In turn, these steps should be followed with respect to aseptic processing: separate personnel from the aseptic environment; limit employees' interaction with sterile materials; where possible, entirely remove personnel from the aseptic environment; and combinations of the above. The means for accomplishing these goals are embodied in following methodologies (6):

• The use of automation technology to reduce or eliminate personnel interventions and, thus, personnel-borne contamination
• The use of separative technologies to minimize the impact of personnel-derived contamination.

These methods are central to our recommendations for the supportive elements of aseptic processing. In defining these elements, the authors are adapting a quality-by-design (QbD) approach as defined in recent regulatory documents (7,8). The details for QbD in aseptic processing are somewhat different from the applications of this concept in the typical formulation or synthesis process. As we outlined in the first half of this paper, the establishment of direct linkage between a monitored condition and the outcome, with respect to an aseptic process, is uncertain. The situation, with respect to the definition of physical-design elements, is very similar. Contemporary aseptic-processing facility and process design include several seemingly rigorous design expectations for performance, including such precepts as:

• Air velocities of 90 FPM (0.45 m/sec) ± 20% for ISO 5 air in critical environments
• Air changes of > 150 per hour in critical environments
• Pressure differentials of NLT 0.05" water column between different classifications.

These expectations, and others like them, should be considered suggestions rather than definitive requirements because they have less correspondence to the process outcome than EM. The authors' recommendations for QbD, with respect to aseptic processing, are non-numeric because it is our strong belief that there are no ready means to demonstrate their suitability. Instead, we suggest that QbD for aseptic processing be driven toward eliminating the impact of personnel on the process. The means to accomplish this vary depending on the particular aspect of the overall process under consideration.

Facilities:

• Facilities should be designed for easy sanitization/decontami-nation through proper use of construction materials, ease of access, and design details that facilitate cleaning
• Facility layouts should minimize the potential for mixups and cross-contamination
• Air system should provide adequate air pressurization to preclude the ingress of contamination from surrounding less-clean environments
• Airflow patterns should facilitate the removal and exclusion of contamination from critical environments
• Air systems should be supplied with HEPA filters that are periodically integrity tested
• Differential pressure should be monitored and alarmed to demonstrate continuous integrity of the core aseptic area
• Temperature and humidity should be controlled to maximize personnel comfort during operations consistent with product stability/safety requirements
• Interlocks should be used to prevent pressure reversal
• Advanced aseptic-processing designs such as closed restricted access barrier systems (RABS) and isolators, should be given preference in selection of processing environments
• All facility and environmental surfaces should be resistant to the potential corrosive action of sanitizing and decontamination agents
• The aseptic portion of the facility should be maintained in clean state at all times and periodically sanitized or decontaminated
• Isolators and closed RABS should be treated with sporicidal agents on a periodic basis.
• A minimum of materials should be retained in the aseptic portion of the facility
• Smoke studies, air-velocity measurements, expectations for unidirectional airflow, absence of eddy's, and other subjective expectations imposed on aseptic-processing HVAC systems should be recognized as useful, but non-definitive means for assessing aseptic processing environmental performance.