Cleaning Validation Sampling Methods
Information & Training. | Product & Process Validation.The method of sampling applied will determine the effectiveness and acceptability of the cleaning process. A cleaning validation plan will define the sampling method and the reason why the specific method(s) was selected. The analytical procedures to be applied in the analysis of the outcomes of the cleaning methods, details regarding test laboratories to be utilized, will all be included in the cleaning validation protocols and SOP’s.
All cleaning validation sampling methods will normally include a visual check which will provide an immediate feedback on the cleaning process deficiencies. The sampling method will then be based on some or all of surface swabbing, sample fluid rinse, coupon sampling, placebo sampling.
Swabbing involves using a wipe or swab that is moistened with high purity water (WFI – water for injection) that is typically wiped over a defined area in a systematic multi-pass way always going from clean to dirty areas to avoid recontamination – i.e. 10 side by side strokes vertically, 10 horizontally and 10 each with the flip side of the swab in each diagonal direction. For TOC analysis very clean low background swabs or wipes and sample vials such should be used.
Rinse water sampling involves taking a sample of an equilibrated post-final rinse that has been re-circulated over all surfaces. Rinse samples should be correlated to a direct measuring technique such as swabbing.
Coupon sampling involves the use of a coupon or an actual removable piece of pipe that is dipped into high purity water to extract residues for analysis. The coupon method can provide an actual measure of any contamination present, there is a need however to ensure that the coupons applied are actually equivalent to the surface under test.
Placebo testing involves using placebo product and analyzing for residues from the previous batch.
Visual inspection.Visual checks provide an immediate feedback on the acceptability of cleaning which is directly related to individual surfaces or items of equipment. A visual test method is somewhat dependent on the perception of the person performing the test and can result in variability between inspectors, time of inspection, etc..
Placebo testing.In order to validate the cleaning process a placebo batch may be processed under the same operating parameters as used for customer product. A sample of the placebo batch is then tested for residual contamination. However, there are considerations that need to be addressed when using placebo product to validate cleaning processes.
One cannot assure that the contaminate will be uniformly distributed throughout the system. For example, if the discharge valve or chute of a blender are contaminated, the contaminant would probably not be uniformly dispersed in the placebo, it would most likely be concentrated in the initial discharge portion of the batch. Additionally, if the contaminant or residue is of a larger particle size, it may not be uniformly dispersed in the placebo.
It is important not to make an assumption that a residual contaminant will be worn off the equipment surface uniformly; such an assumption may be inaccurate. Also the analytical power may be greatly reduced by dilution of any contaminate. Because of such problems, rinse and/or swab samples should be used in conjunction with the placebo method (as recommended by the FDA).
Approach to validating the cleaning process.Ideally in order to optimise the cleaning process, each piece of equipment should be dismantled into its individual components after any cleaning and each part should be individually tested for cleanliness. Via this approach, any deficiencies in the cleaning process will be easier to identify and can be directly related to a specific component within an item of process equipment. However, in many situations it will not be physically or practically possible to dismantle large or complex items of equipment.
Once a cleaning has been implemented, testing of the effectiveness of the cleaning should be performed as soon as possible after the cleaning has been performed to minimize the potential for the introduction of any new contamination. Equally, where any contamination has been identified via any of the cleaning effectiveness test methods, the cause of the contamination must be investigated and identified and actions implemented to prevent any recurrence.
The most difficult to clean or “worst-case” areas of the equipment should be identified and specifically targeted for sampling whenever possible.
Solvents.Where any aqueous or organic solvents are used in the cleaning procedure, the quantity utilized should be sufficient so as to remove residues, but equally should not create a potential for any reaction with or damage to the equipment, or the over-dilution of the residue and the resultant loss of analytical sensitivity.
Residue Detection.Selecting a method to detect cleaner residues can involve specific methods for specific cleaner ingredients such as: High Performance Liquid Chromatography (HPLC), ion selective electrodes, flame photometry, derivative UltraViolet (UV) spectroscopy, Thin Layer Chromatography, enzymatic detection and titration. It can also involve non-specific methods that detect the presence of a blend of ingredients such as: TOC, pH, and conductivity. The FDA prefers specific methods, but will accept non-specific methods with adequate rationales for their use. For investigations of failures or action levels, a specific method is usually preferable.
Analytical Evaluation.Once a visual test has confirmed that there are no obvious deficiencies in the cleaning process, then the analytical test needs to be performed.
If the swab test method has been applied, then the effectiveness of the swab in collecting any potential contamination needs to be understood, also is there any potential for interference between the swab materials and contaminants which could affect analytical results.
For the rinse method, consideration needs to be given to the effectiveness of the rinse solution in terms of recovering residues from the surfaces being tested, the potential for interference by the rinse solution with the analytical test results, the determination of a “recovery efficiency” when calculating residue acceptability levels. The percent of actual amount of residual = calculated residue levels x estimated percent recovery.
When estimating the percent recovery, consideration needs to be given to the potential for interaction between the rinse solvents and the surface residues, the types of solvent applied, the nature of the surfaces under test. The percent recovery for proteins which have a low solubility may be of the order of 20% even down to 10%, for soluble residues higher percent recovery may be expected, to an order of 70% to 90%. An objective should be to seek to improve the percent recovery via an ongoing program of sampling method improvement.
Information & Training.
Product and Process Validation.
- The Validation Master Plan. Performing a Gap Analysis. Validation in the Design Process. Etc..
- How to ensure Validation efforts are aligned with potential Risks.
- How to ensure that Validation activity is appropriately documented, reviewed and aligned with requirements.
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Sources of further information on Cleaning Validation Sampling Methods.
FDA, Guide To Inspections of Validation of Cleaning Processes.
EC, “The Rules Governing Medicinal Products in the European Community,” Volume IV, Good Manufacturing Practices for Medicinal Products.
Health Canada, Cleaning Validation Guidelines (GUIDE-0028).
WHO, “Appendix 3, Cleaning Validation,” WHO Expert Committee on Specification for Pharmaceutical Preparation, World Health Organization, Fortieth Report.
ICH Guidance for Industry, Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients.
PIC/S, Recommendations on Cleaning Validation. Document PI 006- 1, Pharmaceutical Inspection Cooperation Scheme, Geneva, Switzerland.