【正文】 ta should be included in the manufacturing documentation for aseptically filled products. 68 Pure Steam Frequency of testing: 1x per month Testing points Limits Endotoxins Alert level:= EU/ml。 action level: EU/ml Particles HIAC: = 10 micron max. 500 particles/100ml = 25 micron max. 20 particles/100ml MF: = 25 micron max. 100 particles/100ml = 50 micron max. 10 particles/100ml Metal particles = 100 micron max. 1/100ml Chemicals must meet requirements of Pharmacopoea for WFI 69 Nitrogen Frequency of testing: 1x per month Testing points Limits Microbiological Alert level: 10 cfu/m3。 action level: 100 cfu/m3 Compressed air Frequency of testing: 1x per month Testing points Limits Microbiological Alert level: 10 cfu/m3。 action level: 100 cfu/m3 70 Water in autoclave Frequency of testing: Microbial count 1x per week。 endotoxins every 2 weeks。 conductivity continuously Testing points Limits Microbial count Alert level: 5 cfu/100ml。 action level: 10 cfu/100ml Absence of E. coli, coliforms and P. aeruginosa Endotoxins Alert level: EU/ml。 action level: EU/ml Conductivity max. 15 microS/cm 71 Water monitoring ? Control of the microbial quality of water is of great importance in the pharmaceutical manufacturing facility since it may be used for formulating product, as well as for various washing and rinsing processes. ? The source or feed water should meet the requirements of drinking water standard. These requirements ensure the absence of coliforms. ? If use points are routinely flushed prior to use, it is appropriate for samples to be collected with the same flush cycle. ? Sample through hoses and not directly from the tap if manufacturing practices require the use of hoses. ? Start microbiological examination of water promptly after collection. ? If immediate processing is not possible, refrigerate samples at 28176。C upon receipt in the laboratory. Time elapsing between collection and examination generally should not exceed 24 hours. 72 Purified water Testing points Limits Microbial count Alert level: 50 cfu/ml。 action level: 100 cfu/ml Absence of E. coli, coliforms and P. aeruginosa Endotoxins Alert level: EU/ml。 action level: EU/ml Conductivity Alert level: microS/cm。 action level: ( continuously ) TOC Alert level: 250 ppb。 action level: 500 ppb ( continuously ) 73 Water for injections Frequency of testing: daily。 particles monthly Testing points Limits Microbial count Alert level: 5 cfu/100ml。 action level: 10 cfu/100ml Absence of E. coli, coliforms and P. aeruginosa Endotoxins Alert level: EU/ml。 action level: EU/ml Conductivity Alert level: microS/cm。 action level: microS/cm ( continuously ) TOC Alert level: 250 ppb。 action level: 500 ppb Particles HIAC: = 10 micron max. 500 particles/100ml = 25 micron max. 20 particles/100ml MF: = 25 micron max. 100 particles/100ml = 50 micron max. 10 particles/100ml Metal particles = 100 micron max. 1/100ml 74 Compressed gas monitoring ? The following points should be considered: a) Compressed gases used to pressurize or blanket product in sterile holding tanks should be introduced via hydrophobic vent filters and monitored at a frequency that assures that the gas does not challenge the bacterial retention of the filter. b) Compressed air/gas that is used aseptic environments should be filtered through sterilizinggrade filters and tested on a frequency that assures that the air/gas does not adversely effect the environment. c) All pressed air connections which do not affect the air to the workspace should be monitored with less frequency. 75 Air monitoring ? Environmental monitoring program should include routine monitoring of both viable and nonviable airborne particulates. ? Viable bacteria derived from people are typically associated with skin flakes, so higher nonviable particulate counts may be indicative of increased viable counts. ? People are a major contribution of viable and nonviable particulates to the environment. ? Static monitoring may be necessary in addition to dynamic monitoring to satisfy regulatory requirements. 76 Nonviable monitoring ? Demonstrates control of potential contaminants in the environment to which the product, during the manufacturing process, is exposed. ? Particles of and larger are generally recognized as indicators of environmental contamination. Requirements may also include monitoring particles. ? A monly used monitoring method is optical particle counting. It is based on the principle of passing an aerosol through a focused light source, which result in light scattering from single particles. ? Both the size and number of particles can be measured simultaneously. ? In addition to portable particle counters, systems have been developed for permanent installation in manufacturing areas to allow continuous monitoring of the manufacturing process with centralized data storage and alarm capabilities. 77 Viable monitoring ? Microbes in air are generally associated with solid or liquid particles. ? Organisms may adhere to a dust particle or other “raft”, or, if unattached, exist as a freefloating particle suspended in the air. Sites a. Monitoring location: not more than one foot away from the work site, and upstream of the air flow, during filling/closing operations. b. Additional monitoring locations should be chosen for the reminder of the room in which the process is occurring based upon initial validation/qualification sampling of the environment, personnel flow,