Concern Over Prion Diseases
Recent outbreaks of bovine spongiform encephalopathy (BSE; "mad cow disease") and related human spongiform illnesses, generically known as transmissible spongiform encephalopathies (TSEs), have raised concern over the safety of ADCs. The trend toward serum-free media is largely due to concerns over TSEs. This group of diseases includes BSE, scrapie (which affects sheep), chronic wasting disease (deer and elk), and Creutzfeld-Jakob disease (CJD; humans).
Cases of BSE have been sporadic, with the majority limited to Great Britain and Northern Ireland. Significant isolated outbreaks have arisen in other European countries. In North America, five cases of BSE were confirmed between 2002 and 2004. Although the number of animals affected has been in the hundreds of thousands (98% from the U.K.), fewer than 150 cases of the human form of BSE, CJD, have been confirmed worldwide between 1995 and 2002.
BSE and CJD are caused by a prion, an infectious, abnormally shaped, self-replicating protein that is much smaller than viruses or bacteria. CJD is believed to arise from ingestion of tissues, primarily nerve and brain, from infected animals.
Despite a mostly successful effort at eradicating BSE in food animals and the small number of human cases of CJD worldwide, bioprocessors have expressed concern over the use of ADCs in the manufacture and processing of polymeric materials that come into direct contact with bioprocess fluids.
Their apprehension is due to the small size and difficulty in detecting prions, and the fact that most biotech products are injected. Safety standards for injectible drugs are significantly higher than for ingested therapeutics due to the potential for direct infection.
Recently, bioprocessors have developed orthogonal infectious agent removal and inactivation schemes, as add-ons to normal viral clearance, which purportedly remove prions. However, a growing number of biotech experts believe that the unpredictability of BSE/CJD outbreaks, and the seriousness of the human form of prion disease (100% fatal), represent an unnecessary risk.
In response to this perceived risk, many bioprocessors now request fluid-handling products that are free of materials of animal origin. Animal-free materials eliminate unnecessary risk as well as the need to trace materials of construction back to raw materials.
Interest in animal-derived product-free polymers is strongest in Europe, where BSE has been in the news for more than a decade. However, there has been a discernible increase in attention to ADC status from North American and Asian bioprocessors as well.
Increasingly, bioprocessors are asking suppliers to document that construction materials are either ADC-free or, if they employ stearates from animal sources, that the additives were prepared in accordance with standards that guarantee inactivation of any and all infectious agents, including prions.
Since they operate in the epicenter of BSE incidence, regulators in the European Union have a keen interest in the causes and prevention of TSEs. In 2004, the Official Journal of the European Union published a guidance on minimizing risk of transmitting animal spongiform encephalopathy agents through veterinary medicinal products. This document states:
"Tallow derivatives, such as glycerol and fatty acids, manufactured from tallow by rigorous processes, are thought unlikely to be infectioussuch materials manufactured under the conditions at least as rigorous as those given below shall be considered in compliance for this note for guidancetrans-esterification or hydrolysis at not less than 200C for not less than 20 minutes under pressure (glycerol, fatty acids, and fatty acid esters production)"
Generally, processes used to manufacture tallow-based derivatives exceed these specifications.
Increasingly, polymer manufacturers will document that their stearate additives meet or exceed EU standards for tallow-based products. Moreover, many suppliers source stearate additives exclusively from North American sources, which greatly reduces prion contamination risk.
Normally this would be enough to assure biopharmaceutical manufacturers that product-contact surface areas in disposable plastic components pose no risk. However, despite the FDA's recent emphasis on risk-based and science-based manufacturing, biotech remains a highly risk-averse industry. As a result, interest in ADC-free polymers is growing.