the fundamentals of cleaning validation

THE FUNDAMENTALS OF CLEANING VALIDATIONCLEANING VALIDATIONCPhi - 07 October 2014

Elise Gallais

R&D Project Manager

SGS Life Science Services – Clichy France

OUTLINEOUTLINE

GMP Context

Cleaning validation guideline

Focus on analytical method validations

2CPhi - 07 October 2014 CPhi - 07 October 2014

REMINDER OF THE GMP CONTEXTREMINDER OF THE GMP CONTEXT

For Europe: 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( 999 a d 0 d a t) (a d p ec se y t e 006 o t e Cspharmaceutical Inspection Cooperation http://www.picsheme.org).

For USA: 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 mustbe validated ; consequently it’s an obligation for the FDAbe validated...; consequently it s an obligation for the FDA.

In 1993 a inspection guide was published for FDA inspectors, he providesthe FDA main expectations: “FDA expects firms to have writtengeneral procedures on how cleaning processes will be validated”.g p g pThe main items and chapters are:

• “Equipment design”• “Cleaning process written”


• “Analytical methods”• “Establishments of limits”

CLEANING VALIDATION GUIDELINECLEANING 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 andapplicable.

Cleaning procedures were already optimised.

2- Define and justify the surfaces/equipments concerned by the cleaning validation: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 orthat surface isn’t concerned according to the direct contamination riskthat we will evaluate.



3- Define contaminants API, Cleaning agent and microorganisms The question about the API degradation products existence or no, by q g p y

the cleaning procedure have to be evaluated.

4- Selection of worst case requires consideration of at least the 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 rangeover a pH range Adherence of residues to surfaces that must be cleaned (cleanability

from previous experience) Concentration of active pharmaceutical ingredient p g Toxicity of active pharmaceutical ingredient

Risk analysis have to be performed regarding the 4 previous


Risk analysis have to be performed regarding the 4 previous parameters using scoring


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

M i ll bl id (MAR) b d i l i l d- Maximum allowable residues (MAR) based on toxicological data

- MAR based on Minimum Therapeutic Dose (MTD)



Calculation of the acceptance criteria

Calculation of MAR (mgA/ KgB or mgA/L)

or

Calculation of Residue Acceptance Limit (RAL per equipment item):Calculation of Residue Acceptance Limit (RAL per equipment item):

and/orand/or



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: 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/25cm2p



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.Work by soaking and agitation for the small pieces.



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 usedoften the only ones that can be used.



8- Validation protocol establishment: Define the number of trials Dirty Equipment Hold Times: Maximum allowable time 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 geffects of variables that could impact cleaning (e.g. temperature).

Clean Equipment Hold Times: Maximum allowable time intervals between the completion of cleaning and reuse willintervals 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.microbial proliferation.



9- Change Control and New Product Assessment

To ensure that the Cleaning Validation Master Plan remainsTo 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: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


10- Annual Review

On completion of the cleaning validation study, there will be an annual review of the cleaning validation data to ensure continuedannual 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 the review of change control documentation

cleaning procedure deviations

cleaning failure investigations

Significant changes do require to repeat the cleaning validation


FOCUS ON ANALYTICAL METHOD VALIDATIONFOCUS 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

d t i iti l ti d ft it bl i d ( i t t ti )made at initial time and after a suitable period (maximum contact time)

F b li

If degradation observe the impact must be assessed

For swab sampling • 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 samplingVortex and/or sonication is oftenly enough

FOCUS ON ANALYTICAL METHOD VALIDATIONFOCUS 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 testRecovery is then use as a correction factor for routine test

Stability could be a critical aspect especially if analytical control is subcontracted.


CONCLUSIONCONCLUSION

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?What is the project schedule?

How much it will cost?


THANK YOU FOR YOUR PARTICIPATIONTHANK YOU FOR YOUR PARTICIPATION

Life Science ServicesElise GALLAISR&D Project Manager

+ 41 22 739 9548 SGS Life Science Phone: + 33 (0)1 41 06 95 7520-22 rue Charles Paradnias92583 Clichy cedex E-mail : [email protected]

Web : www.fr.sgs.com/lifescience

+ 1 866 SGS 5003+ 65 637 90 111

+ 33 1 41 24 87 87 + 1 877 677 2667


1 877 677 2667

QUESTIONS – ANSWERSQUESTIONS – ANSWERS


the fundamentals of cleaning validation

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