6. CLEANING VALIDATION CONSIDERATIONS
6.4 Direct/Indirect Sampling Methods
The following points should be considered for direct/indirect sampling:
1. There are two methods of sampling that are considered to be acceptable, direct surface sampling (swab method) and indirect sampling (use of rinse solutions).
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-STERILE PROCESS VALIDATION
CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.8 Sampling
7.8.2
[VIP ID: 188690]
“There are two methods of sampling that are considered to be acceptable, direct surface sampling (swab method) and indirect sampling (use of rinse solutions).”
EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999)
4. Cleaning Validation 4.8. Sampling 4.8.2.
(para 1) [VIP ID: 69300]
“There are two methods of sampling that are considered to be acceptable, direct surface sampling (swab method) and indirect sampling (use of rinse solutions). A combination of the two methods is generally the most desirable, particularly in circumstances where accessibility of equipment parts can mitigate against direct surface sampling.”
EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999)
4. Cleaning Validation 4.8. Sampling 4.8.2.
(para 2) [VIP ID: 69330]
“A direct measurement of the product residue or contaminant in the relevant solvent should be made when rinse samples are used to validate the cleaning process.”
GUIDE TO INSPECTIONS OF TOPICAL DRUG PRODUCTS (July 1994) V. CLEANING VALIDATION
Sampling Plan For Contaminants [VIP ID: 119300]
“As part of the validation of the cleaning method, the cleaned surface is sampled for the presence of residues.
Sampling should be by an appropriate method, selected based on factors such as equipment and solubility of residues. For example, representative swabbing of surfaces is often used, especially in hard to clean areas and / or where the residue is relatively insoluble. Analysis of rinse solutions for residues has also been shown to be of value where the residue is soluble and / or difficult to access for direct swabbing. Both methods are useful when there is a direct measurement of the residual substance. However, it is unacceptable to test rinse solutions (such as purified water) for conformance to the purity specifications for those solutions, instead of testing directly for the presence of possible residues.”
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation
4. Sampling [VIP ID: 1341]
“There are two general types of sampling that have been found acceptable. The most desirable is the direct method of sampling the surface of the equipment. Another method is the use of rinse solutions.”
BIOTECHNOLOGY INSPECTION GUIDE (November 1991) CLEANING PROCEDURES
B. Sampling Plan [VIP ID: 1086]
“After cleaning, there should be some routine testing to assure that the surface has been cleaned to the validated level. One common method is the analysis of the final rinse water or solvent for the presence of the cleaning agents last used in that piece of equipment. There should always be direct determination of the residual substance.”
• A combination of the two methods is generally the most desirable, particularly in circumstances where accessibility of equipment parts can mitigate against direct surface sampling.
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION 7.8 Sampling
7.8.2
[VIP ID: 188690]
“…A combination of the two methods is generally the most desirable, particularly in circumstances where accessibility of equipment parts can mitigate against direct surface sampling.
A. Direct Surface Sampling
(i) The suitability of the material to be used for sampling and of the sampling medium should be determined. The ability to recover samples accurately may be affected by the choice of sampling material. It is important to ensure that the sampling medium and solvent are satisfactory and can be readily used.
B. Rinse Samples
(i) Rinse samples allow sampling of a large surface area. In addition, inaccessible areas of equipment that cannot be routinely disassembled can be evaluated. However, consideration should be given to the solubility of the contaminant.
(ii) A direct measurement of the product residue or contaminant in the relevant solvent should be made when rinse samples are used to validate the cleaning process.”
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005)
12. VALIDATION 12.7 Cleaning Validation 12.73
[VIP ID: 24772]
“Sampling should include swabbing, rinsing, or alternative methods (e.g., direct extraction), as appropriate, to detect both insoluble and soluble residues. The sampling methods used should be capable of quantitatively measuring levels of residues remaining on the equipment surfaces after cleaning. Swab sampling may be impractical when product contact surfaces are not easily accessible due to equipment design and / or process limitations (e.g., inner surfaces of hoses, transfer pipes, reactor tanks with small ports or handling toxic materials, and small intricate equipment such as micronizers and microfluidizers).”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
12. VALIDATION 12.7 Cleaning Validation 12.73
[VIP ID: 155770]
“Sampling should include swabbing, rinsing, or alternative methods (e.g., direct extraction), as appropriate, to detect both insoluble and soluble residues. The sampling methods used should be capable of quantitatively measuring levels of residues remaining on the equipment surfaces after cleaning. Swab sampling may be impractical when product contact surfaces are not easily accessible due to equipment design and/or process limitations (e.g., inner surfaces of hoses, transfer pipes, reactor tanks with small ports or handling toxic materials, and small intricate equipment such as micronizers and microfluidizers).”
EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999)
4. Cleaning Validation 4.8. Sampling 4.8.2.
(para 1) a.
[VIP ID: 69310]
“Direct Surface Sampling
The suitability of the material to be used for sampling and of the sampling medium should be determined. The ability to recover samples accurately may be affected by the choice of sampling material. It is important to ensure that the sampling medium and solvent are satisfactory and can be readily used.”
2. An advantage of direct sampling is that "dried out" or insoluble residues can be sampled by physical removal.
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation
4. Sampling
a. Direct Surface Sampling - (para 2)
[VIP ID: 1343]
“Advantages of direct sampling are that areas hardest to clean and which are reasonably accessible can be evaluated, leading to establishing a level of contamination or residue per given surface area. Additionally, residues that are "dried out" or are insoluble can be sampled by physical removal.”
3. Cleaning validation should include swab testing, and not rely solely on rinse water analysis.
Selected FDA 483 Observations (December 2000) Sterile Product Manufacture
[VIP ID: 26500]
“Cleaning validation should include swab testing, and not rely solely on rinse water analysis.”
Selected FDA 483 Observations (May 2000) Active Pharmaceutical Ingredient Manufacture [VIP ID: 16010]
“Bulk pharmaceutical ingredient equipment cleaning validation should include swab samples.”
4. Two advantages of using rinse samples are that a larger surface area may be sampled, and inaccessible systems or ones that cannot be routinely disassembled can be sampled and evaluated.
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005)
12. VALIDATION 12.7 Cleaning Validation 12.73
[VIP ID: 24772]
“Sampling should include swabbing, rinsing, or alternative methods (e.g., direct extraction), as appropriate, to detect both insoluble and soluble residues. The sampling methods used should be capable of quantitatively measuring levels of residues remaining on the equipment surfaces after cleaning. Swab sampling may be impractical when product contact surfaces are not easily accessible due to equipment design and / or process limitations (e.g., inner surfaces of hoses, transfer pipes, reactor tanks with small ports or handling toxic materials, and small intricate equipment such as micronizers and microfluidizers).”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
12. VALIDATION 12.7 Cleaning Validation 12.73
[VIP ID: 155770]
“Sampling should include swabbing, rinsing, or alternative methods (e.g., direct extraction), as appropriate, to detect both insoluble and soluble residues. The sampling methods used should be capable of quantitatively measuring levels of residues remaining on the equipment surfaces after cleaning. Swab sampling may be impractical when product contact surfaces are not easily accessible due to equipment design and/or process limitations (e.g., inner surfaces of hoses, transfer pipes, reactor tanks with small ports or handling toxic materials, and small intricate equipment such as micronizers and microfluidizers).”
EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999)
4. Cleaning Validation 4.8. Sampling 4.8.2.
(para 1) b.
[VIP ID: 69320]
“Rinse Samples
Rinse samples allow sampling of a large surface area. In addition, inaccessible areas of equipment that cannot be routinely disassembled can be evaluated. However, consideration should be given to the solubility of the contaminant and the appropriate volume of the samples.”
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation
4. Sampling b. Rinse Samples - (para 1)
[VIP ID: 1344]
“Two advantages of using rinse samples are that a larger surface area may be sampled, and inaccessible systems or ones that cannot be routinely disassembled can be sampled and evaluated.”
5. A disadvantage of indirect (rinse) samples is that the residue or contaminant may not be soluble or may be physically occluded in the equipment.
EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED!! (October 1999)
4. Cleaning Validation 4.8. Sampling 4.8.2.
(para 1) b.
[VIP ID: 69320]
“Rinse Samples
Rinse samples allow sampling of a large surface area. In addition, inaccessible areas of equipment that cannot be routinely disassembled can be evaluated. However, consideration should be given to the solubility of the contaminant and the appropriate volume of the samples.”
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation
4. Sampling b. Rinse Samples - (para 2)
[VIP ID: 1345]
“A disadvantage of rinse samples is that the residue or contaminant may not be soluble or may be physically occluded in the equipment. ...”
• An analogy that can be used is the "dirty pot." In the evaluation of cleaning of a dirty pot, particularly with dried out residue, one does not look at the rinse water to see that it is clean; one looks at the pot.
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation
4. Sampling b. Rinse Samples - (para 2)
[VIP ID: 1345]
“… An analogy that can be used is the "dirty pot." In the evaluation of cleaning of a dirty pot, particularly with dried out residue, one does not look at the rinse water to see that it is clean; one looks at the pot.”