Cleaning Validation. Olivier Gautier

Transcription

1 Cleaning Validation Olivier Gautier

2 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

3 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.

4 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

5 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

6 Residues to be Removed Cleaning solutions Solvents Cleaning solutions Disinfectants Drug substances API s Biologicals Excipients Preservatives Others Microbiological contamination

7 Sampling -" Why? Determine initial levels of cleanliness Determine final levels Determine removal efficiency Meet FDA requirements

8 Sampling -" What? Product contact surfaces Different kind of surfaces Group by materials of construction Group by sampling method Group method of cleaning Several locations

9 Sampling -" Where? Where cleaning is difficult Irregular surfaces Hard-to-reach areas Porous surfaces Heated surfaces

10 Sampling " How do you sample? Defined locations Defined region Swab sampling Store effectively Transfer for analysis

11 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

12 Cleanroom Swabs Selection Why are some swabs better than others for cleaning validation?

13 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 q Blends (combination of fibers) Polyester/cellulose Composites (sandwich of materials Polypropylene/cellulose

14 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

15 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

16 Product Release

17 Typical Swabbing Pattern and How to Release Demonstration during workshop Step 1 Step 2 Step 3 Step 4

18 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

19 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

20 Recovery Study Basics Swab background determination Swab recovery coupons for different surfaces Spike reference solution Recovery = amount of quantified/original spiked

21 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

22 How to Analyze the Sample HPLC High Performance Liquid Chromatography TOC Total Organic Carbon

23 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

24 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

25 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

26 Rinse Sampling Advantages Large areas can be sampled Inaccessible (internal) locations can be sampled Disadvantage Residue might be insoluble or occluded in equipment

27 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