5. GENERAL CLEANING CONSIDERATIONS
5.7 Analytical Test Methods
1. be specific for the substance to be assayed and provide a sensitivity that reflects the level of cleanliness determined to be acceptable by the company.
Selected FDA 483 Observations (December 2006) Product Manufacture
[VIP ID: 194324]
“Cleaning validation, for equipment, which is not dedicated to one product, should include the evaluation of microbiological control, a recovery study performed to demonstrate the sensitivity and specificity (detection limit) of analytical equipment to demonstrate that residual product is removed after cleaning, documentation of the sampling method or location used in the cleaning validation and the establishment of time limitation of cleaning prior to next use.”
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 15 - QUALIFICATION AND VALIDATION
CLEANING VALIDATION 37
[VIP ID: 187104]
“Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant.”
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN
INSTALLATION AND OPERATIONAL QUALIFICATION NON-STERILE PROCESS VALIDATION
CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.10 Analytical Methods 7.10.2
[VIP ID: 188698]
“The analytical methods used to detect residuals or contaminants should be specific for the substance to be assayed and provide a sensitivity that reflects the level of cleanliness determined to be acceptable by the company.”
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 12.74
[VIP ID: 24773]
“Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant. The method's attainable recovery level should be established. Residue limits should be practical, achievable, verifiable and based on the most deleterious residue. Limits can be established based on the minimum known pharmacological, toxicological, or physiological activity of the API or its most deleterious component.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
12. VALIDATION 12.7 Cleaning Validation 12.74
[VIP ID: 155780]
“Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant. The method’s attainable recovery level should be established. Residue limits should be practical, achievable, verifiable and based on the most deleterious residue. Limits can be established based on the minimum known pharmacological, toxicological, or physiological activity of the API or its most deleterious component.”
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 4.10. Analytical Methods 4.10.2.
[VIP ID: 69370]
“The analytical methods used to detect residuals or contaminants should be specific for the substance to be assayed and provide a sensitivity that reflects the level of cleanliness determined to be acceptable by the company.”
2. include a description of the type of analytical equipment used.
Selected FDA 483 Observations (January 1999) Product Manufacture
[VIP ID: 7094]
“Cleaning validation protocols should include provisions for:
7) a description of the type of analytical equipment used”
3. include parameters for the sensitivity of the analytical methods.
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 12.74
[VIP ID: 24773]
“Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant. The method's attainable recovery level should be established.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
12. VALIDATION 12.7 Cleaning Validation 12.74
[VIP ID: 155780]
“Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant. The method’s attainable recovery level should be established.”
Selected FDA 483 Observations (June 1999) Product Manufacture
[VIP ID: 7235]
“Cleaning validation protocols should include:
3) parameters for the sensitivity of the analytical methods”
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) III. General Requirements
(para 4) [VIP ID: 1326]
“FDA expects firms to prepare specific written validation protocols in advance for the studies to be performed on each manufacturing system or piece of equipment which should address such issues as sampling procedures, and analytical methods to be used including the sensitivity of those methods.”
4. define system suitability linearity requirements for test methods utilising standard curves.
Selected FDA 483 Observations (April 2000) Laboratories
[VIP ID: 15360]
“Cleaning validation of cleaning agents (detergents) should include:
(3) system suitability linearity requirements for test methods utilizing standard curves”
5. include the requirement for printing standard curves when the instrument has the capability.
Selected FDA 483 Observations (April 2000) Laboratories
[VIP ID: 15360]
“Cleaning validation of cleaning agents (detergents) should include:
(4) printing out of standard curves where the instrument has the capability”
6. include tests to show the precision (reproducibility) of the instrument at the time of use.
Selected FDA 483 Observations (April 2000) Laboratories
[VIP ID: 15360]
“Cleaning validation of cleaning agents (detergents) should include:
(5) tests to show the precision (reproducibility) of the instrument at the time of use”
7. address the detection of all possible residues.
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 5
PRODUCTION
PREVENTION OF CROSS-CONTAMINATION IN PRODUCTION 5.19
[VIP ID: 185740]
“Cross-contamination should be avoided by appropriate technical or organisational measures, for example:
g) testing for residues and use of cleaning status labels on equipment.”
Selected FDA 483 Observations (August 1998) Active Pharmaceutical Ingredient Manufacture [VIP ID: 6766]
“BPC cleaning validation should include:
6) analytical procedures for the detection of all possible residues”
Selected FDA 483 Observations (February 1998) Product Manufacture
[VIP ID: 6329]
“Cleaning validation protocols should include:
3) testing for the removal of sanitizing agents and detergents”
EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 5 - PRODUCTION
Prevention of cross-contamination in production 5.19.
[VIP ID: 529]
“Cross-contamination should be avoided by appropriate technical or organisational measures, for example:
(g) testing for residues and use of cleaning status labels on equipment.”
Selected FDA 483 Observations (July 1997) Sterile Product Manufacture
[VIP ID: 2518]
“Cleaning Validation should include:
(2) an assay for residual cleaning agents”
8. include a statement that cleaning swab samples should not be composited prior to analysis.
21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006)
Subpart E -- Control of Components and Drug Product Containers and Closures
Sec. 211.84 Testing and approval or rejection of components, drug product containers, and closures (c)
[VIP ID: 75]
“Samples shall be collected in accordance with the following procedures:
(4) If it is necessary to sample a component from the top, middle, and bottom of its container, such sample subdivisions shall not be composited for testing.”
Selected FDA 483 Observations (September 2001) Active Pharmaceutical Ingredient Manufacture [VIP ID: 40920]
“Cleaning swab samples taken from different locations from each piece of equipment should not be combined into one sample and tested as such.”
Selected FDA 483 Observations (October 1998) Product Manufacture
[VIP ID: 6845]
“Cleaning validation swab samples should not be composited prior to analysis.”
9. include provisions for microbiological testing of swab samples.
Selected FDA 483 Observations (January 1999) Sterile Product Manufacture
[VIP ID: 7105]
“Cleaning validation should include:
1) testing for microbial contamination”
Selected FDA 483 Observations (January 1999) Product Manufacture
[VIP ID: 7094]
“Cleaning validation protocols should include provisions for:
2) microbiological testing of swab samples”
10. include the formula used to calculate the amount of possible contamination based on analysis.
Selected FDA 483 Observations (October 1997) Product Manufacture
[VIP ID: 2480]
“The procedure for the collection of rinse water samples should take into account:
5. formula used to calculate the amount of possible contamination based on analysis”
11. include directions for the handling of unused data.
Selected FDA 483 Observations (April 2000) Laboratories
[VIP ID: 15360]
“Cleaning validation of cleaning agents (detergents) should include:
(8) procedures governing how unused data is handled”
12. include directions for the handling of negative results.
Selected FDA 483 Observations (April 2000) Laboratories
[VIP ID: 15360]
“Cleaning validation of cleaning agents (detergents) should include:
(7) directions for the handling of negative results”
• A negative test may be the result of poor sampling technique.
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 4.10. Analytical Methods 4.10.3.
[VIP ID: 69380]
“…A negative result may also be the result of poor sampling techniques.”
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation
3. Analytical Methods [VIP ID: 1340]
“Determine the specificity and sensitivity of the analytical method used to detect residuals or contaminants. With advances in analytical technology, residues from the manufacturing and cleaning processes can be detected at very low levels. If levels of contamination or residual are not detected, it does not mean that there is no residual contaminant present after cleaning. It only means that levels of contaminant greater than the sensitivity or detection limit of the analytical method are not present in the sample. The firm should challenge the analytical method in combination with the sampling method(s) used to show that contaminants can be recovered from the equipment surface and at what level, i.e. 50% recovery, 90%, etc. This is necessary before any conclusions can be made based on the sample results. A negative test may also be the result of poor sampling technique (see below).”