Managing risk in cv
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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 [email protected]
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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
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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 Selection
Hard to Clean Locations
Residue Selection
Methods Validation
Sampling Sites
Limits Definition
Recovery Studies Worst Case
Definition
Hold Time Definition
Hard to Clean Locations
Engineering Runs
Protocol Definition, Execution, and Summary Report
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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
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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
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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)
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RISK IDENTIFICATION
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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
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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
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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
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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
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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?
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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
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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
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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
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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
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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)
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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
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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
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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
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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)
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Calculating Residue Limits
• Limit in subsequent product (L1)
• Safety factor (in this case) is 1,000
000,11
BProduct of DoseDaily MaximumAProduct in Active of DoseDaily MinimumL1 ×=
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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
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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
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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
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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)
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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 µg
area surfaceequipment shared,000)product)(1 subsequent of size (L1)(BatchL2 =
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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)
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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
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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=
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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
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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)
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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
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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
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RISK ASSESSMENT
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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
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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
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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
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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.
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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
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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
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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
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Questions?
THANK YOU!