6. CLEANING VALIDATION CONSIDERATIONS
6.9 Analytical Test Method Validation
Analytical test method validation protocols should:
1. demonstrate that the methods used to collect cleaning samples are reliable, and that therefore the results are representative and reproducible.
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 7.10.3
[VIP ID: 188700]
“The analytical methods should be challenged in combination with the sampling methods used, to show that the contaminants can be recovered from the equipment surface and to show the level of recovery as well as the consistency of recovery. This is necessary before any conclusions can be made based on the sample results. A negative result may also be the result of poor sampling techniques.”
Selected FDA 483 Observations (May 2002) Laboratories
[VIP ID: 46790]
“Analytical method used for testing swabs in cleaning validation studies should be shown to have suitable sample preparation, HPLC operating conditions, and / or limits of quantitation and detection prior to use.”
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DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED!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]
“The analytical methods should be challenged in combination with the sampling methods used, to show that the contaminants can be recovered from the equipment surface and to show the level of recovery as well as the consistency of recovery. This is necessary before any conclusions can be made based on the sample results. A negative result may also be the result of poor sampling techniques.”
Selected FDA 483 Observations (September 1997) Product Manufacture
[VIP ID: 2498]
“Data should be generated to show that the methods used to collect cleaning samples are reliable, and that therefore the results are representative and reproducible.”
2. include the determination of the limit of detection and quantitation of the test method for products, product degradents, cleaning agents, drug/cleaning agent reaction products and excipients.
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION 7.4 Documentation 7.4.1
[VIP ID: 188662]
“A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following:
- Analytical methods including the limit of detection and the limit of quantitation of those methods,”
Selected FDA 483 Observations (May 2002) Laboratories
[VIP ID: 46790]
“Analytical method used for testing swabs in cleaning validation studies should be shown to have suitable sample preparation, HPLC operating conditions, and / or limits of quantitation and detection prior to use.”
EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - QUALIFICATION AND VALIDATION (September 2001)
CLEANING VALIDATION 37.
[VIP ID: 21370]
“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.”
Selected FDA 483 Observations (July 2001) Product Manufacture
[VIP ID: 40380]
“Cleaning validation should address the following critical issues:
(4) the adequacy of test methods and limit of detection (LOD)/limit of quantization (LQD) of such test methods”
Selected FDA 483 Observations (July 2001) Product Manufacture
[VIP ID: 40380]
“Cleaning validation should address the following critical issues:
(3) the adequacy of using rinse samples to evaluate cleanliness of the percent recovery obtained from rinse samples”
Selected FDA 483 Observations (November 2000) Product Manufacture
[VIP ID: 26190]
“Cleaning validation should include:
(1) calculation of the limit of detection”
Selected FDA 483 Observations (September 2000) Product Manufacture
[VIP ID: 19680]
“Cleaning analytical method validation should include the determination of the limit of detection and quantification.”
Selected FDA 483 Observations (September 1999) Product Manufacture
[VIP ID: 8310]
“Cleaning validation (matrix) studies should address and evaluate:
(2) ability of analytical methods to detect potential product degradents, drug/cleaning agent reaction products and excipients”
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 4.4. Documentation 4.4.1.
(k)
[VIP ID: 69130]
“A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following:
(k) analytical methods including the limit of detection and the limit of quantitation of those methods,”
Selected FDA 483 Observations (September 1988) Product Manufacture
[VIP ID: 6800]
“Limits of detection and quantitation should be established for the residual solvent analytical method.”
Selected FDA 483 Observations (February 1998) Product Manufacture
[VIP ID: 6329]
“Cleaning validation protocols should include:
2) limits of detection”
Selected FDA 483 Observations (February 1998) Active Pharmaceutical Ingredient Manufacture [VIP ID: 6317]
“Minimum detectable chemical residue levels should be determined for products and cleaning agents.”
Selected FDA 483 Observations (April 1997) Product Manufacture
[VIP ID: 2538]
“Cleaning validation should include the determination of the limit of detection of the test method.”
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) V. Establishment of Limits
(para 1) [VIP ID: 1348]
“…It is important to define the sensitivity of the analytical methods in order to set reasonable limits.”
• Determine the specificity and sensitivity of the analytical method used to detect residuals or contaminants. 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.
Selected FDA 483 Observations (August 2007) Laboratories
[VIP ID: 193978]
“The specificity of test methods should be documented. For example, instructions for the identification and quantification of peaks when using integrators should be provided, and integrated peaks in the swab samples taken during cleaning validation runs eluting close to the retention time of the standard peak should be identified or quantified during the validation exercise.”
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.”
3. include accuracy, precision, specificity and linearity.
Selected FDA 483 Observations (October 2007) Laboratories
[VIP ID: 194168]
“A laboratory should establish scientifically sound rationale for cleaning analytical methods, which show linearity ranges that do not correspond to the acceptance criteria for active ingredient residues.”
Selected FDA 483 Observations (September 2000) Product Manufacture
[VIP ID: 19870]
“Cleaning validation of processing equipment should include:
b) analytical method validation to include accuracy, precision, specificity, linearity etc.”
4. include the evaluation of the method against more sensitive test methods where available (e.g.
HPLC), to ensure adequate specificity and sensitivity of impurity detection.
Selected FDA 483 Observations (April 1998) Active Pharmaceutical Ingredient Manufacture [VIP ID: 6372]
“Cleaning validation analytical methods should be evaluated against more sensitive test methods where available (e.g. HPLC), to ensure adequate specificity and sensitivity of impurity detection.”
5. include recovery studies that require the application of an active to a coupon or template which replicates the equipment surface.
Extracted from FDA warning letter 07-NWJ-06 (February 2007) USA
01-Feb-07 7. b)
[VIP ID: 194844]
“Your firm's cleaning validation studies were found to be inadequate and, as a result, there was no assurance that equipment is adequately cleaned between the manufacture of different drug products. [21 CFR 211.67(b)] For example:
b) Recovery studies were performed for numerous drug products by applying a known amount of active pharmaceutical ingredient directly to a swab, instead of applying the active to a coupon or template which would replicate the equipment surface from which the active pharmaceutical ingredient should have been swabbed. The products involved, included: Busipirone HCl Tablets, Hydrocodone Bitartrate and Homatropine Methylbromide Tablets, Mirtazapine Tablets, Oxycodone and Acetaminophen Capsules USP.”
6. include a challenge to the sampling method (i.e. swabbing) to show that the recoveries can be obtained at the specified limits.
Selected FDA 483 Observations (January 2003) Product Manufacture
[VIP ID: 51890]
“Cleaning validation should include a challenge to the sampling method (i.e. swabbing) to show that the recoveries can be obtained at the specified limits.”
7. include percent recovery studies on rinse/swab samples.
Selected FDA 483 Observations (August 2004) Product Manufacture
[VIP ID: 123660]
“Cleaning procedures for Vacuum Blenders should be validated to include:
a. a percent recovery study for the rinse water sampling method.”
Selected FDA 483 Observations (April 2002) Sterile Product Manufacture
[VIP ID: 46670]
“Recovery studies should be performed to qualify the swab method and material utilized for swabbing product contact surfaces at the conclusion of an aseptic fill.”
Selected FDA 483 Observations (March 2002) Product Manufacture
[VIP ID: 46580]
“Cleaning validations should include recovery study data.”
Selected FDA 483 Observations (January 2002) Product Manufacture
[VIP ID: 46280]
“Cleaning validation should include:
(a) Recovery studies for the swab sampling method used.”
Selected FDA 483 Observations (September 2001) Active Pharmaceutical Ingredient Manufacture [VIP ID: 40940]
“Cleaning validation should include recovery studies.”
Selected FDA 483 Observations (July 2001) Product Manufacture
[VIP ID: 40380]
“Cleaning validation should address the following critical issues:
(3) the adequacy of using rinse samples to evaluate cleanliness of the percent recovery obtained from rinse samples”
Selected FDA 483 Observations (April 2001) Active Pharmaceutical Ingredient Manufacture [VIP ID: 27440]
“API Cleaning validation should include:
(2) Residue recovery data showing the efficiency of removal of target residues (including APIs) from equipment contact surfaces.”
Selected FDA 483 Observations (January 2001) Active Pharmaceutical Ingredient Manufacture [VIP ID: 26540]
“Cleaning validation should include tests to demonstrate the swabbed residues can be extracted from the cotton balls used for swabbing.”
Extracted from FDA Warning Letter 320-01-06 (December 2000) India
19/04/2001 [VIP ID: 29310]
“4. Cleaning validation studies for multiple use equipment were inadequate in a that the validation protocol did not identify the cleaning procedure, total surface area was not considered during the validation study, recovery studies were not done to validate the swab sampling method or filtering of rinse samples, some rinse samples were not analyzed, dates of analyses were inaccurate, and analytical data on rinse samples were not checked by a second person. [FDA-483 items 9, 10]”
Selected FDA 483 Observations (September 2000) Product Manufacture
[VIP ID: 19870]
“Cleaning validation of processing equipment should include:
a) percent recovery studies for swabbing methods”
Selected FDA 483 Observations (May 2000) Product Manufacture
[VIP ID: 16120]
“Cleaning validation should include swab recovery studies for products and detergents.”
Selected FDA 483 Observations (November 1999) Product Manufacture
[VIP ID: 8830]
“Cleaning validation should include:
1) percentage recovery”
Selected FDA 483 Observations (December 1998) Sterile Product Manufacture
[VIP ID: 7067]
“Cleaning validation should include:
1) rinse/swab sample recovery studies”
Selected FDA 483 Observations (August 1998) Product Manufacture
[VIP ID: 6796]
“Cleaning validation should include recovery studies.”
Selected FDA 483 Observations (September 1997) Product Manufacture
[VIP ID: 2497]
“Equipment cleaning validation should include:
(2) Percent recovery studies on rinse samples”
• 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.
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation
3. Analytical Methods [VIP ID: 1340]
“…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.”
• The worst case result should be used to calculate a swab recovery factor for cleaning validation, to ensure that the actual contamination is not higher than calculated.
Selected FDA 483 Observations (October 1997) Product Manufacture
[VIP ID: 2483]
“The worst case result should be used to calculate a swab recover factor for cleaning validation, to ensure that the actual contamination is not higher than calculated.”
8. include an assessment of the variability between swabs (applicator tips)
Selected FDA 483 Observations (April 2000) Laboratories
[VIP ID: 15360]
“Cleaning validation of cleaning agents (detergents) should include:
(6) assessment of the variability between swabs (applicator tips)”
9. include the determination of the type of sampling materials used (the sampling medium and solvent used for extraction from the medium) and its impact on the test data.
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation
4. Sampling
a. Direct Surface Sampling - (para 1)
[VIP ID: 1342]
“Determine the type of sampling material used and its impact on the test data since the sampling material may interfere with the test. For example, the adhesive used in swabs has been found to interfere with the analysis of samples. Therefore, early in the validation program, it is important to assure that the sampling medium and solvent (used for extraction from the medium) are satisfactory and can be readily used.”
• For example, the adhesive used in swabs has been found to interfere with the analysis of samples.
Selected FDA 483 Observations (January 2002) Product Manufacture
[VIP ID: 46280]
“Cleaning validation should include:
(b) Assurance that the type of swab used does not contribute interference to the analytical method.”
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation
4. Sampling
a. Direct Surface Sampling - (para 1)
[VIP ID: 1342]
“…For example, the adhesive used in swabs has been found to interfere with the analysis of samples.”
10. include raw data regarding standard and sample preparations, equipment used, reference standards used etc.
Selected FDA 483 Observations (September 2001) Active Pharmaceutical Ingredient Manufacture [VIP ID: 40950]
“Cleaning validation studies should include raw data regarding standard and sample preparations, equipment used, reference standards used etc.”
11. include testing to determine the types of residues obtained from the detergent(s) used.
Selected FDA 483 Observations (July 2000) Product Manufacture
[VIP ID: 19300]
“Cleaning validation should include testing to determine the types of residues obtained from the detergent(s) used.”
12. include all surfaces the disinfectant is used on (such as glass, plastic and epoxy painted surfaces), not just stainless steel.
Selected FDA 483 Observations (March 2003) Product Manufacture
[VIP ID: 52180]
“The qualification of disinfecting agents used to sanitize surfaces in aseptic processing areas (APA) should address all surfaces in the area not just stainless steel (such as glass, plastic and epoxy painted surfaces).”
Selected FDA 483 Observations (April 2002) Product Manufacture
[VIP ID: 46680]
“Disinfectant qualification should include all surfaces the disinfectant is used on, not just stainless steel.”
13. include the determination of the solubility of product and excipient residues in the rinse solvent.
Selected FDA 483 Observations (August 2004) Product Manufacture
[VIP ID: 123660]
“Cleaning procedures for Vacuum Blenders should be validated to include:
b. a solubility study to determine which products are hardest to clean”
Selected FDA 483 Observations (May 2004) Active Pharmaceutical Ingredient Manufacture [VIP ID: 122470]
“API Cleaning Validation protocols should include:
a. an evaluation of product solubility.”
EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 13 - MANUFACTURE OF INVESTIGATIONAL MEDICINAL PRODUCTS (July 2003)
PREMISES AND EQUIPMENT 5
[VIP ID: 64250]
“…Account should be taken of the solubility of the product in decisions about the choice of cleaning solvent.”
Selected FDA 483 Observations (June 2001) Active Pharmaceutical Ingredient Manufacture [VIP ID: 40130]
“Water / solvent solubility should be known for all products listed in a cleaning validation decision matrix.”
Selected FDA 483 Observations (August 1998) Active Pharmaceutical Ingredient Manufacture [VIP ID: 6766]
“BPC cleaning validation should include:
5) determination of the solubility of the residues in the rinse solvent”
14. include the following for production Spectrophotometers used to determine the contaminant concentration in rinse samples:
• assurance that passing test results are within the limits of detection.
• justification for the use of sample blanks.
• assurance that reported sample test results are accurate.
• written procedures for testing rinse samples using blank standards.
• information or data on negative absorbance test results.”
Selected FDA 483 Observations (September 2003) Laboratories
[VIP ID: 70180]
“Method validation for production Spectrophotometers used to determine the contaminant concentration in rinse samples to assure effectiveness of manual cleaning processes between production runs should include:
- assurance that passing test results are within the limits of detection.
- justification for the use of sample blanks.
- assurance that reported sample test results are accurate.
- written procedures for testing rinse samples using blank standards.
- information or data on negative absorbance test results.”
15. challenge the ruggedness of the method by using different laboratories, analysts, days and equipment.
Selected FDA 483 Observations (October 1999) Laboratories
[VIP ID: 136760]
“The validation of analytical methods used to evaluate the effectiveness of equipment cleaning procedures should challenge the ruggedness of the method by using different laboratories, analysts, days and equipment.”