Aseptic Processing: The Holy Grail?

The recent Genzyme warning letter depicts the focus and severity that regulatory bodies place on aseptic processing, but what are the real risks?

Is aseptic processing the greatest risk associate with sterile products, as is often implied by the governments?

The answer: it depends.

The risk associated with aseptic processing can only be properly assessed by looking at the big picture and should not be calculated strictly from a microbial perspective.

Although certain products are required to be sterile, we do not always manufacture them through sterile processing. Sometimes we use aseptic processing due to the sensitivity of the product and the near impossibility of keeping all microbes out of the processing stream. The definition for sterile is: “free from living germs or microorganisms”; while the definition for aseptic is: “free from the living germs of disease, fermentation, or putrefaction.” The subtle distinction between the two is: sterile means no bugs; aseptic means no potentially harmful bugs.

The definition of aseptic processing concedes that we can have bugs in our product. With this said, it is fair to conclude that everyday sterile units are leaving a manufacturing site somewhere in the world in a less than sterile condition. Oh my, isn’t this dangerous and aren’t we going to kill some? Again, it depends.

Even though certain body systems, areas, and/or organs are designed to be sterile (i.e., brain, blood, lungs), microbial infiltration into these areas does occur. As a defense to these intrusions, the body’s immune system leaps into action.

Consider the heroin junky in a back alley with a used syringe and tarnished spoon. He heats up the spoon to melt the heroin, uptakes the liquid heroin into the syringe, and promptly injects it into his veins. I think we can all agree that this process is not aseptic let alone sterile.

So, why aren’t all back-alley heroin addicts dying of septic shock? The answer is likely that the injection is small volume and their immune system is functioning as it was designed. It is reasonable to assume that junkies are routinely injecting themselves with contaminated product, but the injected microbes are not serious pathogens and/or their immune system is neutralizing the invaders before they become a serious issue. If these junkies were injecting large volumes into their blood stream, it is possible for their immune system to become overwhelmed and result in a hazardous outcome.

With this said, we can conclude that aseptic processing is not designed to completely eliminate risks associated with administering sterile products and some patients are receiving sterile products that are less than sterile.

So, what are the real risks? Is the real risk that we give someone an adulterated product (less than sterile) or that we give someone a product that overwhelms their natural defenses and causes them harm?

The real risks associated with aseptic processing are dependent on the product, route of administration, dose volume, dose frequency, patient’s immune system, and specific contaminating microorganism. Products that foster microbial growth and/or can not be fully subjected to a sterilization process carry greater risks (i.e., blood products); Intravenous injections carry greater risks than Intramuscular; Large volume parenterals carry greater risks than small volume parenterals; Multiple dose products carry greater risks than single dose products; Patients with compromised immune systems are at greater risks; and Product contamination with a pathogen carry greater risks than normal flora contaminations.

Obviously, our risks are lower when we have fewer microbes slipping through our processing cracks and therefore, putting less reliance on a body’s immune system. We should strive to control our aseptic processes as tightly as feasible, but we don’t need to over react when we find a crack in the process or a point-of-control deviation. When we encounter these situations, we need to do what 21st Century GMP and ICH guidelines tell us to do, complete a complete risk assessment by evaluating the type of contamination, extent of the contamination, and the product’s type, administration, volume, frequency, and target patient.

The principles of risk assessment require the specifics of a given situation to be assessed and the potential to cause harm to be assigned. When we treat aseptic processing as the “Holy Grail” of the medical manufacturing industry, we completely ignore these principles.

In conclusion, aseptic processing risks should be evaluated on a case-by-case basis and should encompass the complete picture and not just the microbiological perspective. We must recognize that microbial contamination are likely occurring everyday without detection and/or harm. Equally, we must acknowledge microbial contamination in sterile products have caused great harm and even killed people. We simply should not treat all situations the same by either over reacting or under reacting. With sterile products, the stakes can be high, but we shouldn’t automatically assume the worst-case outcome without completing a comprehensive investigation and an appropriate risk assessment.