5. GENERAL CLEANING CONSIDERATIONS
5.5 Cleaning Procedures
1. be specific and not include any ambiguous statements
Selected FDA 483 Observations (July 2001) Product Manufacture
[VIP ID: 40370]
“Cleaning procedures should be specific and should not include statements such as:
(1) "remove as much of liquid or solution from contact parts as possible"
(2) "soak parts in acetone for at least a few hours"
(3) "rinse or wipe with a small amount of acetone or alcohol solvent until there is no presence of dye and / or odor of liquid or solution"
(4) "rinse with hot water until completely free from soap"
(5) "repeat cleaning procedure if necessary”
2. include a list of which personnel are trained and responsible for the cleaning of specific equipment.
Selected FDA 483 Observations (January 2007) Packaging & Labelling
[VIP ID: 194404]
“Written procedures for cleaning and maintenance should include assignment of responsibility, description in sufficient detail of the methods if disassembling and reassembling equipment as necessary to assure proper cleaning and maintenance, and instructions for protection of clean equipment from contamination prior to use.”
21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006)
Subpart D -- Equipment
Sec. 211.67 Equipment cleaning and maintenance (b)
[VIP ID: 56]
“Written procedures shall be established and followed for cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing, or holding of a drug product. These procedures shall include, but are not necessarily limited to, the following:
(1) Assignment of responsibility for cleaning and maintaining equipment;”
Selected FDA 483 Observations (January 2006) Product Manufacture
[VIP ID: 180320]
“Written procedures for cleaning and maintenance should include a list of which personnel are trained and responsible for the cleaning of specific equipment.”
Selected FDA 483 Observations (August 2005) Product Manufacture
[VIP ID: 178300]
“Procedures for the cleaning and maintenance of equipment should assign responsibility for cleaning and maintaining equipment.”
GUIDANCE
PET DRUG PRODUCTS - CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005)
VI. FACILITIES AND EQUIPMENT C. Equipment
1. Production Equipment para 1
[VIP ID: 187394]
“…We also recommend that each PET production facility establish and follow written procedures that address the following issues, where applicable:
- Assignment of responsibility and frequency for cleaning and maintenance of equipment”
Selected FDA 483 Observations (February 2005) Product Manufacture
[VIP ID: 138130]
“Equipment cleaning, maintenance and sanitation procedures should:
a. Assign responsibility for the cleaning process”
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 5.21
[VIP ID: 24566]
“Written procedures should be established for cleaning of equipment and its subsequent release for use in the manufacture of intermediates and APIs. Cleaning procedures should contain sufficient details to enable operators to clean each type of equipment in a reproducible and effective manner. These procedures should include:
(1) Assignment of responsibility for cleaning of equipment;”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
5. PROCESS EQUIPMENT
5.2 Equipment Maintenance and Cleaning 5.21
[VIP ID: 153980]
“Written procedures should be established for cleaning of equipment and its subsequent release for use in the manufacture of intermediates and APIs. Cleaning procedures should contain sufficient details to enable operators to clean each type of equipment in a reproducible and effective manner. These procedures should include:
- Assignment of responsibility for cleaning of equipment;”
Selected FDA 483 Observations (August 1997) Product Manufacture
[VIP ID: 2513]
“Cleaning SOP's should assign responsibility for cleaning equipment…”
3. include a description in sufficient detail of the methods, equipment, and materials used in cleaning the buildings and facilities, and the methods of disassembling and reassembling equipment as necessary to assure proper cleaning.
Selected FDA 483 Observations (January 2007) Packaging & Labelling
[VIP ID: 194404]
“Written procedures for cleaning and maintenance should include assignment of responsibility, description in sufficient detail of the methods if disassembling and reassembling equipment as necessary to assure proper cleaning and maintenance, and instructions for protection of clean equipment from contamination prior to use.”
Selected FDA 483 Observations (December 2006) Product Manufacture
[VIP ID: 194324]
“Written procedures for cleaning and maintenance should include description in sufficient detail of methods, equipment and materials used, instructions for protection of clean equipment from contamination prior to use, and parameters relevant to the operation.”
Selected FDA 483 Observations (November 2006) Product Manufacture
[VIP ID: 194232]
“Procedures for the cleaning and maintenance of equipment should contain sufficient detail of the methods, equipment, and materials used in the cleaning and maintenance operation, and the methods of disassembly and reassembling equipment as necessary to assure proper cleaning and maintenance.”
21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006)
Subpart C -- Buildings and Facilities Sec. 211.56 Sanitation
(b) [VIP ID: 48]
“There shall be written procedures assigning responsibility for sanitation and describing in sufficient detail the cleaning schedules, methods, equipment, and materials to be used in cleaning the buildings and facilities; such written procedures shall be followed.”
21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006)
Subpart C -- Buildings and Facilities Sec. 211.56 Sanitation
(c) [VIP ID: 49]
“There shall be written procedures for use of suitable rodenticides, insecticides, fungicides, fumigating agents, and cleaning and sanitizing agents. Such written procedures shall be designed to prevent the contamination of equipment, components, drug product containers, closures, packaging, labeling materials, or drug products and shall be followed. Rodenticides, insecticides, and fungicides shall not be used unless registered and used in accordance with the Federal Insecticide, Fungicide, and Rodenticide Act (7 U.S.C. 135).”
21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006)
Subpart D -- Equipment
Sec. 211.67 Equipment cleaning and maintenance (b)
[VIP ID: 56]
“Written procedures shall be established and followed for cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing, or holding of a drug product. These procedures shall include, but are not necessarily limited to, the following:
(3) A description in sufficient detail of the methods, equipment, and materials used in cleaning and maintenance operations, and the methods of disassembling and reassembling equipment as necessary to assure proper cleaning and maintenance;”
Selected FDA 483 Observations (November 2005) Sterile Product Manufacture
[VIP ID: 179710]
“Written procedures for cleaning and maintenance should include a description in sufficient detail of methods, equipment and materials used and parameters relevant to the operation.”
GUIDANCE
PET DRUG PRODUCTS - CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005)
VI. FACILITIES AND EQUIPMENT C. Equipment
1. Production Equipment para 1
[VIP ID: 187394]
“…We also recommend that each PET production facility establish and follow written procedures that address the following issues, where applicable:
- Description of cleaning and maintenance procedures in sufficient detail to include disassembly and reassembly of equipment”
Selected FDA 483 Observations (October 2004) Product Manufacture
[VIP ID: 124460]
“Cleaning and maintenance procedures should include:
c. a description in sufficient detail of the methods of disassembling and reassembling equipment as necessary to assure proper cleaning and maintenance.”
Selected FDA 483 Observations (June 2004) Product Manufacture
[VIP ID: 122900]
“Written procedures for cleaning and maintenance should include a description in sufficient detail of the methods of disassembling and reassembling equipment as necessary to assure proper cleaning and maintenance.”
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 7.4.4
[VIP ID: 188668]
“The cleaning process should be documented in an SOP.”
Extracted from FDA Warning Letter 04-NWJ-12 (May 2004) 05/05/2004
[VIP ID: 127790]
“8. Adequate written procedures for the cleaning and maintenance of equipment used in drug manufacture have not been established and followed (21 CFR 211.67(b)). For example, the cleaning validation study for the [redacted] Fluid Bed Dryer does not address the effectiveness of the cleaning process on all parts of the equipment. In addition, procedures for disassembly and cleaning of other major drug processing units have not been established.”
Extracted from FDA Warning Letter 24-04 (February 2004) USA
02/02/2004 [VIP ID: 126330]
“10. There was no cleaning validation for tanks #2, 3, 4. Furthermore, written procedures lacked sufficient detail for the cleaning and cleaning validation of tanks #1, 2, 3, 4 [ref. 21 CFR 211.67(a) & (b)].”
Extracted from FDA Warning Letter 02-BLT-13 (January 2002) USA
03/01/2002 6
[VIP ID: 48050]
“6. Failure to establish adequate written procedures that provide sufficient detail to assure that drug products have the identity, strength, quality, and purity they purport or are represented to possess, in that:
c. The production area cleaning and maintenance procedure and production equipment cleaning and maintenance procedure does not sufficiently describe in detail any step in the cleaning or maintenance of the production area or of the production equipment (21 CFR 211.67). For example, your firm has four written procedures regarding the cleaning and maintenance of the production area and production equipment. However, the written procedures do not describe decontamination / cleaning solutions, decontamination / cleaning methods, or the preparation of cleaning and maintenance documentation to track these activities; "
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 12.72
[VIP ID: 24771]
“The cleaning validation protocol should describe the equipment to be cleaned, procedures, materials, acceptable cleaning levels, parameters to be monitored and controlled, and analytical methods.”
ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000)
12. VALIDATION 12.7 Cleaning Validation 12.72
[VIP ID: 155760]
“The cleaning validation protocol should describe the equipment to be cleaned, procedures, materials, acceptable cleaning levels, parameters to be monitored and controlled, and analytical methods.”
Selected FDA 483 Observations (May 2000) Product Manufacture
[VIP ID: 15900]
“Utensil cleaning procedures should provide adequate instructions to disassemble sampling thieves for thorough 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 4.4. Documentation 4.4.4.
[VIP ID: 69190]
“The cleaning process should be documented in an SOP.”
EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 4 - DOCUMENTATION
Documents required - Procedures and records (Other) 4.26.
[VIP ID: 497]
“There should be written procedures and the associated records of actions taken or conclusions reached, where appropriate, for: …
- maintenance, cleaning and sanitization; …
Selected FDA 483 Observations (August 1997) Product Manufacture
[VIP ID: 2513]
“Cleaning SOP's should assign responsibility for cleaning equipment and describe in sufficient detail:
(2) the methods to be used”
GUIDE TO INSPECTIONS OF TOPICAL DRUG PRODUCTS (July 1994) V. CLEANING VALIDATION
Detailed Cleaning Procedures [VIP ID: 119290]
“Cleaning procedures should be detailed and provide specific understandable instructions. The procedure should identify equipment, cleaning method(s), solvents/detergents approved for use, inspection/release mechanisms, and documentation. For some of the more complex systems, such as clean-in-place (CIP) systems, it is usually necessary to provide a level of detail that includes drawings, and provision to label valves. The time that may elapse from completion of a manufacturing operation to initiation of equipment cleaning should also be stated where excessive delay may affect the adequacy of the established cleaning procedure. For example, residual product may dry and become more difficult to clean.”
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:
1. Detailed Cleaning Procedure:
There should be a written equipment cleaning procedure that provides details of what should be done and materials to be utilized. Some manufacturers list the specific solvent for each BPC and intermediate. For stationary vessels, often clean-in-place (CIP) apparatus may be encountered. For evaluation of these systems, diagrams will be necessary, along with identification of specific valves.”
BIOTECHNOLOGY INSPECTION GUIDE (November 1991) CLEANING PROCEDURES
A. Detailed Cleaning Procedure (para 1)
[VIP ID: 1084]
“There should be a written equipment cleaning procedure that provides details of what should be done and the materials to be utilized. Some manufacturers list the specific solvent for each BDP and intermediate.”
4. consider non-contact parts into which product may migrate (e.g. premises, seals, flanges, mixing shaft, fans of ovens, heating elements etc.).
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 15 - QUALIFICATION AND VALIDATION
CLEANING VALIDATION 38
[VIP ID: 187106]
“Normally only cleaning procedures for product contact surfaces of the equipment need to be validated.
Consideration should be given to non-contact parts. The intervals between use and cleaning as well as cleaning and reuse should be validated. Cleaning intervals and methods should be determined.”
PI 006-2
RECOMMENDATIONS ON VALIDATION MASTER PLAN
INSTALLATION AND OPERATIONAL QUALIFICATION NON-STERILE PROCESS VALIDATION
CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.3 General
7.3.1
[VIP ID: 188640]
“Normally only cleaning procedures for product contact surfaces of the equipment need to be validated.
Consideration should be given to non-contact parts into which product may migrate. For example, seals, flanges, mixing shaft, fans of ovens, heating elements etc.”
EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - QUALIFICATION AND VALIDATION (September 2001)
CLEANING VALIDATION 38.
[VIP ID: 21380]
“Normally only cleaning procedures for product contact surfaces of the equipment need to be validated.
Consideration should be given to non-contact parts.”
5. include air conditioning grills in solution preparation areas.
Selected FDA 483 Observations (September 2002) Sterile Product Manufacture
[VIP ID: 47840]
“Cleaning procedures should include air conditioning grills in solution preparation areas.”
• Planned maintenance procedures for cleanroom Air Handling Units (AHU) should require cleaning of the units.
Selected FDA 483 Observations (September 2002) Sterile Product Manufacture
[VIP ID: 47810]
“Planned maintenance procedures for cleanroom Air Handling Units (AHU) should require cleaning of the units.”
6. include the between use cleaning of columns used in HPLC testing of drug formulations.
Selected FDA 483 Observations (July 1999) Laboratories
[VIP ID: 7500]
“There should be written procedures documenting the between use cleaning of columns used in HPLC testing of drug formulations.”
7. require that a major cleaning be executed between lots of products obtained from an approved drug substance supplier and a non-approved supplier.
Selected FDA 483 Observations (January 2004) Product Manufacture
[VIP ID: 71120]
“Equipment cleaning SOPs for production lines should require that a major cleaning be executed between lots of products obtained from an approved drug substance supplier and a non-approved supplier, to prevent cross-contamination of impurities that may be present in the different drug sources.”
8. define different procedures as required, for multi-use equipment cleaning, depending on what product or intermediate was last produced.
GUIDE TO INSPECTIONS OF BULK PHARMACEUTICAL CHEMICALS (May 1994) PART II - SPECIFIC INTERPRETATIONS FOR BPC OPERATIONS
Equipment
(a) Multipurpose Equipment (para 1)
[VIP ID: 3434]
“…The cleaning program should take into consideration the need for different procedures depending on what product or intermediate was produced.”
GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) III. General Requirements
(para 1) [VIP ID: 1323]
“FDA expects firms to have written procedures (SOP's) detailing the cleaning processes used for various pieces of equipment. If firms have one cleaning process for cleaning between different batches of the same product and use a different process for cleaning between product changes, we expect the written procedures to address these different scenario. Similarly, if firms have one process for removing water soluble residues and another process for non-water soluble residues, the written procedure should address both scenarios and make it clear when a given procedure is to be followed.”
9. include diagrams and identify specific valves for clean-in-place (CIP) systems.
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:
1. Detailed Cleaning Procedure:
There should be a written equipment cleaning procedure that provides details of what should be done and materials to be utilized. Some manufacturers list the specific solvent for each BPC and intermediate. For stationary vessels, often clean-in-place (CIP) apparatus may be encountered. For evaluation of these systems, diagrams will be necessary, along with identification of specific valves.”
BIOTECHNOLOGY INSPECTION GUIDE (November 1991) CLEANING PROCEDURES
A. Detailed Cleaning Procedure (para 2)
[VIP ID: 1085]
“For stationary vessels, often clean-in-place (CIP) apparatus may be encountered. For evaluation of these systems, diagrams will be necessary, along with identification of specific valves.”
10. include diagrams or a narrative description of hard to clean areas.
Selected FDA 483 Observations (July 2000) Product Manufacture
[VIP ID: 19120]
“Where cleaning SOPs or validation protocols make reference to 'Hard to Reach' areas, they should include diagrams or narrative descriptions of these areas.”
11. provide instructions for the cleaning and storage of sampling equipment.
PE 009-5
GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 6
QUALITY CONTROL SAMPLING 6.11
[VIP ID: 185856]
“The sample taking should be done in accordance with approved written procedures that describe:
- instructions for the cleaning and storage of sampling equipment.”
EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 6 - QUALITY CONTROL
Sampling 6.11.
[VIP ID: 612]
“The sample taking should be done in accordance with approved written procedures that describe:
- instructions for the cleaning and storage of sampling equipment.”
12. include the method for protection of clean equipment from contamination prior to use.
Selected FDA 483 Observations (January 2007) Packaging & Labelling
[VIP ID: 194404]
“Written procedures for cleaning and maintenance should include assignment of responsibility, description in sufficient detail of the methods if disassembling and reassembling equipment as necessary to assure proper cleaning and maintenance, and instructions for protection of clean equipment from contamination prior to use.”
Selected FDA 483 Observations (December 2006) Product Manufacture
[VIP ID: 194324]
“Written procedures for cleaning and maintenance should include description in sufficient detail of methods, equipment and materials used, instructions for protection of clean equipment from contamination prior to use, and parameters relevant to the operation.”
Selected FDA 483 Observations (September 2006) Sterile Product Manufacture
[VIP ID: 194010]
“Procedures for the cleaning and maintenance of equipment should include the protection of clean equipment from contamination prior to use. For example, bulk drug solution mixing tanks should be covered or held in a manner that would prevent environmental contamination while being stored in a non-classified storage area following cleaning.”
Selected FDA 483 Observations (June 2006) Sterile Product Manufacture
[VIP ID: 193766]
“Procedures for the cleaning and maintenance of equipment should include requirements regarding the protection of clean equipment from contamination prior to use, and there should be data to support the established sterilization expiration date for sterilized filling equipment.”
21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006)
Subpart D -- Equipment
Sec. 211.67 Equipment cleaning and maintenance (b)
[VIP ID: 56]
“Written procedures shall be established and followed for cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing, or holding of a drug product. These procedures shall include, but are not necessarily limited to, the following:
(5) Protection of clean equipment from contamination prior to use;”
GUIDANCE
PET DRUG PRODUCTS - CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005)
VI. FACILITIES AND EQUIPMENT C. Equipment
1. Production Equipment para 1
[VIP ID: 187394]
“…We also recommend that each PET production facility establish and follow written procedures that address the following issues, where applicable:
- Protection of clean equipment from contamination prior to use”
Selected FDA 483 Observations (February 2005) Product Manufacture
[VIP ID: 138130]
“Equipment cleaning, maintenance and sanitation procedures should:
c. Detail the method for protection of the cleaned equipment prior to use.”
Selected FDA 483 Observations (October 2004) Product Manufacture
[VIP ID: 124460]
“Cleaning and maintenance procedures should include:
e. instructions for protection of clean equipment from contamination prior to use.”
Selected FDA 483 Observations (April 1998) Product Manufacture
[VIP ID: 6391]
“Utensils, such as scoops, used for the weighing of raw materials should be consistently washed and stored so as to remain clean.”
Selected FDA 483 Observations (August 1997) Product Manufacture
[VIP ID: 2513]
“Cleaning SOP's should assign responsibility for cleaning equipment and describe in sufficient detail:
(5) protection of cleaned equipment prior to use”
13. include directions for the use of cleaning and disinfecting agents.
PI 012-2
RECOMMENDATION ON STERILITY TESTING (July 2004)
9. CLEANING, SANITISATION AND DISINFECTION 9.5
[VIP ID: 190292]
“Records should be retained in respect of routine preparation of cleaning and disinfecting agents, directions for their use, and validation of their efficacy.”
• Specifying which cleaning agent(s) will be used and at what concentration(s) (to include the cleaning of floors and table tops in processing areas).
Extracted from FDA Warning Letter 2003-NOL-01 (October 2002) USA
10/10/2002 [VIP ID: 49860]
“Written procedures are not established for the use of suitable cleaning and sanitizing agents designed to prevent the contamination of equipment, drug product containers, closures and packaging, or labeling materials [21 CFR 211.56(c)];”
Extracted from FDA Warning Letter 02-BLT-13 (January 2002) USA
03/01/2002 6
[VIP ID: 48050]
“6. Failure to establish adequate written procedures that provide sufficient detail to assure that drug products have the identity, strength, quality, and purity they purport or are represented to possess, in that:
c. The production area cleaning and maintenance procedure and production equipment cleaning and maintenance
c. The production area cleaning and maintenance procedure and production equipment cleaning and maintenance