As a further guide to the reader, the authors have applied this method to various facilities used for aseptic processing (see
Appendix 1, posted at
http://www.pharmtech.com/). The facilities discussed are models based on real installations, though the authors have altered some of the characteristics
to prevent identification. The risk assessment of these facilities was used to fine-tune the model. The authors believe the
relative (and, of course, subjective) capabilities of the facilities are consistent with the values obtained and demonstrate
the potential utility of the present model for application in aseptic risk assessment. Should readers visit each of the facilities
the examples are based on, they might develop a similar perspective.
* The authors do not support increases in environmental monitoring in these already very clean environments in a misguided
effort to find what should not be present. Increasing monitoring scrutiny typically increases the number of interventions
and thus increases the risk of contamination. In any case, there are no means to prove the absence of microorganisms from
an environment; additional samples provide no benefit.
** Sanitization of the lyophilizer is not considered in compliance with CGMP regulations, but some laboratory-scale lyophilizers
cannot be sterilized.
James Akers is the president of Akers Kennedy & Associates, Kansas City, MO. James Agalloco* is the president of Agalloco & Associates, 856 US Highway 206, Suite B-11, Hillsborough, NJ 08844, tel. 908.874.7558, firstname.lastname@example.org
He also is a member of Pharmaceutical Technology's Editorial Advisory Board.
*To whom all correspondence should be addressed.
1. US Food and Drug Administration, Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practices (FDA, Rockville, MD, Sept. 2004)
2. FDA, Pharmaceutical CGMPs for the Twenty-First Century—A Risk-Based Approach, (FDA, Rockville, MD, Sept. 2004)
3. Parenteral Drug Association, "Process Simulation Testing for Aseptically Filled Products, Technical Report No. 22," J. Pharm. Sci. Technol.
50 (6 suppl.), 1996.
4. B. Reinmuller, "Dispersion and Risk Assessment of Airborne Contaminants in Pharmaceutical Cleanrooms," Royal Institute of Technology, Building Services Engineering
5. W. Whyte, "Reduction of Microbial Dispersion by Clothing," J. Parenter. Sci. Technol.
39 (1), 51–60 (1985).
6. W. Whyte, "A Cleanroom Contamination Control System," Eur. J. Parenter. Sci.
7 (2), 55–61 (2002).
7. W. Whyte and T. Eaton, "Microbial Risk Assessment in Pharmaceutical Cleanrooms," Eur. J. Parenter. Pharm. Sci.
9 (1), 16–23 (2004).
8. W. Whyte and T. Eaton, "Microbiological Contamination Models for Use in Risk Assessment During Pharmaceutical Production,"
Eur. J. Parenter. Pharm. Sci.
9 (1), (2004).
11. J. Agalloco, PDA Course Notes on Aseptic Processing, 1988 to date.
12. J. Agalloco. "Management of Aseptic Interventions," Pharm. Technol.
29 (3), 56–66 (2005).
Appendix I: Application of the method
In this appendix, the proposed methodology evaluates five different aseptic processing systems. Execution of the methodology
describes the facilities better than a written summary, but a brief description of each is provided by way of introduction.
In each of the facilities, a freeze-dried formulation is used for the evaluation. The authors have chosen to simplify the
process by providing the weighted interventions, line speeds, process duration, and thus the intervention risk for each system.
The authors recommend using the method described in the text, but in the interest of brevity we have eliminated that step
in these examples. The intervention risk for each of these is included in the listing below.
Facility A. An older facility producing a range of small-volume parenterals of various formulations and configurations. Weighted interventions
per hour: 90; fill speed: 120 vials/min; process duration: 6 h, and intervention risk (IR ): 0.0125 interventions per container.
Facility B. A heavily automated facility built in the late 1980s and dedicated to the production of a single freeze-dried product in
multiple containers and strengths. Weighted interventions per hour: 5; fill speed: 300 vials/min; process duration-5 h; and
intervention risk (IR ): 0.00027 interventions per container.
Facility C. An early-generation isolator-based facility intended for a variety of products and formulations. Weighted interventions per
hour: 60; fill speed: 80 vials/min; process duration: 4 h; and intervention risk (IR ): 0.0125 interventions per container.
Facility D. A small-volume suite producing clinical materials. Weighted interventions per hour: 60; fill speed: 30 vials/min; process
duration: 2 h; and intervention risk (IR ): 0.033.
Facility E. A low-volume clinical suite relying on manual filling. Interventions required per container: 4, thus the intervention risk
(IR ): 4. Process duration: 4 h.
The latest media fills at each of these facilities were free of microbial contamination, which reveals the relative inability
of process simulations to evaluate relative risk.