The following points should be considered when establishing the cleaning validation acceptance limits:
1. Part of the answer to the question, "how clean is clean?", is, "how good is your analytical system?".
The sensitivity of modern analytical apparatus has lowered some detection thresholds past parts per million, down to parts per billion.
BIOTECHNOLOGY INSPECTION GUIDE (November 1991) CLEANING PROCEDURES
C. Analytical Method/Cleaning Limits (para 1)
[VIP ID: 1087]
“Part of the answer to the question, "how clean is clean?", is, "how good is your analytical system?" The sensitivity of modern analytical apparatus has lowered some detection thresholds below parts per million (ppm), down to parts per billion (ppb).”
GUIDE TO INSPECTIONS OF BULK PHARMACEUTICAL CHEMICALS (May 1994) PART II - SPECIFIC INTERPRETATIONS FOR BPC OPERATIONS
Equipment
(e) Cleaning of Product Contact Surfaces (para 3)
[VIP ID: 3444]
“Specific inspectional coverage for cleaning should include:
3. Analytical Method/Cleaning Limits:
Part of the answer to the question, "how clean is clean?", is, "how good is your analytical system?". The sensitivity of modern analytical apparatus has lowered some detection thresholds past parts per million, down to parts per billion.”
2. FDA does not intend to set acceptance specifications or methods for determining whether a cleaning process is validated. It is impractical for FDA to do so due to the wide variation in equipment and products used throughout the bulk and finished dosage form industries.
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) V. Establishment of Limits
(para 1) [VIP ID: 1348]
“FDA does not intend to set acceptance specifications or methods for determining whether a cleaning process is validated. It is impractical for FDA to do so due to the wide variation in equipment and products used throughout the bulk and finished dosage form industries.”
3. The firm's rationale for the residue limits established should be logical based on the manufacturer's knowledge of the materials involved and be practical, achievable, and verifiable.
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION 7.11 Establishment of Limits 7.11.1
[VIP ID: 188702]
“The pharmaceutical company's rationale for selecting limits for product residues should be logically based on a consideration of the materials involved and their therapeutic dose. The limits should be practical, achievable and verifiable.”
EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - QUALIFICATION AND VALIDATION (September 2001)
CLEANING VALIDATION 36.
[VIP ID: 21360]
“…The rationale for selecting limits of carry over of product residues, cleaning agents and microbial contamination should be logically based on the materials involved. The limits should be achievable and verifiable.”
Selected FDA 483 Observations (December 1999) Active Pharmaceutical Ingredient Manufacture [VIP ID: 14010]
“API cleaning validation protocols should state the acceptable limits for the amount of active ingredient or other chemicals remaining after cleaning.”
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 4.11. Establishment of Limits 4.11.1.
[VIP ID: 69390]
“The pharmaceutical company's rationale for selecting limits for product residues should be logically based on a consideration of the materials involved and their therapeutic dose. The limits should be practical, achievable and verifiable.”
GUIDE TO INSPECTIONS OF TOPICAL DRUG PRODUCTS (July 1994) V. CLEANING VALIDATION
Equipment Residue Limits (para 1)
[VIP ID: 119310]
“Because of improved technology, analytical methods are becoming much more sensitive and capable of determining very low levels of residues. Thus, it is important that a firm establish appropriate limits on levels of post-equipment cleaning residues. Such limits must be safe, practical, achievable, verifiable and must ensure that residues remaining in the equipment will not cause the quality of subsequent batches to be altered beyond established product specifications. During inspections, the rationale for residue limits should be reviewed.”
GUIDE TO INSPECTIONS OF BULK PHARMACEUTICAL CHEMICALS (May 1994) PART II - SPECIFIC INTERPRETATIONS FOR BPC OPERATIONS
Equipment
(e) Cleaning of Product Contact Surfaces (para 4)
[VIP ID: 3445]
“The residue limits established for each piece of apparatus should be practical, achievable, and verifiable. When reviewing these limits, ascertain the rationale for establishment at that level.”
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) V. Establishment of Limits
(para 1) [VIP ID: 1348]
“…The firm's rationale for the residue limits established should be logical based on the manufacturer's knowledge of the materials involved and be practical, achievable, and verifiable.”
BIOTECHNOLOGY INSPECTION GUIDE (November 1991) CLEANING PROCEDURES
C. Analytical Method/Cleaning Limits (para 2)
[VIP ID: 1088]
“The residue limits established for each piece of apparatus should be practical, achievable, and verifiable.”
• The manufacturer should be able to document, by means of data, that the residual level permitted is scientifically sound.
Selected FDA 483 Observations (May 2004) Active Pharmaceutical Ingredient Manufacture [VIP ID: 122470]
“API Cleaning Validation protocols should include:
d. data for the maximum allowable limit not to exceed.”
Selected FDA 483 Observations (May 2004) Active Pharmaceutical Ingredient Manufacture [VIP ID: 122470]
“API Cleaning Validation protocols should include:
b. justification for the acceptance criteria.”
Selected FDA 483 Observations (April 2001) Active Pharmaceutical Ingredient Manufacture [VIP ID: 27440]
“API Cleaning validation should include:
(1) Approved specifications for acceptable residue limits based on a scientific rationale such as safety.”
Selected FDA 483 Observations (January 2001) Active Pharmaceutical Ingredient Manufacture [VIP ID: 26560]
“Cleaning residue limits should be supported by a scientific rationale backed up by research.”
Selected FDA 483 Observations (May 2000) Active Pharmaceutical Ingredient Manufacture [VIP ID: 16020]
“There should be a scientific justification for the specification for residuals stated in the cleaning validation (simply stating <10ppm is not enough!)”
GUIDE TO INSPECTIONS OF BULK PHARMACEUTICAL CHEMICALS (May 1994) PART II - SPECIFIC INTERPRETATIONS FOR BPC OPERATIONS
Equipment
(e) Cleaning of Product Contact Surfaces (para 4)
[VIP ID: 3445]
“…The manufacturer should be able to document, by means of data, that the residual level permitted is scientifically sound.”
BIOTECHNOLOGY INSPECTION GUIDE (November 1991) CLEANING PROCEDURES
C. Analytical Method/Cleaning Limits (para 2)
[VIP ID: 1088]
“…When reviewing these limits, ascertain the rationale for establishment at that level.”
4. Cleaning validation should include an explanation of how allowed residue limits will affect the next synthesis stage or the next product type to be in contact with the equipment.
Selected FDA 483 Observations (January 2001) Active Pharmaceutical Ingredient Manufacture [VIP ID: 26570]
“Cleaning validation should include an explanation of how allowed residue limits will effect the next synthesis stage or the next product type to be in contact with the equipment.”
5. Limits that have been mentioned by industry representatives in the literature or in presentations include analytical detection levels such as 10 PPM, biological activity levels such as 1/1000 of the normal therapeutic dose, and organoleptic levels such as no visible residue.
Selected FDA 483 Observations (August 1998) Active Pharmaceutical Ingredient Manufacture [VIP ID: 6766]
“BPC cleaning validation should include:
1) a rationale (considering toxicology etc) for the allowable carryover from the equipment”
Selected FDA 483 Observations (November 1997) Active Pharmaceutical Ingredient Manufacture [VIP ID: 6261]
“Cleaning validation should include determination of the minimal allowable drug substance residue, from a therapeutic aspect, following equipment cleaning.”
GUIDE TO INSPECTIONS OF BULK PHARMACEUTICAL CHEMICALS (May 1994) PART II - SPECIFIC INTERPRETATIONS FOR BPC OPERATIONS
Equipment
(e) Cleaning of Product Contact Surfaces (para 1)
[VIP ID: 3442]
“Cleaning of multiple use equipment is an area where validation must be carried out. The manufacturer should have determined the degree of effectiveness of the cleaning procedure for each BPC or intermediate used in that particular piece of equipment.”
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) V. Establishment of Limits
(para 1) [VIP ID: 1348]
“…Some limits that have been mentioned by industry representatives in the literature or in presentations include analytical detection levels such as 10 PPM, biological activity levels such as 1/1000 of the normal therapeutic dose, and organoleptic levels such as no visible residue.”
BIOTECHNOLOGY INSPECTION GUIDE (November 1991) CLEANING PROCEDURES
(para 2) [VIP ID: 1082]
“Validation data should verify that the cleaning process will reduce the specific residues to an acceptable level.
However, it may not be possible to remove absolutely every trace of material, even with a reasonable number of cleaning cycles. The permissible residue level, generally expressed in parts per million (ppm), should be justified by the manufacturer.”
6. Carry-over of product residues should meet defined criteria, for example the most stringent of the following criteria:
(a) no more than 0.1% of the normal therapeutic dose of any product will appear in the maximum daily dose of the following product,
(b) no more than 10 PPM of any product will appear in another product,
(c) no quantity of residue should be visible on the equipment after cleaning procedures are
performed. Spiking studies should determine the concentration at which most active
ingredients are visible,
(d) for certain allergenic ingredients, penicillins, cephalosporins or potent steroids and cytotoxics, the limit should be below the limit of detection by best available analytical methods. In practice this may mean that dedicated plants are used for these products.
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION 7.11 Establishment of Limits 7.11.3
[VIP ID: 188706]
“Carry-over of product residues should meet defined criteria, for example the most stringent of the following three criteria:
(a) No more than 0.1% of the normal therapeutic dose of any product will appear in the maximum daily dose of the following product,
(b) No more than 10 ppm of any product will appear in another product,
(c) No quantity of residue should be visible on the equipment after cleaning procedures are performed. Spiking studies should determine the concentration at which most active ingredients are visible,
(d) For certain allergenic ingredients, penicillins, cephalosporins or potent steroids and cytotoxics, the limit should be below the limit of detection by best available analytical methods. In practice this may mean that dedicated plants are used for these products.”
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 4.11. Establishment of Limits 4.11.3.
[VIP ID: 69410]
“Carry-over of product residues should meet defined criteria, for example the most stringent of the following criteria:
(a) no more than 0.1% of the normal therapeutic dose of any product will appear in the maximum daily dose of the following product,
(b) no more than 10 ppm of any product will appear in another product,
(c) no quantity of residue should be visible on the equipment after cleaning procedures are performed. Spiking studies should determine the concentration at which most active ingredients are visible,
(d) for certain allergenic ingredients, penicillins, cephalosporins or potent steroids and cytotoxics, the limit should be below the limit of detection by best available analytical methods. In practice this may mean that dedicated plants are used for these products.”
7. Consideration should be given to the cumulative effect on recirculated mother liquors as used in API production.
Selected FDA 483 Observations (August 1998) Active Pharmaceutical Ingredient Manufacture [VIP ID: 6766]
“BPC cleaning validation should include:
3) the cumulative effect on recirculated mother liquors as used in production
8. Unlike finished pharmaceuticals where the chemical identity of residuals are known (i.e., from
actives, inactives, detergents) bulk processes may have partial reactants and unwanted
by-products which may never have been chemically identified. In establishing residual limits, it may not
be adequate to focus only on the principal reactant since other chemical variations may be more
difficult to remove. There are circumstances where TLC screening, in addition to chemical
analyses, may be needed. In a bulk process, particularly for very potent chemicals such as some
steroids, the issue of by-products needs to be considered if equipment is not dedicated. The
objective of the inspection is to ensure that the basis for any limits is scientifically justifiable.
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004)
7. CLEANING VALIDATION 7.11 Establishment of Limits 7.11.5
[VIP ID: 188710]
“In establishing residual limits, it may not be adequate to focus only on the principal reactant since chemical variations (active decomposition materials) may be more difficult to remove.”
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) V. Establishment of Limits
(para 2) [VIP ID: 1349]
“Check the manner in which limits are established. Unlike finished pharmaceuticals where the chemical identity of residuals are known (i.e., from actives, inactives, detergents) bulk processes may have partial reactants and unwanted by-products which may never have been chemically identified. In establishing residual limits, it may not be adequate to focus only on the principal reactant since other chemical variations may be more difficult to remove.
There are circumstances where TLC screening, in addition to chemical analyses, may be needed. In a bulk process, particularly for very potent chemicals such as some steroids, the issue of by-products needs to be considered if equipment is not dedicated. The objective of the inspection is to ensure that the basis for any limits is scientifically justifiable.”
9. Incidental carryover is another type of in-process mixing that occurs frequently. Examples include:
(a) Residue adhering to the wall of a micronizer used for milling the finished BPC;
(b) Residual layer of damp crystals remaining in a centrifuge bowl after discharge of the bulk of the crystals from a prior batch; and
(c) Incomplete discharge of fluids or crystals from a processing vessel upon transfer of the material to the next step in the process.
These practices are usually acceptable since we do not normally require complete cleanup between successive batches of the same drug during a production campaign. However, in the case of non-dedicated production units, complete cleaning procedures designed to prevent contamination that would alter the quality of the substance must be employed when changing from one BPC to another. The effectiveness of these cleaning procedures may require the use of analytical testing for the substances involved.
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005)
5. PROCESS EQUIPMENT
5.2 Equipment Maintenance and Cleaning 5.24
[VIP ID: 24569]
“Non-dedicated equipment should be cleaned between production of different materials to prevent cross-contamination.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
5. PROCESS EQUIPMENT
5.2 Equipment Maintenance and Cleaning 5.24
[VIP ID: 154010]
“Non-dedicated equipment should be cleaned between production of different materials to prevent cross-contamination.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
5. PROCESS EQUIPMENT
5.2 Equipment Maintenance and Cleaning 5.23
[VIP ID: 154000]
“Where equipment is assigned to continuous production or campaign production of successive batches of the same intermediate or API, equipment should be cleaned at appropriate intervals to prevent build-up and carry-over of contaminants (e.g. degradants or objectionable levels of micro-organisms).”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
8. PRODUCTION AND IN-PROCESS CONTROLS 8.5 Contamination Control
8.50
[VIP ID: 154920]
“Residual materials can be carried over into successive batches of the same intermediate or API if there is adequate control. Examples include residue adhering to the wall of a micronizer, residual layer of damp crystals remaining in a centrifuge bowl after discharge, and incomplete discharge of fluids or crystals from a processing vessel upon transfer of the material to the next step in the process. Such carryover should not result in the carryover of degradants or microbial contamination that may adversely alter the established API impurity profile.”
GUIDE TO INSPECTIONS OF BULK PHARMACEUTICAL CHEMICALS (May 1994) PART II - SPECIFIC INTERPRETATIONS FOR BPC OPERATIONS
Production and Process Controls (b) In Process Blending/Mixing (para 2)
[VIP ID: 3457]
“Incidental carryover is another type of in-process mixing that occurs frequently. Examples include:
1) Residue adhering to the wall of a micronizer used for milling the finished BPC;
2) Residual layer of damp crystals remaining in a centrifuge bowl after discharge of the bulk of the crystals from a prior batch; and
3) Incomplete discharge of fluids or crystals from a processing vessel upon transfer of the material to the next step in the process.
These practices are usually acceptable since we do not normally require complete cleanup between successive batches of the same drug during a production campaign. However, in the case of non-dedicated production units, complete cleaning procedures designed to prevent contamination that would alter the quality of the substance must be employed when changing from one BPC to another. The effectiveness of these cleaning procedures may require the use of analytical testing for the substances involved.”
10. When the cleaning process is used only between batches of the same product (or different lots of the same intermediate in a bulk process) the firm need only meet a criteria of, "visibly clean" for the equipment. Such between batch cleaning processes do not require validation.
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation
(para 2) [VIP ID: 1330]
“Determine the number of cleaning processes for each piece of equipment. Ideally, a piece of equipment or system will have one process for cleaning, however this will depend on the products being produced and whether the cleanup occurs between batches of the same product (as in a large campaign) or between batches of different products. When the cleaning process is used only between batches of the same product (or different lots of the same intermediate in a bulk process) the firm need only meet a criteria of, "visibly clean" for the equipment. Such between batch cleaning processes do not require validation.”
11. Residue limits should be established for each item of equipment.
Selected FDA 483 Observations (March 1999) Product Manufacture
[VIP ID: 7162]
“Cleaning validation should include:
2) acceptance criteria for detergent residues”
Selected FDA 483 Observations (October 1998) Product Manufacture
[VIP ID: 6863]
“Detergent residue limits should be established for each item of equipment.”
12. Sanitiser residue limits should be established for critical production areas (e.g. filling lines).
Selected FDA 483 Observations (May 1999) Sterile Product Manufacture
[VIP ID: 7200]
“Sanitizer residue limits should be established for critical production areas (e.g. filling lines).”
13. If a detergent or soap is used for cleaning, determine and consider the difficulty that may arise when attempting to test for residues. A common problem associated with detergent use is its composition. Many detergent suppliers will not provide specific composition, which makes it difficult for the user to evaluate residues. As with product residues, it is important and it is expected that the manufacturer evaluate the efficiency of the cleaning process for the removal of residues. However, unlike product residues, it is expected that no (or for ultra sensitive analytical test methods - very low) detergent levels remain after cleaning. Detergents are not part of the manufacturing process and are only added to facilitate cleaning during the cleaning process. Thus, they should be easily removable. otherwise, a different detergent should be selected.
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) VI. Other Issues
b. Detergent [VIP ID: 1353]
“If a detergent or soap is used for cleaning, determine and consider the difficulty that may arise when attempting to test for residues. A common problem associated with detergent use is its composition. Many detergent suppliers will not provide specific composition, which makes it difficult for the user to evaluate residues. As with product residues, it is important and it is expected that the manufacturer evaluate the efficiency of the cleaning process for the removal of residues. However, unlike product residues, it is expected that no (or for ultra sensitive analytical test methods - very low) detergent levels remain after cleaning. Detergents are not part of the manufacturing process and are only added to facilitate cleaning during the cleaning process. Thus, they should be easily removable.
otherwise, a different detergent should be selected.”
14. The impact of cleaning agent residual levels should be assessed.
Selected FDA 483 Observations (September 1998) Product Manufacture
[VIP ID: 6827]
“Cleaning validation should include:
3) the impact of cleaning agent residual levels”
Selected FDA 483 Observations (October 2003) Active Pharmaceutical Ingredient Manufacture [VIP ID: 70720]
“Cleaning validation should evaluate residual solvents used during cleaning.”
15. Detergent residual levels should be defined.
CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.9 Detergents
7.9.1
[VIP ID: 188692]
“…Acceptable limits should be defined for levels of detergent after cleaning. Ideally, there should be no residues
“…Acceptable limits should be defined for levels of detergent after cleaning. Ideally, there should be no residues