Miscellaneous Considerations

In addition to the more specific points for consideration generated as part of the review the following general notes were also compiled:

1. Sanitation procedures shall apply to work performed by contractors or temporary employees as well as work performed by full-time employees during the ordinary course of operations.

21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April, 2003)

Subpart C - Buildings and Facilities 21 CFR 211.56 (d)

“Sanitation procedures shall apply to work performed by contractors or temporary employees as well as work performed by full-time employees during the ordinary course of operations.”

2. Environmental monitoring should include monitoring of the sanitisation fluid container used by operators to sanitise gloved hands and surfaces during the aseptic filling of products.

Selected FDA 483 Observations (July 1998) Sterile Product Manufacture

[VIP ID: 6297]

“Environmental monitoring should include monitoring of the sanitization fluid container used by operators to sanitize gloved hands and surfaces during the aseptic filling of products.”

3. Where non-disposal gloves are used during the weighing of more than one material, they should be routinely cleaned following the weighing of each material.

Selected FDA 483 Observations (April 1998) Product Manufacture

[VIP ID: 6389]

“Where non-disposal gloves are used during the weighing of more than one material, they should be routinely cleaned following the weighing of each material.”

4. Disinfectants and detergents dilutions should be kept in previously cleaned containers and should only be stored for defined periods unless sterilised.

PE 009-5

GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS

SANITATION 38

[VIP ID: 186074]

“Disinfectants and detergents should be monitored for microbial contamination; dilutions should be kept in previously cleaned containers and should only be stored for defined periods unless sterilised. Disinfectants and detergents used in Grades A and B areas should be sterile prior to use.”

PI 007-2

RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 9. IMPORTANT FACTORS IN VALIDATION OF ASEPTIC MANUFACTURING 9.4 Disinfection

9.4.1

[VIP ID: 189032]

“There should be documented procedures describing the preparation and storage of disinfectants and detergents.

These agents should be monitored for microbial contamination; dilutions should be kept in previously cleaned containers and should only be stored for defined periods unless sterilised. Disinfectants and detergents used in Grade A and B areas should be sterile at the time of use. If spray bottles are used they should be sterile before being filled and have a short in-use shelf life.”

EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003)

Sanitation 38

[VIP ID: 63310]

“Disinfectants and detergents should be monitored for microbial contamination; dilutions should be kept in previously cleaned containers and should only be stored for defined periods unless sterilised. Disinfectants and detergents used in Grades A and B areas should be sterile prior to use.”

• Sterile filtered disinfectants and sanitising agents used in an aseptic core should be periodically monitored.

PI 007-2

RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 9. IMPORTANT FACTORS IN VALIDATION OF ASEPTIC MANUFACTURING 9.4 Disinfection

9.4.1

[VIP ID: 189032]

“…Disinfectants and detergents used in Grade A and B areas should be sterile at the time of use. If spray bottles are used they should be sterile before being filled and have a short in-use shelf life.”

Selected FDA 483 Observations (April 1998) Sterile Product Manufacture

[VIP ID: 6347]

“Sterile filtered disinfectants and sanitizing agents used in an aseptic core should be periodically monitored.”

5. Disinfectants and sanitising agents should be sterile filtered prior to introduction into an aseptic core.

Selected FDA 483 Observations (April 1998) Sterile Product Manufacture

[VIP ID: 6348]

“Disinfectants and sanitizing agents should be sterile filtered prior to introduction into an aseptic core.”

• Strains of factory isolates from firms controlled environments should be used in the evaluation of sanitising solutions.

Selected FDA 483 Observations (April 1999) Sterile Product Manufacture

[VIP ID: 7177]

“Strains of factory isolates from firms controlled environments should be used in the evaluation of sanitizing solutions.”

6. Environmental monitoring should include the trending of isolates.

Selected FDA 483 Observations (April 2000) Sterile Product Manufacture

[VIP ID: 15660]

“Environmental monitoring should include:

(1) trending of isolates”

• Monitoring of clean areas should be undertaken regularly in order to detect the development of resistant strains.

EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003)

Sanitation 37

[VIP ID: 63300]

“... Monitoring should be undertaken regularly in order to detect the development of resistant strains.”

7. All concentrations of disinfectants should be evaluated for detrimental effects on the microbial growth media used.

Selected FDA 483 Observations (July 1998) Sterile Product Manufacture

[VIP ID: 6759]

“All concentrations of disinfectants should be evaluated for detrimental effects on the microbial growth media used.”

8. Aseptic fill surface disinfectants should be sporicidal.

Selected FDA 483 Observations (July 1998) Sterile Product Manufacture

[VIP ID: 6757]

“Aseptic fill surface disinfectants should be sporicidal.”

9. Where disinfectants are used in clean areas, more than one type should be employed.

EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003)

Sanitation 37

[VIP ID: 63300]

“... Where disinfectants are used, more than one type should be employed. ...”

10. Carts used to transport partially stoppered vials should be sanitised and monitored for viable contamination.

Selected FDA 483 Observations (May 1999) Sterile Product Manufacture

[VIP ID: 7202]

“Carts used to transport partially stoppered vials should sanitized and monitored for viable contamination.”

11. The manufacturer should ensure, either by a written commitment or by a contract that he is notified by the detergent supplier of any critical changes in the formulation of the detergent.

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 4.9. Detergents 4.9.2.

[VIP ID: 69350]

“The composition of detergents should be known to the manufacturer. … The manufacturer should ensure, either by a written commitment or by a contracts that he is notified by the detergent supplier of any critical changes in the formulation of the detergent.”