Before the rise of aseptic processing technologies, horribly contaminated humans, shedding clouds of particles roamed controlled spaces, invading Pharma’s sterile processes. Sure, gowning, booting and hair-netting the contaminated helped tame the beasts and manage the risk, but their presence could not be denied …that is until now. Over the last 10 years advancements in aseptic processing equipment have been arming pharmaceutical manufacturers with the defensive systems they need to create a true “No Man’s Land” where human intervention and its risk are banished forever.
It’s pretty hard to understate the multiple layers of risk that need to be managed to successfully and compliantly accomplish aseptic drug processing. Drug safety and regulatory imperatives dictate drug makers create intensive, pervasive and verifiable systems to assure sterility in aseptic processing environments.
According to the Food and Drug Administration’s (FDA) 2004 “Guidance for Industry Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice,” in aseptic process: “the drug product, container and closure are first subjected to sterilization methods separately, as appropriate, and then brought together.”
Because there is no process to sterilize the product in its final container, says the FDA, it is critical that containers be filled and sealed in an extremely “high-quality” environment. The FDA guidance generally recommends that before final assembly the individual parts of the final product should be subjected to various sterilization processes. For example, says the FDA guidance, glass containers might be subjected to dry heat; rubber closures subjected to moist heat and liquid dosage forms subjected to filtration. As most are aware, each of these processes requires validation and control. To think that legitimate sterile drug manufacturers would ignore the risks to public health and its bottom line and willfully manufacture nonsterile product is a stretch, but the path to perdition is often paved with good intentions. Poorly instituted cGMP conditions can, says the FDA, “ultimately pose a life-threatening health risk to a patient.”
U.S. regulators note for each process there is the potential to introduce errors that ultimately lead to product contamination. “Any manual or mechanical manipulation of the sterilized drug, components, containers or closures prior to or during aseptic assembly poses the risk of contamination and thus necessitates careful control.”
Aseptic processes should be designed to intrinsically minimize exposure to potential contamination hazards that come from (relatively) routine manufacturing operations. To achieve a high assurance of sterility, regulators recommend drug makers take some pretty logical steps like optimize process flow, limit the duration of exposure of sterile product elements, provide the highest possible environmental control, and configuring equipment to prevent the entrainment of low-quality air into the Class 100 (ISO 5) area.
Further, to prevent unnecessary activities that increase the potential for introducing contaminants, FDA guidance notes personnel and material flow, the layout of equipment and incumbent operator ergonomics should all be optimized to limit the number and duration of personnel present in an aseptic processing environment. Essentially, best practice calls for limiting the frequency of entries and exits made into and out of aseptic processing rooms and their critical areas, including isolators.
To be clear, drug manufacturers now understand that any intervention, delay or stoppage during aseptic processing greatly increases contamination risk. The design of equipment used in aseptic processing, says FDA, should limit the number and complexity of aseptic interventions by operators. “For example, personnel intervention can be reduced by integrating an on-line weight check device, thus eliminating a repeated manual activity within the critical area. Rather than performing an aseptic connection, sterilizing the preassembled connection using sterilize-in-place (SIP) technology also can eliminate a significant aseptic manipulation. Automation of other process steps, including the use of technologies such as robotics, can further reduce risk to the product.”
Preceding the section outlining the above in its guidance, the FDA offered a caveat noting that the design concepts discussed were not intended to be exhaustive (read prescriptive). They did, however, declare “appropriate technologies that achieve increased sterility assurance are also encouraged.” Encouragement is one thing, but at the time, their vision of GMP-refined aseptic manufacturing — where human interventions become the exception rather than the rule — was a reality challenged by many factors, driven by both internal and external forces buffeting the industry.