As industry momentum continues, oligonucleotide manufacturers are making the leap from benchtop production to commercial scale. The challenges of large-scale oligo manufacturing, however, are exponential in comparison to small scale, lab-based operations.
Before scaling up to commercial oligo production, facility owners should consider several points so that you have the capacity and flexibility required for long-term success. From supply chain to end-product type, there are a number of variables throughout your manufacturing process that will influence the facility design decisions you make now. To plan a sufficient commercial oligo manufacturing facility—despite future uncertainties—these are the five questions you should ask yourself.
1. How might your oligo manufacturing facility change in the first five years?
When building any new facility, owners typically face long return-on-investment periods and must plan accordingly. This approach is much harder in the world of oligos, however, as the landscape shifts constantly due to rapid innovation. How can you know what to build for the future when the industry is changing rapidly? Even undefined shell space can add significant initial cost to a project and, without a solid plan, can end up resulting in suboptimal growth. Fortunately, there are ways to make more certain plans for an uncertain future.
Define multiple metrics
The time-tested metrics used for expansion planning are manufacturing capacity and product pipelines, but these metrics may be onerous to develop accurately in the oligo industry due to its ever-evolving products, increasing demand, and drug-platform improvements. Instead, consider supplementing these traditional measures with alternate metrics to gain a broader perspective.
For example, consider the correlation between headcount and revenue growth. To double the revenue of your oligo manufacturing facility, what additional staff is required? If you’re planning on doubling revenue over five years, how is that staff count growing over those five years? Is the additional office space needed now, or can expansion come in a few years? If so, this will take the guesswork out of how much space is needed for offices, amenities, etc. in the initial build.
While laying a flexible foundation for future growth is important, there should be some boundaries. What will your facility do? And what will it not do? For example, will this facility include a QA testing lab? That decision alone will significantly impact facility footprint. Also, consider what will drive revenue growth: Only oligos? Peptides too? (Of note, this question can be harder to answer for a contract manufacturer as they must respond to market trends more nimbly.) Setting boundaries wherever it makes sense to do so will help define a facility’s basic needs and provide another starting point for facility planning.
Plan for phase two
Think through the implications of ramping up to higher production in the future. The return of investment on a second phase will be directly affected by how much downtime is needed to complete it, so facility owners should ask:
- How long can the manufacturing facility afford to not be making product/revenue/profit while transitioning from Phase One to Phase Two?
- How long will it take to execute and implement the second phase?
- What are the construction impacts and what are the start-up and validation impacts?
Preliminary planning for future phases of expansion is critical to dial down any negative impacts on what is already built. For example, if there are plans to build an additional manufacturing train, then you need to consider the utility system design during initial construction to accommodate it. At first glance, building utility systems that will be shared between the initial and future production lines may appear to cost less. But if you consider how this shared approach will result in downtime to existing production during expansion and associated revenue loss, then a production line-dedicated system may actually be more cost-effective in the long run. Other important considerations for phased expansion are:
- Equipment move-in pathways and installation areas in shared spaces
- Extra capacity for additional piping and space to install it in congested areas
- Extra space for expanded support activities (e.g. process and janitorial cleaning)
- Increased material and personnel traffic in common areas
- Changes to environmental permit limits and regulations
- Increasing cost of additional utility usage rights
Know the codes
When planning for the future, think about how decisions will impact code requirements. Start by considering the quantity of solvents that might be needed at full-scale production. Because solvents used in oligo manufacturing are often toxic, flammable, corrosive, and acidic materials, a thorough knowledge of international building codes and fire codes is key. For example, a facility’s egress requirements are different based on headcount and which chemicals are being used, so an understanding of possible future headcount is important to avoid regulatory headaches as the staff count grows.
2. Is the end product a drug substance or a drug product?
Whether your facility produces drug substances or drug products can have an impact on your regulatory considerations and manufacturing needs. Determining what claims you’ll make about your end product can help ensure that your facility is not under or overdesigned. Start by asking:
- What claims will be made about the product that is leaving the facility?
- How might these evolve over time?
- What consequences will those claims have on the facility design?
Keep in mind that from a regulatory point-of-view, drug substances are treated differently than drug products. While a substance is not ready to go to the market, a drug product is ready for sale. A facility manufacturing substances is considered an intermediate and has fewer regulatory requirements imposed upon it. Depending on which category the facility falls into, the types of spaces and storage needed will change.
Another differentiator between the two end product claims is that a drug product requires fill finish services. Fill-finish services are extremely expensive per square foot. They are the most vulnerable part of the entire process, require expensive equipment, and come under intense regulatory scrutiny. Many manufacturers choose to outsource this challenging piece of the process. But is there a chance that it would ever be brought in-house? If so, facility owners need to plan ahead for space and utilities.
3. How secure is the supply chain?
This is an area of facility planning where strategic warehousing decisions come into play. The upstream processing of oligos requires complex raw materials. These materials are expensive, hazardous, custom-ordered, and can be complex to transport. This typically requires increased onsite storage for raw materials, and as raw material consumption increases, warehouse capacities can become strained, creating the risk of a production bottleneck.
As an example, if a facility is being built in the middle of Wyoming with no major airport nearby, a bad snowstorm may delay the delivery of raw materials. Such a manufacturing facility might require a bigger warehouse to mitigate the risk of potential supply chain interruptions. Factoring in the likelihood of varying area-specific supply disruptions is key to a secure supply chain.
Finished oligo substances and/or products need to be stored safely in a clean environment. A facility owner needs to ask: How easy is it to move product out of the warehouse? Is the facility storing one week or one month’s worth of finished product? How robust is the distribution network? The answers will determine how much warehousing space needs to be set aside for products awaiting shipment.
4. What do the downstream purification processes involve?
Downstream oligo processing has many possible configurations and therefore requires the most manufacturing flexibility. When trying to identify how much downstream flexibility is needed, ask:
- How many filtration steps are required?
- Is capability for both ion exchange and reverse phase chromatography needed?
- Will the facility produce both single- and double-stranded oligos?
A newly-built oligo manufacturing facility might inadvertently introduce bottlenecks into its downstream process if its design doesn’t account for the various kinds of oligos it could produce in the future. Planning how future downstream needs will be integrated for both existing and any future lines will allow for proper optimization of process flexibility and specificity.
5. Is process engineering help needed? (Be honest.)
It takes more than an oligo recipe to achieve commercial oligo manufacturing success. As manufacturers make the leap from benchtop production to a large-scale facility, small functions that were previously straightforward become anything but. Even if the chemistry is the same at a commercial scale, the logistics are most certainly not. The spare parts that used to fill a junk drawer now require a whole room—and require someone to organize and document all of it!
We’ve found that many clients initially think they only require architectural help, but they are quickly overwhelmed by the details involved in carefully planning a facility at this scale. Many facility owners are gobsmacked when they learn the magnitude of commercial-scale cleaning or the ergonomic challenges when making the leap from 1-liter to 1000-liter of chemical additions. Adding solvents in benchtop production is relatively easy but pouring in 1000-liter of flammable solvent requires a complex system of pumps and tubing. What previously required a steady hand now needs more serious equipment.
Consulting process engineers who specialize in larger-scale oligo production can smooth out every step of the process: cleaning, organizing small parts, adding chemicals to reactors, moving salts, and managing consumables. Leveraging the experience of engineers who are experienced with pushing the boundaries of the exciting, challenging world of oligos will set up a facility for long-term success.
It is possible for oligo manufacturing facility owners to successfully plan for the expansion required to support commercial growth, even when all future conditions aren’t known. Although the field of oligos is evolving rapidly, by choosing the right metrics, defining boundaries, and thinking through future supply chain and downstream processing needs, facility designers can prepare for what lies ahead. As you wait to see where the world of oligos will bring you, facility owners can rely on experienced process engineers to guide you through the challenges of commercial-scale oligo production. The future of oligo manufacturing is bright!