Aseptic manufacturing facilities

Two types of compressed air systems are found in an aseptic manufacturing facility ... 

Three vacuum systems are commonly used in modern aseptic manufacturing facilities (1) house vacuum systems, (2) vacuum systems dedicated to lyophilization equipment, and (3) vacuum systems dedicated to autoclaves or other sterilization equipment. 

The layout of a typical air handling system serving an aseptic Ailing room or clean room is depicted in Fig. 2. A primaiy bank of HEPA Alters is usually situated in a plant room physically separated but not remote from the aseptic manufacturing facility. 

Water and Drainage. Water is a potential source of microbiological contamination that cannot be excluded from aseptic manufacture. Its control becomes complicated by the variety of purposes for which it may be used and the various types of distribution system that may be encountered. Identifiable potential sources of contamination from water in aseptic manufacturing facilities include (a) ingredient water for sterile products, (b) water supplies for equipment and component cleaning, (c) water supplies to laundries, (d) water supplies for hand washing, and (e) steam supplies to autoclaves. 

At any moment all of the water in an aseptic manufacturing facility must be in the product, in the distribution system, or passing through the drains. Serious measures must be taken lo ensure that drainage systems do not become sources of microbiological contamination and proliferation. 

At first glance it might seem that the term aseptic manufacturing facility is synonymous with the term clean room. It is not. Although aseptic filling is always done in a clean room, the clean room is only one component of a complex of barrier systems that make up an aseptic manufacturing facility. 

Figure 6 diagrammalically represents the successive series of barriers to contamination that exist in typical aseptic manufacturing facilities,... 

The interrelationships between standards of cleanliness and activities needed for gray areas and those of white areas are critical to the successful operation of aseptic manufacturing facilities. 

Calibration should be traceable to national or international standards through an unbroken chain of comparisons. For instrumentation affecting sterility control in aseptic manufacturing facilities this usually involves comparison of values measured with the item of equipment under test, say a particle counter or a pressure differential gauge, with values measured with a standardized device. In many cases this may mean the use of external contract calibration services, with all that this implies in relation to assuring that the contractor s calibration control systems are themselves under good control. 

Complete records of all calibrations should be maintained. This must include unique identification of each item of instrumentation, its location within the aseptic manufacturing facility, and its calibration history and evidence of its traceability to recognized standards. 

All instrumentation within aseptic manufacturing facilities should be identified during validation, and the potential of each instrument for causing deleterious effects to sterility should be independently evaluated. All instruments should be calibrated and scheduled for routine recalibration and for routine preventative maintenance. A system should be set up to ensure that any failure to meet these predetermined schedules is flagged to Quality Assurance to evaluate the effect on sterility. 

Facilities The fabric and fittings of aseptic manufacturing facilities should be reviewed during validation and when the facility is revalidated. Even with new facilities it is possible for builders or contractors to have modified the intended specifications. With older facilities it is not unknown to find unaccept-... 

Frequency of Revalidation New aseptic manufacturing facilities and filling lines must be validated before they are allowed to be used for routine production. Thereafter, routine monitoring is a form of continuous abbreviated revalidation. However, the major validation activities are totally impossible when lines and facilities are operational. Revalidation and. if necessary, replacement of deterio-... 

The purpose of routine monitoring of aseptic manufacturing facilities is to obtain some measure of the level of control being achieved. The ideal is that monitoring should be done in a way that will promptly reveal any failure of the control systems to meet their intended purpose. As often as not, practice falls somewhat short of this ideal. 

Two systems are available, polychromatic white light and lasers. Lasers are able to concentrate more energy in a smaller spot and are therefore able to register smaller particles. The lower limits of sensitivity for white light systems are in the order of 0.3 pm, and for lasers about 0.15 pm. For aseptic manufacturing facilities it is not normally necessary to measure particles smaller than 0.5 pm. Instiuments should have the capability of sampling at least one ft per minute. 

Sample Location Selection, Uniform contamination over a complete aseptic manufacturing facility is remotely improbable. It would require a total breakdown of systems and would be evident in many ways other than environmental monitoring. The selection of locations for environmental monitoring becomes therefore a matter of professional judgement that should take account of two major considerations locations where, if contaminated, product quality would be most seriously affected and locations that due to some vicissitude of design or control are susceptible to microbiological contamination or proliferation. 

In the absence of reliable data indicating a history of control for an aseptic manufacturing facility, it is good sense to list all those events that might have a deleterious effect on the provision of an aseptic environment (batch changes, shift changes, process interruptions, etc.). The environment should at first be... 

Table 7 Proposed [16.17] Target Levels for Environmental Monitoring of Aseptic Manufacturing Facilities...

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