Increasingly, more drug products are now derived from blood and blood components, cells, tissues, genetic components, recombinant therapeutic proteins, live or attenuated or dead viruses/bacteria etc. Broadly, we call them “biologics”

Vaccines are one of the most widely used biologics in modern medicine. Their widespread use can be attributed to the preventive roles they offer in public healthcare system. As most vaccines are administered to healthy children; parents, peadiatricians, and the public at large want to be assured of their short and long term safety. Many novel vaccines are produced in animal cell substrates, and theoretically emerging infectious diseases may be transmitted from animals to humans due to their origin and production processes. It is therefore essential to isolate and remove known adventitious agents; but the bigger task is to identify potential adventitious agents in vaccines and to identify emerging infectious diseases these adventitious agents may cause – a huge challenge indeed for any drug regulatory agency to regulate such “unknowns”. As such, ensuring that vaccine products to be free of adventitious agents is a regulatory goal before marketing approval can be granted for public consumption.

Production of viral vaccines generally involves inoculation of a cell substrate with a vaccine seed and purification of bulk product from these cells after a sufficient time for replication of the virus or production of vaccine proteins. Other raw materials (e.g., tissue culture reagents, stabilizers) may be added to the product at various stages of production. Thus, adventitious agents could theoretically enter a viral vaccine through any of these steps and ingredients. Close control of the vaccine manufacturing environment (by producing vaccines in sophisticated modern facilities), appropriate testing of the raw materials, and testing of both the bulk and final products can help ensure that adventitious agents have not entered the vaccine. Most vaccines are subjected to inactivation or purification steps that can reduce the likelihood of contamination with adventitious agents.

Some past examples of diseases caused by use of bilogicals are:

• contamination of yellow fever vaccine with hepatitis B virus in the 1940s, 
• contamination of early polio and adenovirus vaccines with simian virus 40 in the late 1950s and early 1960s,
• contamination of blood products with hepatitis viruses and HIV, and
• contamination of dura mater grafts with the Creutzfeldt-Jakob disease agent.

In these examples, either human or animal materials used in production usually caused the contamination.

Current research on emerging infectious diseases may help provide further assurance that new vaccines do not contain adventitious agents. Powerful methods used to discover viruses associated with emerging infectious diseases are also being adapted to ensure that new vaccines (some of which may be produced in novel cell substrates) are free of adventitious agents.

Ng Cheng Tiang
Pharmaceutical Society of Singapore

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