Cleaning Validation Design - Grouping
• Equipment Grouping Strategy Example
• From: Risk-Based Cleaning Validation in Biopharmaceutical API Manufacturing, A. Hamid Mollah, Ph.D., Edward K. White, BioPharm
International, Nov. 1, 2005,
• Product Grouping Strategy
• Products may also be grouped in terms of “Worst Case” to clean.
• Use Risk Based tools for Justification
• Failure Mode & Effects Analysis (FMEA), Fault Tree Analysis
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Analytical Methodology
…analytical methods should be:
Specific
Sensitive
Accurate
Provide results that are reliable.
Procedures for analytical method and equipment maintenance,
documentation practices, and calibration practices supporting process-
development efforts should be documented or described.- Guidance for Industry
Process Validation: General Principles and Practices, January. 2001, U.S. Department of Health and Human Services, Food and Drug
Administration, Center for Drug Evaluation and Research (CDER), Current Good Manufacturing Practices (CGMP) Revision 1
• Most common Process Analytical Techniques (PAT)
• Conductivity
• pH
• Total Organic Carbon
• Others (Chlorine Assay Kit, Detergent Surfactant Kit, protein assay kit)
• HPLC, FTIR, ELISA , total protein & Endotoxin
• Are Specific Assays the Most Appropriate?
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Sampling Methodology Comparison
• Most common Sampling Schemes
• Rinse Samples (indirect)
• Swabbing (direct)
• Can be a combination of both.
• Closed system rinse sampling options
• Sampling technology should not contaminate or cause contamination of sample
• Examples; Novaseptum, Sta-Pure etc. for Rinse samples
Sampling Method Pro's Con's
Relies on uniform distribution of
Maintains System Closure residue and covereage of reinse
step
Rinse
Rinse represents all contact areas Does not directly sample
eve the "hard to reach" surface
Analysis can be on‐line or off‐line
Risk of contamination higher
Direct Sample of Surface
with direct operator interface
Swab Sampling spot is defined Analysis off line
Must have very well defined
procedures, training
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Comparison of Sampling Procedures
Rinse and swab measure two different things so do not
expect a correlation between the two
Swabs focus on small area Rinses focus on larger area
Swab measures worst case Rinse measures average
If both done correctly on same surfaces,
Rinse may pass but swab may fail
If swab passes, rinse should also pass
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Establishing Acceptable Limits
Limits should be:
• Practical, achievable and verifiable
• Example – is the WFI TOC limit an acceptable limit for a 10 m2 system
• Logical, based on knowledge of materials
• Assuming non-uniform distribution of compounds
• Assessed on a case-by-case basis
There should be no residue from:
• Previous product, by-products and degradants
• Microbiological material or its by-products
• Cleaning process (e.g. detergents, solvents, by-products, degradants)
Limit Setting Approach
Can be product-specific
Allows product grouping / bracketing to choose a worst
case product (based on documented scientific
evidence) according to product, equipment & risk
– very soluble products
– products with similar potency
– therapeutic dose
– highly toxic products
– difficult to detect products
Safety factors for different dosage forms depends on
physiological response / toxicity / dosage route
Cleaning Acceptance Criteria.
Acceptance Criteria - The three most commonly used criteria
are :
Visually clean. No residue visible on equipment after cleaning.
No more than 10 ppm of one product will appear in another product .
No more than 0.1% of the normal therapeutic dose of one product will
appear in the maximum daily dose of a subsequent product. - Supplementary
Training Modules on Good Manufacturing Practice, Cleaning Validation, World Health Organization, Feb 2009, Kampala, Uganda
Risk Based Acceptance Criteria (Mollah & White)
• Maximum allowable carryover (MACO) and safety factors
• Process risk versus patient risk
• Manufacturing stage (pre, post, and during purification)
• Cross-contamination between products or product intermediates
• Single vial concept and worst-case cleaning
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Examples of Cleaning Limit Criteria
Calculation Examples - 1
Visually clean -
Spiking studies determine the concentration at which most active
ingredients are visible
“A typical visual limit is NLT 4 μg / cm2.”
“Visually clean” may not be adequate in the case of
• Potent drugs
• Microbial contamination
• Endotoxin
Suitable for swab sample and not for rinse sample
More suitable for non-potent drug products and APIs.
N.B. PIC/S advocates spiked coupon study for determination of visual
inspection limits (and for training of inspectors).
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