Cleaning Validation Olivier Gautier

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

Cleanroom Swabs

·  Selection · Why are some swabs better than others for

cleaning validation?

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

Product Release

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

How to Analyze the Sample

HPLC TOC High Performance Liquid

Chromatography Total Organic Carbon

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

Swab Sampling

·  Advantages ·  Can sample hard-to-clean areas ·  Insoluble residues can be physically removed

and analyzed�

·  Disadvantages ·  Small sample areas ·  Interference from swab material