Paradise Lost

Misdirection in the implementation of isolation technology

By James Agalloco, Agalloco & Associates

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When isolators were introduced into the pharmaceutical industry they were properly viewed with some degree of skepticism. The early designs were relatively crude in appearance and certainly lacked sophistication. With a few years of technology development and successful operational experience it seemed that the isolator would change the way in which sterile products were made across the world. 

I was bold enough to predict the rapid demise of manned cleanrooms as the highly capable isolator proved its superiority both operationally and financially.[1] The isolator was expected to be the paradigm changer that the pharmaceutical industry needed to attain the next level of performance and product safety. The virtual elimination of contamination compounded with expected lower costs would create an operational paradise. A number of unanticipated changes to isolator designs occurred on the way to that rosy future that has dramatically lessened the expected impact. This article will review the ways in which the vision of the future envisioned in 1995 has been diminished and outline changes to current practices in isolator and barrier that would enable the industry to fully realize the potential in isolation technology.

The essential difference between isolators and manned aseptic processing area is the absence of personnel from the operating environment. The operator is universally recognized to be the largest contributor to microbial contamination in conventional aseptic processing. First, the operator carries on/in them a population of microorganisms of greater than 1014 CFU. Second, these microorganisms must be somehow contained within their gowning materials.  Third, microorganisms from the operator are continuously dispersed into the environment because their gowning materials and methods are not absolute. 

Manned aseptic environments especially those locales where exposed sterile items are handled have been specifically designed to address the microbial contamination threat associated with the operators required presence. The predominant design elements used to control manned environments include:

  • Unidirectional (laminar) airflow – to provide a sweeping action and avoid re-circulation of air over the sterile materials.
  • A defined air velocity (90 FPM ± 20%) – to avoid potential air turbulence that might disrupt the desired unidirectional flow.
  • A large number of air changes – a consequence of the expected air velocity.
  • Monitoring of pressure differentials - to assure that the air flows in the direction away from the critical environments where sterile materials are handled.
  • Decontamination of the environment – post-batch and periodic sanitization of the non-product contact surfaces of the equipment and cleanroom.

The design features and monitoring practices outlined above are a substantial part of the expected norms when using manned aseptic processing. These design components are all intended to reduce the adverse impact of microbes and particles derived from the operating personnel who are the acknowledged primary contamination source.

However, aseptic isolators were specifically designed to exclude personnel from the environment in which sterile materials are exposed, and it is appropriate to question whether measures intended for use with aseptically gowned personnel are necessary in an environment in which they are not present. The first isolators used in this industry demonstrated superior performance when compared to manned aseptic environments yet they lacked two primary design components commonly associated with those manned environments:

  • They employed turbulent airflow delivered through HEPA filter cartridges remote from the isolator chamber (unidirectional flow is used in cleanrooms to mitigate the impact of the personnel).
  • Air returns were located in the ceiling of the isolator chambers (floor level returns are used in cleanrooms to prevent re-entrainment of potential contaminants at work height).

The absence of these and other cleanroom design features in these early isolators had no adverse effect on their operational performance.[2] The expected operational advantages of isolators in aseptic processing projected at that time were not contingent on any refinement of the basic designs. The first isolator-based aseptic fill lines installed evidenced performance far exceeding that of any manned cleanroom, yet they did not include any of the accoutrements of manned aseptic filling operations!

The promise of isolation technology was superior aseptic processing performance at a fraction of the operating cost of traditional manned operations.  The simplicity of these early isolator systems also suggested easy fabrication, short lead times, lower facility costs and a comparatively easy qualification / validation.  The future for isolation technology appeared to be near limitless. 

Paradise Lost – Complications ensued and opportunity missed

Regrettably, the expected ‘paradise’ of isolators for aseptic processing was never fully realized.  Despite evidence that comparatively simple isolator designs were capable of outstanding performance aspects of cleanroom design began to appear in 2nd generation isolators. The wrong-headed notion that an isolator was little more than a small cleanroom requiring all of the accoutrements of cleanroom design.[i] Unidirectional (also called laminar flow) air is a requirement in manned cleanrooms of ISO 5 and better classification that serves to reduce the dispersion of personnel derived contamination into critical locales by minimizing the formation of eddy’s and moving contaminated air to low wall returns. Unidirectional flow patterns are rarely absolute even in the best cleanrooms. Horizontal surfaces of process equipment and the presence of gowned personnel preclude anything truly resembling unidirectional air. The absence of the primary contamination source, the human operator, when using isolation technology largely mitigates the contamination risk without the need for a specific air direction.  Sterility test isolators (which only rarely employ unidirectional air flow) and the 1st generation isolators demonstrated environmental performance equivalent to that of the more complex isolator designs that include unidirectional flow.  Particle generation from equipment operation and component handling with modern filling and stoppering equipment is a lesser concern and can be readily controlled by means other than airflow direction.

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