Cleaning validationCleaning validation

Created by :

Maryorie Rossa Mia Amelia

Narita Nine Febriyanti Ninna Niagama Novi Nurleni

What is Cleaning Validation ?What is Cleaning Validation ?

Equipment cleaning validation is the process of establishing documented evidence that a particular cleaning procedure will consistently reduce equipment surface residuals to a predetermined acceptable level.

“Residuals” are any product, degradate, intermediate, excipient, raw material/reactant or cleaning agent that may reside on any equipment surface following processing and/or cleaning.

Why cleaning validation is so important

Pharmaceuticals can be contaminated by Pharmaceuticals can be contaminated by potentially dangerous substancespotentially dangerous substances

Essential to establish adequate cleaning Essential to establish adequate cleaning proceduresprocedures

““Particular attention should be accorded to the Particular attention should be accorded to the validation of … cleaning procedures” (WHO)validation of … cleaning procedures” (WHO)

““Cleaning validation should be performed in order Cleaning validation should be performed in order to confirm the effectiveness of a cleaning to confirm the effectiveness of a cleaning procedure” (PIC/S)procedure” (PIC/S)

““The data should support a conclusion that The data should support a conclusion that residues have been reduced to an ‘acceptable’ residues have been reduced to an ‘acceptable’ level” (FDA)level” (FDA)

Cleaning Validation Overview

ObjectivesAssurance of product purity, safety,

efficacy and qualityPrevention of product cross contamination by byproduct, residual product, microbial residue and residual detergent.

To discuss principles and approaches to cleaning validation including:Protocols and reportsPersonnel and equipmentUse of detergentsMicrobiologySamplingAnalytical methods and Acceptable limits

Strategy on cleaning validation

Product contact surfacesAfter product change over Between batches in

campaignsBracketing products for cleaning validationPeriodic re-evaluation and revalidation

Cleaning validation protocol (1)

Objective of the validation and identification of the process

Responsibility for performing and approving validation study

Description of equipment to be usedValidation criteriaStatus of equipment (qualified, calibrated according

to the maintenance program etc.) used in the process to be validated

Status of utilities (water, gases etc.) needed during the validation

Training of personnel responsible for the process and personnel operating with the process

Cleaning validation protocol (2)

Should include: Status of the SOPs concerning the cleaning and other

related activitiesResponsibilities of personnel in the validation processInterval between end of production and cleaning, and

commencement of cleaning procedureCleaning procedures to be usedAny routine monitoring equipment usedNumber of cleaning cycles performed consecutivelySampling procedures used and rationaleSampling locations (clearly defined) and the defined

area size

Record of cleaning validation

Should include : Data on recovery studies Analytical methods including Limit of Detection

and Limit of Quantitation Acceptance criteria and rationale When revalidation will be required Must have management and QA involvement Management commitment and QA involvement

Results and reports

Cleaning record signed by operator, checked by production and reviewed by QA

Final Validation Reports, including conclusions Statement if there were any changes to the

validation protocol Clear statement if the validation results meet

the criteria stated in the validation protocol Training performed Approval/rejection as described in SOP and/or

validation protocol

Personnel

Manual cleaning methods are difficult to

validateCannot validate people; can measure

proficiencyMust have good trainingMust have effective supervisionMust have reliable personnel

Equipment

Cleaning of contact surfaces to be validated, with consideration to “non-contact” parts. Critical areas should be identified.

Dedicated equipment for: products which are difficult to clean, equipment which is difficult to clean, products with a high safety risk where it is

not possible to achieve the required cleaning acceptance limits using a validated cleaning procedure.

• If one SOP for cleaning a piece of equipment, review:– products being produced, – cleaning in a large campaign, – cleaning between batches of different products.

• The design of equipment may influence the effectiveness of the cleaning process.

• Consider design, e.g. V-blenders, transfer pumps or filling lines.

Equipment (2)

Validation

Microbiological aspects• Prevent microbial growth and remove contamination• Documented evidence

– routine cleaning– storage of equipment

• The period and conditions– storage of unclean equipment before cleaning– between cleaning and equipment reuse

• Equipment stored in a dry condition after cleaning (no stagnant water)

• Control of bioburden important

Validation

How to sample

• Swab/swatch

• Rinse fluid

• Placebo

• The sample transport and storage conditions should be defined

Validation

Swab samples • Direct sampling method• Reproducibility• Extraction efficiency• Document swab locations • Disadvantages

– inability to access some areas– assumes uniformity of contamination surface– must extrapolate sample area to whole surface

Validation

Rinse samples • Basic principle: to be used only to support other sampling methods,

however may be used in …

• Indirect method

• Combine with swabs

• Useful for cleaning agent residues/monitoring the procedure

• pH, conductivity, TOC

• Insufficient evidence of cleaning

• Sample very large surface areas

Validation

Recovery

< 50% is consideredquestionable

> 80% is considered good > 50% is considered

reasonable

Establishing acceptable limits

• Limits: Practical, achievable and verifiable• Rationale: Logical, based on knowledge of materials• Each situation assessed individually• Principal reactant and other chemical variations• Screening (thin-layer chromatography) in addition to

chemical analyses where necessary

There should be no residue from:• Previous product• Reaction by-products and degradants• Cleaning process itself (e.g. detergents or solvents)Remember: Uniform distribution of contaminants is

not guaranteed

Establishing acceptable limits (2) The limit-setting approach can :

– be product-specific– group products into families and choose a worst

case product– group products into groups according to risk, e.g.

very soluble products, products with similar potency, highly toxic, or difficult to detect products

– use different safety factors for different dosage forms based on physiological response (this method is essential for potent materials)

Establishing acceptable limits (3)• Limits may be expressed as:

– a concentration in a subsequent product (ppm),

– limit per surface area (mcg/cm2), or – in rinse water as ppm.

• Limits for carry-over of product residues should meet defined criteria.

• What are the three most commonly used criteria?

Establishing acceptable limits (4) The three most commonly used criteria are:

– Visually clean No residue visible on equipment after cleaning. Spiking studies to determine the concentration at which most active ingredients are visible. (May not be suitable for high potency, low-dosage drugs.)

– No more than 10 ppm of one product will appear in another product (basis for heavy metals in starting materials).

– No more than 0.1% of the normal therapeutic dose of one product will appear in the maximum daily dose of a subsequent product.

Establishing acceptable limits (6)

• The most stringent of three options should be used• Certain allergenic ingredients and highly potent material should be

undetectable by the best available analytical methods

– e.g. penicillins and cephalosporins– e.g. anovulent steroids, potent steroids and

cytotoxics• Dedicated manufacturing facilities needed

Conclusion• Cleaning is an important part of pharmaceutical

development of medicines• Cleaning and cleaning validation is a major concern

and source of inspectional observations• "Clean" is a subjective measure – definition is needed• The manufacturer needs a cleaning validation strategy• Assess each situation on its merits• Scientific rationale must be developed

– equipment selection– contamination distribution– significance of the contaminant

• “Visually clean” may be all that is required

THANK’S 4 UR ATTENTION