New uses for oligonucleotides and increasing demand are driving oligo manufacturers to scale up to commercial production.
After 30 years of research, the oligonucleotide field is moving towards greater commercialization. Although oligo producers may have spent many years working in the lab setting, they may find themselves in uncharted territory as they scale to commercialization. And with that comes unique challenges as site and code requirements change.
The most significant hazards of large-scale oligo synthesis occur in the upstream process, which involves the use of many hazardous, highly flammable chemicals. It is these first few steps of manufacturing that really set oligo manufacturing apart from other forms of drug production—and this is especially true at a commercial scale.
In a lab setting, oligo manufacturers typically operate within a B (Business) occupancy class, which is in the same category as an office space, as long as they are staying below the Maximum Allowable Quantity (MAQ) code regulations of hazardous chemicals. However, once they are scaling up to large-scale production, larger quantities of hazardous chemicals are required (eg. flammable liquids) which require an H occupancy (High Hazard occupancy). Essentially, a commercial scale oligo manufacturer is a chemical plant making a drug product—and its owners need to be prepared for the corresponding hazards and regulatory scrutiny. As oligo manufacturers scale up, they need to understand site and code requirements.
It’s important to think through the perimeter of the building site. In considering any site for large-scale oligo synthesis, the importance of open space around the building cannot be overstated for these reasons:
- Storage tanks: Space is required around the building to locate bulk storage tanks. At production scale, it is no longer viable to feed the entire process from 55-gallon drums. Instead, bulk tanks are required which need to be filled from a tanker truck. The oligo manufacturing process also generates liquid waste, which is removed most economically with a bulk tank truck.
- Fire access: Due to the nature of chemical manipulations done within an oligo facility and the corresponding explosion or fire risk, it is best to plan for a fire department access road all the way around the building.
- Spill containment: Hazardous occupancies are required by code to be prepared to contain a chemical spill with at least 20 minutes of fire water. Typically this is done with an exterior containment tank.
- Other exterior needs: Other exterior requirements include generators and liquid nitrogen tanks.
When choosing a large-scale oligo synthesis manufacturing site, a standalone building is ideal. This allows for maximizing the use of control areas inside the building, as well as H occupancies. Additionally, the chemicals used may affect neighboring operations if there was a spill. In some areas, depending on quantity, there are restrictions such as distance from a school that also need to be considered. For these reasons, multi-tenant facilities are not an ideal location for a commercial-scale oligo manufacturing site.
Current Good Manufacturing Practices (CGMP)
Oligos are considered an active pharmaceutical ingredient, or API. Moving from lab scale to production scale requires that product be manufactured in a CGMP facility. Appropriate transition space is required to move people and materials in and out of the manufacturing space. Gown in and gown out rooms require enough space to enter, apply overgowning, and cross over the CGMP line. Material air locks require space to move material in for staging until someone can pick it up from the other side. Material air locks also typically have to accommodate equipment move-in paths for movable equipment. Other considerations are a CGMP wash room, and a CGMP janitor closet for cleaning.
It is essential to select the appropriate scale and square footage at the beginning of a project. It will be expensive or even impossible to make changes to the building’s square footage retroactively. When considering layout, keep in mind that the exterior of the building requires more points of egress so people can exit quickly in the event of a fire or explosion. Inside the building, large rooms require two exits. Also, the overall layout should be designed with shorter travel distances in mind as required by building codes. To accommodate the larger quantities of solvent, the building may require a fire-proof steel or concrete frame and have fire sprinklers.
Cold storage requirements
The beginning, middle, and end of the oligo process requires cold storage—usually in the form of a walk-in or drive-in cold room. There needs to be an adequate amount of cold storage space to keep up with production. Inadequate space for raw materials, in-process fractions, or finished goods could become a bottleneck in the process. In a multiproduct facility, resins may be stored in a cold room for reuse between batches.
A chemical spill could cause a spark, and a spark could cause an explosion. Therefore, an oligo manufacturing facility requires electrically classified power.
All lights within an oligo facility may require electrical classification. Power conduits should be exposed and sealed off so that vapors cannot get in, rather than the traditional construction technique of recessing electricity into the wall. Although cleanroom designers typically shun ledges—as they can collect dust and require extra cleaning time—the dangers associated with large-scale oligo synthesis demand this approach. The tradeoff of exposed, explosion-resistant sealed conduit in the room outweighs the challenges of cleaning.
Multiple HVAC considerations come together to create a safe oligo manufacturing facility. Firstly, there needs to be a robust building exhaust system on standby to rapidly disperse gases if a spill is detected by the automatic monitoring system. It should be on an emergency generator in case of power failure.
The flammability of the chemical used will determine the volume of exhaust air that the emergency dispersion system must handle. Additionally, the exhaust air volume calculation will be based on the flammability, toxicity, and potential leakage rates of the particular chemical used. It’s critical that leaking gas is removed before it is allowed to build up to explosive levels. In some cases, redundant exhaust systems may be required. Solvent handling areas should use negative pressure to prevent vapors from spreading throughout the building.
Oligo manufacturing is trending significantly towards commercialization with many manufacturers making the leap from a lab setting into large scale production. As we’ve seen, there are numerous safety considerations associated with this leap. Before snatching up a potential new site, it’s important to think through whether it has nearby neighbors, an open yard, adequate square footage, and sufficient cold storage options. Scaling up also brings along many code requirements pertaining to spill containment, electrical classification, and HVAC which merit close attention.
If manufacturers take the time to carefully plan around these site and code requirements, they will be set up for long-term success in one of the most exciting branches of the pharma industry. We are here to help with that!