This document discusses cleaning validation in the pharmaceutical industry. It covers the objectives of cleaning validation, why it is important, potential contaminants, validation strategies, protocols, analytical methods, setting limits, and other considerations like personnel and microbiological aspects. The overall goal of cleaning validation is to confirm that cleaning procedures are effective in reducing residue levels to an acceptable level to prevent contamination between product batches.

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Validation Part 2:
Cleaning validation
Supplementary Training Modules on
Good Manufacturing Practices

2. Module 1, Part 2: Cleaning validation Slide 2 of 25 © WHO – EDM Jan 02
Validation
Objectives
To review:
 General requirements
 Validation protocol requirements
 How to check limits
 Analytical requirements
 Sample methods

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Validation
Why cleaning validation is so important (1)
 Pharmaceuticals can be contaminated by
potentially dangerous substances
 Essential to establish adequate cleaning procedures

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Validation
Why cleaning validation is so important (2)
 “Particular attention should be accorded to the
validation of … cleaning procedures” (WHO)
 “Cleaning validation should be performed in order
to confirm the effectiveness of a cleaning
procedure” (PIC/S)
 “The data should support a conclusion that
residues have been reduced to an ‘acceptable’
level” (FDA)

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Possible contaminants
 Product residues
 Cleaning agent residues and breakdown
 Airborne matter
 Lubricants, ancillary material
 Decomposition residues
 Bacteria, mould and pyrogens
Validation

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Validation
Strategy on cleaning validation
 Product contact surfaces
 After product changeover
 Between batches in campaigns
 Bracketing products for cleaning validation
 Periodic re-evaluation and revalidation

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Validation
Cleaning validation protocol (1)
Should include :
 Objective of the validation
 Responsibility for performing and approving
validation study
 Description of equipment to be used

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Validation
Cleaning validation protocol (2)
Should include:
 Interval between end of production and cleaning, and
commencement of cleaning procedure
 Cleaning procedures to be used
 Any routine monitoring equipment used
 Number of cleaning cycles performed consecutively
 Sampling procedures used and rationale
 Sampling locations (clearly defined)

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Validation
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

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Validation
Results and reports
 Cleaning record signed by operator, checked by
production and reviewed by QA
 Final Validation Reports, including conclusions

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Validation
Personnel
 Manual cleaning methods are difficult to
validate
 Cannot validate people; can measure proficiency
 Must have good training
 Must have effective supervision

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Validation
Microbiological aspects
 Include in validation strategy
 Analyse risks of contamination
 Consider equipment storage time
 Equipment should be stored dry
 Sterilization and pyrogen contamination

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Validation
How to sample
 Swab/swatch
 Rinse fluid
 Placebo
 The sample transport and storage conditions
should be defined

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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

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Validation
Rinse samples
 Indirect method
 Combine with swabs
 Useful for cleaning agent residues
 pH, conductivity, TOC
 Insufficient evidence of cleaning
 Sample very large surface areas

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Validation
Analytical method (1)
 Validate analytical method
 Must be sensitive assay procedure:
 HPLC, GC, HPTLC
 TOC
 pH
 conductivity
 UV
 ELISA

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Validation
Analytical method (2)
Check:
 Precision, linearity, selectivity
 Limit of Detection (LOD)
 Limit of Quantitation (LOQ)
 Recovery, by spiking
 Consistency of recovery

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Setting limits (1)
 Regulatory authorities do not set limits for
specific products
 Logically based
 Limits must be practical, achievable and
verifiable
 Allergenic and potent substances
 Limit setting approach needed
Validation

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Setting limits (2)
 Uniform distribution of contaminants not
guaranteed
 Decomposition products to be checked
 Setting limits; cleaning criteria:
 visually clean
 10ppm in another product
 0.1% of therapeutic dose
Validation

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Setting limits: “Visually clean”
 Always first criteria
 Can be very sensitive but needs verification
 Use between same product batches of same
formulation
 Illuminate surface
 Spiking studies
Validation

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Setting limits: “10ppm”
 Historical
 In some poisons regulations
 Pharmacopoeias limit test
 Assumes residue to be harmful as heavy metal
 Useful for materials for which no available
toxicological data
 Not for pharmacologically potent material
Validation

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Setting limits: not more than 0.1%
 Proportion of MINIMUM daily dose of current
product carried over into MAXIMUM daily dose
of subsequent product
 Need to identify worst case
Validation

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Other issues
 Clean-In-Place (CIP) systems
 Placebo studies
 Detergent residues; composition should be
known
 Scrubbing by hand
Validation

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Validation
Questions for the GMP Inspector to ask
 How is equipment cleaned?
 Are different cleaning processes required?
 How many times is a cleaning process repeated
before acceptable results are obtained?
 What is most appropriate solvent or detergent?
 At what point does system become clean?
 What does visually clean mean?

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Conclusion
 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
Validation