MANAGING RISK IN CLEANING       VALIDATION                               Michael Gietl                        Technical Se...
Agenda•  Regulatory background•  Risk identification  –  Residues  –  Sampling  –  Analytical methods  –  Microbial consid...
Cleaning Validation Master Plan  Equipment                    Cleaning SOP                          Critical ProcessCharac...
Why Clean?•  Possible Reasons  –  My boss said I have to do it  –  The FDA/EMEA won’t approve my product without it  –  I ...
Cleaning Validation•  “Documented evidence that an approved   cleaning procedure will consistently reduce   active pharmac...
Regulatory Requirements•  Worldwide GMPs  –  EU Annex 15 (Paragraph 36) (2006) & GMP Part II     (formerly Appendix 18) (2...
RISK IDENTIFICATION Copyright © 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corp...
Types of Soils•  Potential Residues for consideration:  –  API (Drug substance)  –  Excipients / Colorants / Dyes / Fragra...
Cleaning Chemistry•  Cleaning depends on process control…TimeActionConcentration / ChemistryTemperature•  Cleaning also de...
Cleaning Chemistry•  Laboratory experiments and engineering studies   will help to establish the following criteria:  –  T...
Understanding Your Soils•  Which materials represent the greatest risk to   the next process•  Is there justification to l...
Sampling•  Sampling locations should be selected based   on:  –  Hard to clean locations or complex geometries (hot     sp...
Sampling Methods      Parameter                                        Swab                          Rinse                ...
Identify and Define SamplingMethods•    Swabs – area to be used•    Rinse – define and qualify method•    Microbial – reco...
Analytical Methods•  Analytical methods are preferred to be specific to   the analyte•  Non-specific methods may be used p...
Microbiological Residues•  Bioburden and endotoxin contaminants should   be considered when required to be limited in the ...
Residue Limits•  FDA Guide to Inspection of Cleaning Validation   (7/1993)  –  Rationales should be logical, practical, ac...
Residue Limits•  Fourmen and Mullen approach for active:  –  Most stringent of dose calculation and 10 ppm (in next     pr...
Residue Limits•  Possible uses of “limit”   –  Daily amount allowed (ADI or ADE)   –  Concentration in next product   –  A...
Residue Limits•  Need to determine how much product we just   cleaned will be administered to each patient   taking the ne...
The Three Types of Limits•  Limits associated with the nature of the   substance being cleaned (pharmacological   properti...
Calculating Residue Limits•  Limit in subsequent product (L1)      Minimum Daily Dose of Active in Product A     1 L1 =   ...
Minimum Daily Dose of Activein Product A•  How much of the product we just cleaned   (Product A)  –  May be expressed as o...
Maximum Daily Dose ofProduct B•  Amount that will be administered to each patient   taking the next product (Product B)  –...
Safety Factor Term•  We want the amount of residual soil to be “safe”,   therefore may add a safety factor  –  Safety fact...
Safety Factor Term(Continued)•  One option is to apply safety factors uniformly   within a plant   –  Topical Products: 10...
Calculating Residue Limits•  Limit per Surface Area (L2)     (L1)(Batch size of subsequent product)(1,000)L2 =            ...
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...
Surface Area Term•  How much of the soil may remain on the   surface?  –  Size of the equipment  –  May represent full sha...
Calculating Residue Limits•  Limit in the analyzed sample       (L2)(swabbed surface area)  L3 =       amount desorption s...
Limits for Cleaning Agents•  No therapeutic index for cleaning agents•  Commonly, only information available is LD50•  LD5...
Other Considerations•  Route of administration   –  Topical, oral, parenteral, etc.•  Type of patient likely to receive pr...
Things to Avoid in SettingLimits•  Limits based on analytical assay     –  LOQ (maybe?)     –  LOD (never!)•    Limits bas...
Clean Hold Time (CHT) andDirty Hold Time (DHT)•  Clean Hold Time  –  Following cleaning, how long equipment remains     “c...
RISK ASSESSMENT Copyright © 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporat...
Product Grouping (Matrixing)•  Develop overall approach to cleaning validation   for current products and provide framewor...
Product Grouping (2)•  Toxicity: Generally reflects rank of groups in   terms of potency.   –  Example:      Product Group...
Product Grouping (3)•  Solubility: Solubility of active in water/solvent/   cleaning agent being used to clean equipment• ...
Product Grouping (4)•  Cleanability: Represents situation where product   may be difficult to clean or high risk to clean ...
Product GroupingCleanability Factor                               Description                                        Examp...
Risk Assessment Matrix  (Example)Product Name         Potency                Toxicity               Solubility            ...
Equipment Grouping•  Similar equipment design  –  Materials of construction  –  Equivalent geometries/design risks  –  Equ...
Risk Control and Tools toManage Risk(Partial List)•  Failure Mode Effect and Analysis (FMEA)•  Hazard Analysis and Critica...
Questions?                                    THANK YOU!Copyright © 2012 STERIS Corporations. All Rights Reserved. CONFIDE...
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Managing risk in cv

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Managing risk in cv

  1. 1. MANAGING RISK IN CLEANING VALIDATION Michael Gietl Technical Service Specialist STERIS Corporation michael_gietl@steris.comCopyright © 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
  2. 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. 3. Cleaning Validation Master Plan Equipment Cleaning SOP Critical ProcessCharacterization Definition Parameters Product Product Characteristics Grouping EquipmentTrain 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. 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. 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. 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. 7. RISK IDENTIFICATION Copyright © 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
  8. 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. 9. Cleaning Chemistry•  Cleaning depends on process control…TimeActionConcentration / ChemistryTemperature•  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. 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. 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. 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. 13. Sampling Methods Parameter Swab Rinse Placebo Physical Removal Good Poor ModerateTechnique Dependent Yes No NoHard to reach locations Poor Good GoodAdaptable 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. 14. Identify and Define SamplingMethods•  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. 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. 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. 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. 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. 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. 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. 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. 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. 23. Minimum Daily Dose of Activein 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. 24. Maximum Daily Dose ofProduct 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. 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. 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. 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. 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. 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. 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. 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. 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. 33. Things to Avoid in SettingLimits•  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. 34. Clean Hold Time (CHT) andDirty 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. 35. RISK ASSESSMENT Copyright © 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
  36. 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. 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. 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. 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. 40. Product GroupingCleanability 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. 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 180Oxycodone HCl 4 3 2 2 48 Copyright © 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
  42. 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. 43. Risk Control and Tools toManage 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. 44. Questions? THANK YOU!Copyright © 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.
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