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

1. THE FUNDAMENTALS OF
CLEANING VALIDATION
CPhi - 07 October 2014
Elise Gallais
R&D Project Manager
SGS Life Science Services – Clichy France

2. OUTLINE
 GMP Context
 Cleaning validation guideline
 Focus on analytical method validations
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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”
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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.
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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
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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)
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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
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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
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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.
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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.
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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.
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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
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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
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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
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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.
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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?
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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
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18. QUESTIONS –– ANSWERS
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