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The Fundamentals of Cleaning Validation

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In this presentation from CPhi 2014, Elise Gallais outlines the guidelines for cleaning validation: and focuses on analytical methods and their validation.

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The Fundamentals of Cleaning Validation

  1. 1. THE FUNDAMENTALS OF CLEANING VALIDATION CPhi - 07 October 2014 Elise Gallais R&D Project Manager SGS Life Science Services – Clichy France
  2. 2. OUTLINE  GMP Context  Cleaning validation guideline  Focus on analytical method validations CPhi - 07 October 2014 2
  3. 3. REMINDER OF THE GMP CONTEXT  For Europe:  About the producing pharmaceutical drug product, the obligation of validate the “critical” cleanings is described in the GMP appendix 15 (1999 and 2014 draft) (and precisely in the P.I. 006 of the PICs pharmaceutical Inspection Cooperation http://www.picsheme.org).  For USA:  The US GMPs (21 CFR 210-211) don’t expressly mention the “cleaning procedures validation“; but it’s specified that all critical procedures must be validated...; consequently it’s an obligation for the FDA.  In 1993 a inspection guide was published for FDA inspectors, he provides the FDA main expectations: “FDA expects firms to have written general procedures on how cleaning processes will be validated”. The main items and chapters are: • “Equipment design” • “Cleaning process written” • “Analytical methods” • “Establishments of limits” 3 CPhi - 07 October 2014
  4. 4. CLEANING VALIDATION - GUIDELINE  1- Define the prerequisites and perform optimizations before validations:  Check that all the material, chemical, human resources are well qualified and that written procedures exist and are clear, detail and applicable.  Cleaning procedures were already optimised.  2- Define and justify the surfaces/equipments concerned by the cleaning validation:  For “closed” equipment: the whole equipment inside surfaces will be considered as critical and also consider the open parts (raw matter introduction and/or finish products exit)  For “opened” procedures: risk analysis will allow justifying that this or that surface isn’t concerned according to the direct contamination risk that we will evaluate. 4 CPhi - 07 October 2014
  5. 5. CLEANING VALIDATION - GUIDELINE  3- Define contaminants  API, Cleaning agent and microorganisms  The question about the API degradation products existence or no, by the cleaning procedure have to be evaluated.  4- Selection of worst case requires consideration of at least the following:  Solubility of residues in water and solvents, including cleaning agents over a pH range  Adherence of residues to surfaces that must be cleaned (cleanability from previous experience)  Concentration of active pharmaceutical ingredient  Toxicity of active pharmaceutical ingredient Risk analysis have to be performed regarding the 4 previous parameters using scoring 5 CPhi - 07 October 2014
  6. 6. CLEANING VALIDATION - GUIDELINE  5- Calculation of the acceptance criteria Chemical residues Residues The stricker criteria will be selected between the following one: - 10 ppm of API in the following batch - Maximum allowable residues (MAR) based on toxicological data - MAR based on Minimum Therapeutic Dose (MTD) 6 CPhi - 07 October 2014
  7. 7. CLEANING VALIDATION - GUIDELINE  Calculation of the acceptance criteria  Calculation of MAR (mgA/ KgB or mgA/L) or  Calculation of Residue Acceptance Limit (RAL per equipment item): and/or 7 CPhi - 07 October 2014
  8. 8. CLEANING VALIDATION - GUIDELINE  5- Calculation of the acceptance criteria Microbial and Endotoxin Residues  Equipment used in Solids and Liquids (non-sterile) Products area: • Surface rinse method <100 cfu/ml • Swab and contact plate method <50 cfu/25cm2 (a lower limit may be applied if data is available to support it)  Equipment used in Liquids (sterile) Products area: • Surface rinse method <10 cfu/100 ml • Endotoxin <0.25 EU/ml • Swab and contact plate method <5 cfu/25cm2 8 CPhi - 07 October 2014
  9. 9. CLEANING VALIDATION - GUIDELINE  6- Choose sampling methods:  The direct sampling methods are expected with high priority by the agencies. That is the samples by swabbing or wiping.  In case of direct sample impossibility on the surface (and only in that case) the rinsing methods are admitted: • Sample in the last rinsing cycle of the cleaning method. • Make a additional rinsing ( possibility to reduce the volume and/or to choice another solvent) • Work by soaking and agitation for the small pieces. 9 CPhi - 07 October 2014
  10. 10. CLEANING VALIDATION - GUIDELINE  7- Specific analytical methods or not?  The health agencies prefer the specific methods for the chemical residues research, but the non specified methods such as the Total organic carbon (TOC) or the conductivity for example, are acceptable if they are adapted to the researched contaminants and are validated to the researched concentrations (include for the FDA).  For biotechnological, the active molecule is generally degraded by the cleaning method, for this reason, the non specific methods are often the only ones that can be used. 10 CPhi - 07 October 2014
  11. 11. CLEANING VALIDATION - GUIDELINE  8- Validation protocol establishment:  Define the number of trials  Dirty Equipment Hold Times: Maximum allowable time intervals for periods between use and cleaning will be established and verified, and will include consideration of the effects of variables that could impact cleaning (e.g. temperature).  Clean Equipment Hold Times: Maximum allowable time intervals between the completion of cleaning and reuse will be established and verified. This is to provide confidence that the storage conditions of equipment do not allow microbial proliferation. 11 CPhi - 07 October 2014
  12. 12. CLEANING VALIDATION - GUIDELINE  9- Change Control and New Product Assessment To ensure that the Cleaning Validation Master Plan remains valid, each new product will be assessed against the model compound and documented. Events that will lead to a change of the rationale include:  Introduction of new products / equipment types  Modifications to product formulation / cleaning procedures / cleaning agents / equipment / staff  Changes to regulatory requirement Ch ill b f ll d d d h t l Changes will be formally recorded under change control 12 CPhi - 07 October 2014
  13. 13. CLEANING VALIDATION - GUIDELINE  10- Annual Review On completion of the cleaning validation study, there will be an annual review of the cleaning validation data to ensure continued compliance with this global policy. This review should include, but is not limited to:  the review of change control documentation  cleaning procedure deviations  cleaning failure investigations Significant changes do require to repeat the cleaning validation 13 CPhi - 07 October 2014
  14. 14. FOCUS ON ANALYTICAL METHOD VALIDATION  Method developement is an important step to define the following critical aspect:  Sensitivity: LOQ of selected method should be below the RAL  Interferences: from excipients, cleaning agents, swabs (if needed swabs could be rinse to reduce interference)  Interaction API and cleaning agent: stability of API must be assessed in presence of cleaning agent at it use concentration.Injections should be made at initial time and after a suitable period (maximum contact time) If degradation observe the impact must be assessed  For swab sampling F b li • definition of sampling solvent: based on solubility and also take in consideration the compatibility with equipement and to not bring other contamination • swab extraction: mostly the solvent used is identical to sampling Vortex and/or sonication is oftenly enough 14 CPhi - 07 October 2014
  15. 15. FOCUS ON ANALYTICAL METHOD VALIDATION  Find the same prameters as described in ICH Q2R1:  Specificity, LOD, LOQ, Linearity, same requirement as ICH  Accuracy and precision are replace by the swab or rinse recovery determination: • Swab technic and swab surfaces must be define in a procedure before • Recouvrey are determined by spiking known amount on surface representing your equipments • At least 2 operators are needed to validate the recovery • Recovery is then use as a correction factor for routine test  Stability could be a critical aspect especially if analytical control is subcontracted. 15 CPhi - 07 October 2014
  16. 16. CONCLUSION  Do not start a validation without answers to the following questions:  Why I would like to validate (verification strategy could be an other solution)?  Did my procedures are well described and followed?  Who will be in charge of the project and who will be involved?  What is the project schedule?  How much it will cost? 16 CPhi - 07 October 2014
  17. 17. THANK YOU FOR YOUR PARTICIPATION Life Science Services Elise GALLAIS R&D Project Manager + 41 22 739 9548 SGS Life Science Phone: + 33 (0)1 41 06 95 75 20-22 rue Charles Paradnias 92583 Clichy cedex E-mail : elise.gallais@sgs.com France Web : www.fr.sgs.com/lifescience + 1 866 SGS 5003 + 65 637 90 111 + 33 1 41 24 87 87 + 1 877 677 2667 17 CPhi - 07 October 2014
  18. 18. QUESTIONS –– ANSWERS 18 CPhi - 07 October 2014

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