Bacterial challenge studies should be conducted under process conditions by means of inoculating the product to be evaluated
with B. diminuta to achieve a challenge level of 1 × 107 cfu/cm2 and evaluating the filtrate for the presence of the challenge organism. In the event that B. diminuta is not viable in the product formulation, precondition the filter by recirculating product through it to simulate process
conditions and follow this with a microbial challenge by modifying the process to ensure the viability of the challenge organism
(e.g., change temperature), modifying the formulation to ensure the viability of the challenge organism (e.g., adjust pH, remove bactericidal component), reducing the exposure time to ensure the challenge organism remains viable, or
change from B. diminuta to a microorganism that has been isolated from the formulation. It is important to use the product formulation if possible,
because there have been instances in which B. diminuta has penetrated a sterilizing filter in contact with the product formulation but has been retained by the same filter when
inoculated into a surrogate fluid.
The ability to predict the successful outcome of a particular sterile filtration event requires a filter manufacturing enterprise
that is highly capable and consistent, a dependable and accurate method to conduct integrity testing, and possession of the
understanding and ability to implement effective filtration validation strategies.
Russell E. Madsen* is president of the Williamsburg Group, LLC, 18907 Lindenhouse Rd., Gaithersburg, MD 20879, tel. 301.869. 5016, madsen@thewilliamsburggroup.com
James E. Akers is president of Akers Kennedy and Associates. Maik W. Jornitz is group vice-president of global product management, bioprocess of Sartorius North America. Theodore H. Meltzer is a consultant for Capitola Consulting. Madsen, Akers, and Meltzer also are members of Pharmaceutical Technology's editorial advisory board.
*To whom all correspondence should be addressed.
References
1. M.W. Jornitz and T.H. Meltzer, Filtration Handbook: Integrity Testing (DHI Publishing, River Grove, IL, 1st ed., 2003).
2. Parenteral Drug Association, "Technical Report No. 26: Sterilizing Filtration of Liquids," PDA J. Pharm. Sci. Technol.
52 (S1) (1998).
3. P.R. Johnston and T.H. Meltzer, "Comments on Organism Challenge Levels in Sterilizing-Filter Efficiency Testing," Pharm. Technol.
3 (11), 66–110 (1979).
4. M.W. Jornitz and T.H. Meltzer, Sterile Filtration: A Practical Approach (Marcel Dekker, New York, NY, 1st ed., 2001), p. 623.
5. US Food and Drug Administration, Guideline on Sterile Drug Products Produced by Aseptic Processing (FDA, Rockville, MD, 1987).
6. M.W. Jornitz, "Integrity Testing," in Sterile Filtration, M.W. Jornitz, Ed. (Springer-Verlag, Heidelberg, Germany, 2006), pp. 143–180.
7. M.W. Jornitz et al., "Considerations in Sterile Filtrations, Part I: The Changed Role of Filter Integrity Testing," PDA J. Pharm. Sci. Technol.
56 (1), 4–10 (2002).
8. F. Bowman, M.P. Calhoun, and M. White, "Microbiological Methods for Quality Control of Membrane Filters," J. Pharm. Sci.
56 (2), 222–225 (1967).
9. S. Sundaram et al., "An Application of Membrane Filtration for Removal of Diminutive Bioburden Organisms in Pharma Products and Processes," PDA J. Pharm. Sci. Technol.
53 (4), 186–201 (1999).
10. M.S. Cooper, "Microbial Retentive Filtration," Microbiol. Update
18 (11), 2–3 (2001).
11. R.E. Madsen, "Filter Validation," in Sterile Filtration, M.W. Jornitz, Ed. (Springer-Verlag, Heidelberg, Germany, 2006), pp. 125–141.
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