IMPLICATIONS FOR THE INDUSTRY
The nontuberculosis mycobacteria appear to represent a potential risk to the biopharmaceutical industry, due to their propensity
for forming biofilms, their ability to proliferate in water under relatively low nutrient conditions, their resistance to
typical water disinfection methods, and their relatively slow growth in nutrient media (2–5). The former properties render
these organisms capable of existing in water piping and other surfaces in contact with water or aqueous media. Their growth
characteristics make these agents easy to overlook, especially when surveillance methods, such as short-term bioburden assays,
are employed. In this case study, the bioreactor run was terminated early because of an overly high value for an in-process
monitoring parameter. However, routine bioburden testing performed on bulk harvest samples taken from the terminated bioreactor
failed to detect the presence of the mycobacterial contaminant. Eventual detection of the contaminant in the course of adventitious
virus testing of this bioreactor harvest sample was possible because that assay was relatively long in duration (28 days)
and the antibiotics used in the assay (gentamicin, amphotericin B) were apparently ineffective against the species of mycobacterium
involved. The route of entry of the mycobacterium into the bioreactor process was not determined.
The mycobacteria involved in this case are pathogenic in humans, especially those who are immunocompromised (6, 7). It is
difficult to estimate the frequency of occurrence of mycobacterial contamination in the biologics manufacturing industry,
because some episodes may lead to premature bioreactor termination, such as that occurring in this case, with little evidence
to implicate a mycobacterium. A few cases of contaminated vaccines and tissue extracts have been reported in the literature
(8, 9). One can only speculate about the actual risk to the biopharmaceutical industry of this type of contamination.
At the time the work was performed1, Raymond Nims, PhD*, was a scientific director, Alfred Chun, was a laboratory director, Angela Marino, was a laboratory supervisor, and Suzanne Dieringer-Boyer, was a scientist, all at Biologics Testing at BioReliance, Rockville, MD, email@example.com
1. R. Nims et. al., "Adventitious Agents: Concerns and Testing for Biopharmaceuticals," in: Process Validation in Manufacturing of Biopharmaceuticals: Guidelines, Current Practices, and Industrial Case Studies, A.S. Rathore and G. Sofer, Eds., (CRC Press, Boca Raton, FL, 2005), pp. 143–167.
2. C. Le Dantec et al., Appl. Environ. Microbiol. 68 (11), 5318–5325 (2002).
3. L. Hall-Stoodley, C.W. Keevil, and H.M. Lappin-Scott, J. Appl. Microbiol.
85, 60S–69S (1999).
4. L. A. Carson et. al., Appl. Environ. Microbiol.
36 (6), 839–846 (1978).
5. C. Le Dantec et. al., Appl. Environ. Microbiol.
68 (3), 1025–1032 (2002).
6. B.G. Metchock et. al., "Mycobacterium," in: Manual of Clinical Microbiology, Murray, et al., Eds., (ASM Press, 7th ed., 1999) pp. 399–437.
7. W.J. Koh, O.J. Kwon, and K.S. Lee, Korean J. Radiol.
3 (3), 145–157 (2002).
8. J.G.A. Borghans and J.L. Stanford, Am. Rev. Respir. Dis.
107 (1), 1–8 (1973).
9. K. Galil et al., Emerg. Inf. Dis.
5 (5), 681–687 (1999).
Current Author Affiliations:
Raymond Nims is currently at RMC Pharmaceutical Solutions, Inc., Longmont, CO, Alfred Chun is currently at Cangene bioPharma,
Baltimore, MD, and Suzanne Dieringer-Boyer is currently at the National Biodefense Analysis and Countermeasures Center (NBACC),