Assessing Filling Technologies For Contamination Risk - The authors compare the exposure risk from viable particles from the air supply in four well-established aseptic filling technologies. -

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Assessing Filling Technologies For Contamination Risk
The authors compare the exposure risk from viable particles from the air supply in four well-established aseptic filling technologies.


BioPharm International
Volume 25, Issue 3, pp. 46-58

CONCLUSION

Aseptic filling carries an element of risk by definition, primarily because of the introduction of the human element in the production environment. Recently, Vonberg and Gastmeier performed an in-depth analysis of an outbreak database. This database contains more than 2000 outbreaks recorded, with 261 of them related to nosocomial infections due to drug injection. The 128 most recent ones with publication of causes, representing 2,250 infected patients, have been analyzed in detail. Three quarters of them were linked to the drug and 20% of these drug products were badly manufactured. According to these data, it is estimated that 2% of patients affected by outbreaks leading to nosocomial infections were contaminated by badly manufactured injectable drugs (12). This number can be extrapolated to all nosocomial infections, 1.7 million patients in the US in 2002 (13), concluding that approximately 30,000 patients have been infected by badly manufactured injectables, of which 3,000 died.

To illustrate that the risk of aseptic filling is well recognized, the EMA considers a filling process to be acceptable if not more than one contaminated unit is detected within more than 10,000 media fill units. For example, getting one positive unit among 12,000 media fill units means a contamination rate below 0.04% with a 95% confidence limit.

Very advanced technologies such as BFS and closed vial technology are sources of improvement as they can reduce the risk of product contamination by the surrounding airflow by more than two logs compared with classical technologies such as open vial filling. The media fill data, obtained in both GMP and challenging conditions, show how a low exposure filling technology can prevent accidental intrusion of contaminant in an injectable drug.

It is reasonable to assume that several other potential contamination sources (e.g., operator mistakes, inadequate sanitization, or glove contamination) may result in similar differences as the probability of contamination is always proportional to the probability of entry.

According to data from Vonberg and Gastmeier, such improvement may represent several thousand of nosocomial infections avoided in the US each year (12).

Such large differences in contamination risk suggest that the pharmaceutical industry should think about innovative solutions to improve quality for patients. Regulatory authorities have endorsed such innovative solutions with acceptance of CVFS in ISO8 environment and with the statement that BFS equipment in ISO8 environment meets GMP standards. With the same philosophy, FDA is increasingly emphasizing concepts instead of terminology (14). In particular, FDA recommends designing manufacturing processes based on scientific evidence of robustness. The calculation conducted in this article shows that higher confidence could be placed in BFS and closed vial technology compared with other open container technologies.

Using the most advanced technologies and requiring more science-based design are probably the best ways to reduce risk for the patient. Moreover, the pharmaceutical industry will benefit from simpler and more robust filling technologies.

ACKNOWLEDGMENTS

The authors would like to thank Patrick Baleriaux for his recommendations on this article. Aseptic Technologies receives grants from the Region Wallonne and from the Agence Wallone à l'Exportation (AWEX). Technology has been licensed by Medical Instill Technologies Inc.

Benoît Verjans* is chief commercial officer at Aseptic Techonlogies, Gembloux, Belgium, and Charles H. Reed is director of sales and marketing at Weiler Engineering, Elgin, IL.

*To whom correspondance should be addressed,
.


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