Cleaning Validation -"What is it?
· Clean · Establish a documented, effective cleaning protocol · Clean using what? · How often? · What is clean?
· Validate · Prove that you cleaned · Sample · Test the sample for recovery
Cleaning Validation -"What is the Goal?
· Confirm that the remaining residue in the production equipment of one product is below established acceptable limits so that it does not impair the quality and safety of the next product manufactured in the same equipment.
Cleaning Validation - "Why?
· US Food and Drug Administration (FDA) issued Guide to Inspections – Validation of Cleaning Process in 1993
· Sources of Contamination of drug product or drug substance: · Can be generated in the production environment during
manufacturing · Cross-contamination of drug either by:
· Other active pharmaceutical ingredient (API) from previous batch runs
· By residues from the cleaning agents used · Can alter the strength, chemical identity of the drug · Safety risk to patients consuming the drug
Cleaning Validation -"How?
· Clean the equipment · Develop the method for cleaning · Document this procedure�
· Show that the equipment is clean · Validation
· Develop procedure for recovering residue from process equipment
· Develop analytical method for sampling, detecting and quantifying residue
Residues to be Removed · Cleaning solutions
· Solvents · Cleaning solutions · Disinfectants
· Drug substances · API’s · Biologicals · Excipients · Preservatives
· Others · Microbiological contamination
Sampling -"Why?
· Determine initial levels of cleanliness · Determine final levels · Determine removal efficiency · Meet FDA requirements
Sampling -"What?
· Product contact surfaces · Different kind of surfaces
· Group by materials of construction · Group by sampling method · Group method of cleaning
· Several locations
Sampling -"Where?
· Where cleaning is difficult · Irregular surfaces · Hard-to-reach areas · Porous surfaces · Heated surfaces
Sampling –"How do you sample?
· Defined locations · Defined region · Swab sampling · Store effectively · Transfer for analysis
Sampling - "What Material?
· Swabs, vials, filters, syringes, solvents and coupons are all part of the analytical method for confirming the equipment meets established limits.
· Material suitability · Filters can remove material because of reactivity or high surface area · Any organic solvent interferes with TOC measurements · Some solvents are more suitable in dissolving the residue of interest · Coupons may not be representative of equipment
· Contamination characteristics · Filters can elute interferences · Swabs can have background interference
Swab Materials – "Head and Handle
q Man-made fibers § Polyester § Nylon § Rayon
q Natural fibers § Cotton § Cellulose
q Man-made materials § Polyurethane foam
§ Polypropylene
q Blends (combination of fibers) § Polyester/cellulose
q Composites (sandwich of materials § Polypropylene/cellulose
Swab Considerations
· Capture and release residue of interest · Particulate burden · Chemical composition of the swab · NVR (non-volatile residues)
· What is left after evaporation of a liquid which was used to extract contaminants from a material of interest
Swab - Functional Requirements
· Ability of the swab to recover the residue from the surface
· Ability of the swab to release the residue to an extracting solution for analysis
· Minimum contaminant release from the swab to the surface
· Minimum blank contribution from the swab
Typical Swabbing Pattern and How to Release
Demonstration during workshop
Step 3
Step 2
Step 4
Step 1
Cleaning Validation Fundamentals
· Drug product or cleaning residue must elute from swab for analysis.
· Cleaning validation requires a suitable method that is sensitive, specific if possible, quantifiable, linear and repeatable process. · Recovery · Stability · Linearity · Selectivity · Interferences
Recovery Study Basics · Principle
· Use known amounts of “well-characterized materials” on coupons that are representative of the surfaces to be sampled.
· Well-characterized materials · Materials that respond well to the analytical technique to be
employed · Materials that can be prepared in solutions of known
concentration (standards) · Technique
· Dispense known volumes of standards over the area to be sampled
· Swab by the recommended technique
Recovery Study Basics
· Swab background determination · Swab recovery coupons for different surfaces · Spike reference solution · Recovery = amount of quantified/original spiked
Cleaning Validation – Points to Consider
· Residues being removed · Sampling method · Analytical method · Timing of cleaning and testing · Cleaning parameters studied
· Acid/Base, Hot/Cold, Time · Final levels of residuals · Acceptable levels of residuals
HPLC/UV-Vis
· Positives · Good sensitivity to functional groups in drug actives · Good specificity · Good for APIs · Technology well-established�
· Negatives · Can be expensive · Prone to interferences · Requires functional group for response – does not detect
detergent residues
TOC
· Positives · Simple to measure · Minimal method development · Relatively inexpensive · Detects detergent residues which lack functional groups�
· Negatives · Non-specific – cannot provide characterization as to the type of
residue detected · Any organic carbon source is an interference · Must have back-up selective method if validation fails
Sampling – Rinse or Swab
· Rinse · Indirect sampling method · All residues must be soluble · Reach all product contact surfaces�
· Swab · Direct sampling method – most desirable*�
*FDA Guide to Inspections Validation of Cleaning Processes
Rinse Sampling
· Advantages · Large areas can be sampled · Inaccessible (internal) locations can be sampled�
· Disadvantage · Residue might be insoluble or occluded in
equipment