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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

    Copyright © 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
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
         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 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
    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 on…Cleaning 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                                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
     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)

      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




     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
   (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

     Copyright © 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
Calculating Residue Limits

•  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




     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
       (L2)(swabbed surface area)
  L3 =
       amount desorption solvent

•  Recovery factor from swab recovery studies may
   be employed here, or apply to analytical result




    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 à increasingly difficult to clean
  –  Be aware of potential changes in active/excipient
     physicial 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/                                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




     Copyright © 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
Risk Assessment Matrix
  (Example)
Product Name         Potency                Toxicity               Solubility             Cleanability                      Risk
                      Factor                 Factor                 Factor                   Factor                        Priority
                                                                                                                         (PxTxSxC)



Acetaminophen               2                     2                        3                         3                      36

  Fentanyl                  5                     3                        4                         3                      180

Oxycodone HCl               4                     3                        2                         2                      48




        Copyright © 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
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!




Copyright © 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.

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Managing risk in cv

  • 1. 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.
  • 2. 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.
  • 3. 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 Copyright © 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
  • 4. 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 Copyright © 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
  • 5. 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.
  • 6. 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) Copyright © 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
  • 7. RISK IDENTIFICATION Copyright © 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
  • 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 –  Bioburden –  Mycoplasma / Prions / Viral particles –  Endotoxin Copyright © 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
  • 9. 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.
  • 10. 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.
  • 11. 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.
  • 12. 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.
  • 13. 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 Copyright © 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
  • 14. 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.
  • 15. 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.
  • 16. 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.
  • 17. 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.
  • 18. 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.
  • 19. 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.
  • 20. 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.
  • 21. 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.
  • 22. 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 Copyright © 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
  • 23. 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.
  • 24. 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.
  • 25. 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.
  • 26. 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 Copyright © 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
  • 27. Calculating Residue Limits •  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 Copyright © 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
  • 28. 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.
  • 29. 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.
  • 30. Calculating Residue Limits •  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 Copyright © 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
  • 31. 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.
  • 32. 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.
  • 33. 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.
  • 34. 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 Copyright © 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
  • 35. RISK ASSESSMENT Copyright © 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
  • 36. 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.
  • 37. 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.
  • 38. 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.
  • 39. 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.
  • 40. 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 Copyright © 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
  • 41. Risk Assessment Matrix (Example) Product Name Potency Toxicity Solubility Cleanability Risk Factor Factor Factor Factor Priority (PxTxSxC) Acetaminophen 2 2 3 3 36 Fentanyl 5 3 4 3 180 Oxycodone HCl 4 3 2 2 48 Copyright © 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
  • 42. 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.
  • 43. 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.
  • 44. Questions? THANK YOU! Copyright © 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.