conversion factor to account for ppm and to convert kg to g
area surfaceequipment shared
,000)product)(1 subsequent of size (L1)(BatchL2
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
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)
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
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
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
Calculating Residue Limits
Limit in the analyzed sample
Recovery factor from swab recovery studies may be employed here, or apply to analytical result
solvent desorptionamount
area) surface ed(L2)(swabbL3
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
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
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
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)
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
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
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
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 increasingly difficult to clean
Be aware of potential changes in active/excipientphysicial or chemical properties
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
RISK ASSESSMENT
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
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
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
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
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
Product Grouping (3)
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
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
Product Grouping (4)
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.
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
Product Grouping
Cleanability Factor Description Example
1 Easiest to clean Very soluble tablets;
product does not stick to
surfaces
2 Average cleaning
time/effort
Uncoated tablets,
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
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
Risk Assessment Matrix
(Example)
Product Name Potency
Factor
Toxicity
Factor
Solubility
Factor
Cleanability
Factor
Risk
Priority
(PxTxSxC)
Acetaminophen 2 2 3 3 36
Fentanyl 5 3 4 3 180
Oxycodone HCl 4 3 2 2 48
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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
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
Risk Control and Tools to
Manage Risk
(Partial List)
Failure Mode Effect and Analysis (FMEA)
Hazard Analysis and Critical Control Points (HACCP)
Hazard and Operability (HAZOP)
Cause & Effect Analysis (Fishbone Diagram)
Fault Tree Analysis
Quality Risk Classification and Filtering
Copyright 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
Questions?
THANK YOU!