Supplementary Training Modules on Good Manufacturing Practices Validation

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Supplementary Training Modules on Good Manufacturing Practices Validation Part 2: Cleaning validation Module 1,

Supplementary Training Modules on Good Manufacturing Practices Validation Part 2: Cleaning validation Module 1, Part 2: Cleaning validation Slide 1 of 25 © WHO – EDM Jan 02

Validation Objectives To review: l General requirements l Validation protocol requirements l How to

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

Validation Why cleaning validation is so important (1) l Pharmaceuticals can be contaminated by

Validation Why cleaning validation is so important (1) l Pharmaceuticals can be contaminated by potentially dangerous substances l Essential to establish adequate cleaning procedures Module 1, Part 2: Cleaning validation Slide 3 of 25 © WHO – EDM Jan 02

Validation Why cleaning validation is so important (2) l “Particular attention should be accorded

Validation Why cleaning validation is so important (2) l “Particular attention should be accorded to the validation of … cleaning procedures” (WHO) l “Cleaning validation should be performed in order to confirm the effectiveness of a cleaning procedure” (PIC/S) l “The data should support a conclusion that residues have been reduced to an ‘acceptable’ level” (FDA) Module 1, Part 2: Cleaning validation Slide 4 of 25 © WHO – EDM Jan 02

Validation Possible contaminants l Product residues l Cleaning agent residues and breakdown l Airborne

Validation Possible contaminants l Product residues l Cleaning agent residues and breakdown l Airborne matter l Lubricants, ancillary material l Decomposition residues l Bacteria, mould and pyrogens Module 1, Part 2: Cleaning validation Slide 5 of 25 © WHO – EDM Jan 02

Validation Strategy on cleaning validation l Product contact surfaces l After product changeover l

Validation Strategy on cleaning validation l Product contact surfaces l After product changeover l Between batches in campaigns l Bracketing products for cleaning validation l Periodic re-evaluation and revalidation Module 1, Part 2: Cleaning validation Slide 6 of 25 © WHO – EDM Jan 02

Validation Cleaning validation protocol (1) Should include : l Objective of the validation l

Validation Cleaning validation protocol (1) Should include : l Objective of the validation l Responsibility for performing and approving validation study l Description of equipment to be used Module 1, Part 2: Cleaning validation Slide 7 of 25 © WHO – EDM Jan 02

Validation Cleaning validation protocol (2) Should include: l Interval between end of production and

Validation Cleaning validation protocol (2) Should include: l Interval between end of production and cleaning, and commencement of cleaning procedure l Cleaning procedures to be used l Any routine monitoring equipment used l Number of cleaning cycles performed consecutively l Sampling procedures used and rationale l Sampling locations (clearly defined) Module 1, Part 2: Cleaning validation Slide 8 of 25 © WHO – EDM Jan 02

Validation Record of cleaning validation Should include : l Data on recovery studies l

Validation Record of cleaning validation Should include : l Data on recovery studies l Analytical methods including Limit of Detection and Limit of Quantitation l Acceptance criteria and rationale l When revalidation will be required l Must have management and QA involvement l Management commitment and QA involvement Module 1, Part 2: Cleaning validation Slide 9 of 25 © WHO – EDM Jan 02

Validation Results and reports l Cleaning record signed by operator, checked by production and

Validation Results and reports l Cleaning record signed by operator, checked by production and reviewed by QA l Final Validation Reports, including conclusions Module 1, Part 2: Cleaning validation Slide 10 of 25 © WHO – EDM Jan 02

Validation Personnel l Manual cleaning methods are difficult to validate l Cannot validate people;

Validation Personnel l Manual cleaning methods are difficult to validate l Cannot validate people; can measure proficiency l Must have good training l Must have effective supervision Module 1, Part 2: Cleaning validation Slide 11 of 25 © WHO – EDM Jan 02

Validation Microbiological aspects l Include in validation strategy l Analyse risks of contamination l

Validation Microbiological aspects l Include in validation strategy l Analyse risks of contamination l Consider equipment storage time l Equipment should be stored dry l Sterilization and pyrogen contamination Module 1, Part 2: Cleaning validation Slide 12 of 25 © WHO – EDM Jan 02

Validation How to sample l Swab/swatch l Rinse fluid l Placebo l The sample

Validation How to sample l Swab/swatch l Rinse fluid l Placebo l The sample transport and storage conditions should be defined Module 1, Part 2: Cleaning validation Slide 13 of 25 © WHO – EDM Jan 02

Validation Swab samples l Direct sampling method l Reproducibility l Extraction efficiency l Document

Validation Swab samples l Direct sampling method l Reproducibility l Extraction efficiency l Document swab locations l Disadvantages ä ä ä inability to access some areas assumes uniformity of contamination surface must extrapolate sample area to whole surface Module 1, Part 2: Cleaning validation Slide 14 of 25 © WHO – EDM Jan 02

Validation Rinse samples l Indirect method l Combine with swabs l Useful for cleaning

Validation Rinse samples l Indirect method l Combine with swabs l Useful for cleaning agent residues l p. H, conductivity, TOC l Insufficient evidence of cleaning l Sample very large surface areas Module 1, Part 2: Cleaning validation Slide 15 of 25 © WHO – EDM Jan 02

Validation Analytical method (1) l Validate analytical method l Must be sensitive assay procedure:

Validation Analytical method (1) l Validate analytical method l Must be sensitive assay procedure: ä HPLC, GC, HPTLC ä TOC ä p. H ä conductivity ä UV ä ELISA Module 1, Part 2: Cleaning validation Slide 16 of 25 © WHO – EDM Jan 02

Validation Analytical method (2) Check: l Precision, linearity, selectivity l Limit of Detection (LOD)

Validation Analytical method (2) Check: l Precision, linearity, selectivity l Limit of Detection (LOD) l Limit of Quantitation (LOQ) l Recovery, by spiking l Consistency of recovery Module 1, Part 2: Cleaning validation Slide 17 of 25 © WHO – EDM Jan 02

Validation Setting limits (1) l Regulatory authorities do not set limits for specific products

Validation Setting limits (1) l Regulatory authorities do not set limits for specific products l Logically based l Limits must be practical, achievable and verifiable l Allergenic and potent substances l Limit setting approach needed Module 1, Part 2: Cleaning validation Slide 18 of 25 © WHO – EDM Jan 02

Validation Setting limits (2) l Uniform distribution of contaminants not guaranteed l Decomposition products

Validation Setting limits (2) l Uniform distribution of contaminants not guaranteed l Decomposition products to be checked l Setting limits; cleaning criteria: ä visually clean ä 10 ppm in another product ä 0. 1% of therapeutic dose Module 1, Part 2: Cleaning validation Slide 19 of 25 © WHO – EDM Jan 02

Validation Setting limits: “Visually clean” l Always first criteria l Can be very sensitive

Validation Setting limits: “Visually clean” l Always first criteria l Can be very sensitive but needs verification l Use between same product batches of same formulation l Illuminate surface l Spiking studies Module 1, Part 2: Cleaning validation Slide 20 of 25 © WHO – EDM Jan 02

Validation Setting limits: “ 10 ppm” l Historical l In some poisons regulations l

Validation Setting limits: “ 10 ppm” l Historical l In some poisons regulations l Pharmacopoeias limit test l Assumes residue to be harmful as heavy metal l Useful for materials for which no available toxicological data l Not for pharmacologically potent material Module 1, Part 2: Cleaning validation Slide 21 of 25 © WHO – EDM Jan 02

Validation Setting limits: not more than 0. 1% l Proportion of MINIMUM daily dose

Validation Setting limits: not more than 0. 1% l Proportion of MINIMUM daily dose of current product carried over into MAXIMUM daily dose of subsequent product l Need to identify worst case Module 1, Part 2: Cleaning validation Slide 22 of 25 © WHO – EDM Jan 02

Validation Other issues l Clean-In-Place (CIP) systems l Placebo studies l Detergent residues; composition

Validation Other issues l Clean-In-Place (CIP) systems l Placebo studies l Detergent residues; composition should be known l Scrubbing by hand Module 1, Part 2: Cleaning validation Slide 23 of 25 © WHO – EDM Jan 02

Validation Questions for the GMP Inspector to ask l How is equipment cleaned? l

Validation Questions for the GMP Inspector to ask l How is equipment cleaned? l Are different cleaning processes required? l How many times is a cleaning process repeated before acceptable results are obtained? l What is most appropriate solvent or detergent? l At what point does system become clean? l What does visually clean mean? Module 1, Part 2: Cleaning validation Slide 24 of 25 © WHO – EDM Jan 02

Validation Conclusion l The manufacturer needs a cleaning validation strategy l Assess each situation

Validation Conclusion l The manufacturer needs a cleaning validation strategy l Assess each situation on its merits l Scientific rationale must be developed ä ä ä l equipment selection contamination distribution significance of the contaminant “Visually clean” may be all that is required Module 1, Part 2: Cleaning validation Slide 25 of 25 © WHO – EDM Jan 02