The Myth Called "Sterility" - Pharmaceutical Technology

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The Myth Called "Sterility"
The authors propose a process-centric approach for carrying out aseptic-processing and suggest further dialogue. This articles contains bonus online-exclusive material.

Pharmaceutical Technology
Volume 34


  • Despite the limitations, with respect to its performance noted in the first part of this effort, monitoring of aseptic processing should be performed.
  • Monitoring of any type must not subject the product to increased risk of contamination. No monitoring is preferable to monitoring that risks contamination of sterile materials.
  • EM must be recognized as interventions and subject to the similar constraints and expectations.
  • Monitoring must be recognized as subject to adventitious contamination unrelated to the environment, material, or surface being sampled.
  • Viable monitoring should not be considered an in-process sterility test.
  • EM results should not be considered as 'proof' of either sterility or non-sterility.
  • Microbial monitoring can never recover all microorganisms present in an environment, nor on a surface.
  • The absence or presence of microorganisms in an environmental sample is not confirmation of asepsis, nor is it indicative of process inadequacy.
  • Significant excursions from the routine microbial prolife should be investigated.
  • Detection of low numbers of microorganisms within the critical zones of manned cleanrooms should be considered a rare event. Such a finding does not correlate to a loss of process control, since it is within the normal range of observations.
  • Investigations into recoveries of low numbers of microorganisms in manned cleanrooms should be recognized as predominantly make-work exercises.
  • Process simulation are indicators of capability, but cannot definitely establish the sterility of any material.
  • Process simulations in excess of 5-10,000 units are of relatively limited value; their greatest utility is in the evaluation of aseptic set-up practices.


The first section of this work addresses the limitations of monitoring tools used for aseptic processing. The current methods cannot prove sterility (or its absence). It is the authors' contention that to achieve success with aseptic processing, the practitioner must properly address the relevant issues outlined in the latter half of this work. There is nothing industry can do to provide proof of sterility. The authors believe, however, that adherence to the recommendations herein will make aseptically-produced products as safe as currently possible.

The methods proposed are largely incompatible with existing aseptic processing guidance, regulatory, and pharmacopeial doctrine because the authors have, essentially, deconstructed monitoring as a means for defining or accepting aseptic-processing activities and endeavored to outline a comprehensive QbD approach for establishing it more appropriately. If industry is to continue to improve aseptic processing beyond its current capabilities and, even to proper control contemporary aseptic-processing operations, the authors believe that greater attention should be focused on the design elements. We offer this work as an opening statement in what we hope will be a continued dialogue through which sterile products can be manufactured by—and controlled—in the safest means possible.

James Agalloco* is president of Agalloco & Associates and a member of Pharmaceutical Technology's Editorial Advisory Board, 908.874.7558,
. James Akers is president of Akers Kennedy & Associates.

*To whom all correspondence should be addressed.


1. J. Agalloco and J. Akers, Pharm. Technol., 29 (11), 74-88 (2005).

2. J. Agalloco and J. Akers, Pharm. Technol., 30 (7), 60-76 (2006).

3. H. Katayama et al., PDA J Pharm Sci and Tech., 62 (4), 235-243 (2008).

4. J. Agalloco and J. Akers, Pharm. Technol., 30 (7) (2006) 60-76.

5. J. Agalloco and J. Akers, supplement to Pharm. Technol., Aseptic Processing, 31, s8-11 (2007).

6. J. Agalloco and J. Akers, supplement to Pharm. Technol., Aseptic Processing, 29, s16-23 (2005).

7. M. Nasr, "Quality by Design (QbD)-A Modern System Approach to Pharmaceutical Development and Manufacturing-FDA Perspective," presentation at FDA Quality Initiative Workshop at ISPE meeting (Bethesda, MD, February 2007).

8. ICH Q8(R2) Pharmaceutical Development (ICH, Geneva, 2009).

9. L. Mestrandrea, presentation at the 4th Annual PDA Global Conference on Pharmaceutical Microbiology (Bethesda, MD, Oct. 2009).


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