Supplementary Training Modules on

Good Manufacturing Practice

Validation

Prof. A. Haggag
Professor of Biochemistry
Faculty of Pharmacy
University of Tanta
Tanta City, EGYPT

Member, WHO-Expert Committee

on Specifications for Pharmaceutical Preparations

Module 1, Part 2: Cleaning validation Slide 1 of 25 © WHO – EDM Jan 02

 Supplementary Training Modules on
Good Manufacturing Practices

Validation Part 2:
Cleaning validation

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

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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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 Validation
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

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 Validation
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

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 Validation
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

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 Validation
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

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 Validation
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

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

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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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 Validation
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

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