A Path to Carbon-Free Processes in Pharmaceutical Manufacturing
As pharmaceutical manufacturing evolves, the goals of cost reduction and sustainability have become increasingly intertwined. As industry stakeholders face increasing pressure to deliver high-quality products while also minimizing environmental impact, facility design plays a pivotal role. New approaches involving energy-efficient technologies can not only enhance operational efficiency but also drive significant cost savings and carbon reduction.
Pharmaceutical manufacturing facilities, especially cGMP facilities, consume significantly more energy than other types of buildings. Between 1995 and 2019, greenhouse gas emissions related to pharmaceuticals rose by 77%. Total carbon emissions in the biotech and pharma sectors reached 397 million tCO2-e in 2023. With increasing pressure to reduce their carbon footprint, facilities are making inroads toward economically decarbonizing their operations without compromising product quality or patient safety.
While searching for a cost-effective solution to reduce construction costs for an immuno-oncology manufacturing facility with a cGMP suite, AEI worked with the owner and contractor to open the door to an innovative solution that not only addressed budget constraints but also created a zero-carbon process. The owner’s initial choice to use single-use technology (SUT) for the process vessels and ultra-filtration for the generation of water for injection (WFI) set the stage for allowing ozone sterilization of the WFI system. Implementing this method eliminated the use of steam throughout the entire sterilization process, creating an effective, energy-efficient solution that saved the project $1 million.
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- 77% increase in greenhouse gas emissions related to pharmaceutical production since 1995
Overcoming the Cost of Electrification
For this project, the client opted to utilize ultrafiltration to produce WFI and employed heat sanitization to sterilize the WFI storage tank and loop system as required by the User Requirements Specification (URS). Steam applications are typically the go-to for heat sanitization, with natural gas-fired boilers being the most economical choice for generating steam for pharmaceutical processes.
Electrically generated steam has always been an option. However, if large amounts of steam are required, electricity becomes cost-prohibitive compared to natural gas, which costs one-fifth of electricity per pound of steam produced. Following a building life cycle assessment and a cost comparison of electrification versus natural gas, it was determined that the high operational costs of heating systems would make an all-electric facility design unaffordable.
The initial concept design for the WFI system included heat sanitization using steam generated from a gas-fired boiler, along with a process cooling water system sized to cool down the WFI loop after sanitization. However, as the design progressed, finding space for the steam system in the mechanical service yard—including the boiler and associated condensate return, boiler feedwater tank, valve assemblies, and redundant units for the process cooling system—became challenging due to site constraints, with costs continuing to escalate.
Eventually, the contractor’s estimates exceeded the budget authorized by the board, and the team needed to make a course correction, or the owner would not be able to afford the project. Any idea that saved costs would be considered.
Removing Steam from the Process Safely
The key to further reducing the budget rested in eliminating the need for steam altogether. The use of steam had already been reduced by utilizing ultrafiltration for WFI, which removed the need for distillation and single-use technologies (SUTs). It also eliminated the need for clean-in-place (CIP) or steam-in-place (SIP) systems, which also use steam to generate high sanitizing temperatures.
The only remaining processes requiring steam were the sanitization of the WFI storage tank and distribution loop, and the WFI heating for the media fill step. The question was, how could steam be removed entirely from this process without compromising safety?
Ozone Tank and Loop Sanitization
One way to fully eliminate the need for steam in the sanitizing process is to employ ozone sterilization technology. Used for years as a drinking water disinfectant, ozone is a highly effective sterilizing agent that destroys a wide range of microorganisms. An ozone sterilizer creates its own sterilant internally from USP-grade oxygen, steam-quality water, and electricity, which is then converted back to oxygen and water vapor at the end of the cycle, leaving no harmful residues. It’s considered relatively cost-effective to operate and maintain and can work quickly, allowing for greater efficiency in sterilization processes.
Implementing ozone sterilization technology within the WFI tanks and distribution loop was a relatively straightforward task, as AEI had previous experience with implementing ozone sanitization in WFI and purified water (PW) storage tanks. Ozone sterilization of the WFI piping distribution loop would occur during off-hours, as is typical for all sanitization cycles. While the WFI Tank would always contain ozone, removing ozone from the loop during normal operation required only turning on the ozone destruct UV light. Initiating a sanitization cycle was as simple as turning off the UV light.
The use of ozone, however, created some concerns that needed to be addressed before moving forward with implementation. First, the complex molecule produced by the facility was sensitive to oxidation, and the owner was concerned that the generation and destruction of ozone in the WFI tank would increase the oxygen content of the WFI used in the process. The issue of oxygen levels and the use of ozone for WFI sanitization is a significant concern at the industry level, and considerable attention has been devoted to this topic in guidance documents and the International Society for Pharmaceutical Engineering’s (ISPE) Guidelines.
In this case, the processes being used would result in only a minor increase in oxygen concentration. In a WFI system that employs “cold” ultrafiltration generation and hot sanitization, the typical level of dissolved oxygen is about 8 PPM. Oxygen levels drop during and after a sanitization cycle, then rise when oxygen is reintroduced into the head of the WFI tank.
The amount of ozone needed in the WFI tank ranges from 20 to 200 PPB, depending on the length of the WFI loop—the longer the loop, the more ozone is needed for sanitization. Additionally, while ozone has a half-life decay time of approximately 15 minutes in the open, the half-life decay is closer to 60 to 80 minutes in a closed WFI loop due to the low TOC levels.
This means that, even if the WFI loop were long and required 200 PPB of ozone in the WFI tank, the resulting oxygen concentration in the WFI loop would likely not exceed 8.2 PPM. This is a very minor increase compared to what the dissolved oxygen levels would normally be in WFI without ozone (i.e., 8 PPM). Given these low levels, the owners did not need to worry about their molecule being compromised.
Additionally, owners questioned whether trace amounts of ozone would bypass the ozone destruct UV unit as the WFI leaves the tank and is drawn from the loop for use. For this, engineering controls would be enacted, including proper sizing of the UV ozone destruct unit and downstream ozone detection. But what if an amount below the detectable limit—approximately 5 PPB—bypasses the ozone destruction unit and enters the WFI.
Several factors exist to mitigate the impact. First, the ozone’s half-life is approximately 15 minutes once it's drawn for use. Additionally, ozone will react with the organic material in the media before it can be introduced to active pharmaceutical ingredients (APIs) or a cell containing APIs.
As part of a parallel investigation, the owner asked the contract drug manufacturing organization (CDMO) producing the molecule about how the WFI was made and the oxygen levels in the WFI. Ultimately, as the CDMO was already using ozone sanitization for the ultrafiltration-generated WFI loop circulating at ambient, the additional oxygen and potential for ozone were already present in the process and had not affected the molecule.
The second concern was personnel exposure to ozone levels in the processing rooms when the ozone-laden WFI was flushed through the point-of-use (POU) WFI valves to sterilize them and down the drains. The eight-hour exposure limit for ozone in the air is 70 PPB, while the one-hour exposure limit is 90 PPB. If the concentration of ozone in the WFI system is less than 70 PPB, one might think, no worries. However, the way water is discharged could significantly increase the amount of ozone released into the air.
Studies in the fresh food industry on using ozonated water to wash raw vegetables show that approximately 85% of the ozone transfers to the air almost immediately when sprayed onto the vegetables. Splashing and spraying water ultimately releases the ozone, while slower, gentler water pressure results in more ozone remaining in the water. This offers a valuable lesson for those in the pharmaceutical industry who need to develop a protocol for POU valve sterilization.
Considering that one gallon of WFI contains six orders of magnitude more water molecules than the number of air molecules in a 1,000 cubic foot room, discharging water in an uncontrolled way could result in a six-fold increase in ozone levels in the air. Thus, having the WFI flow through a POU valve and discharge into an open carboy would result in unacceptably high ozone levels. A simple solution is to contain the flow in a hose and direct it into a drain. This mitigates the risk of operator exposure to ozone while keeping the room cleaner.
Electric-Based Single-Pass Heater for Media Fill
Achieving the temperatures needed for the media fill step was not an issue. Because WFI is drawn infrequently for the media steps, electricity use is low and thus not prohibitively expensive. A sanitary, electric-based single-pass heater was chosen to meet temperature requirements without using steam. These were rather challenging to purchase at the time, as only a German-made product was available.
The heaters were set up in a side loop, flowing only the required media fill through the media WFI heaters, point-of-use (POU) valves, and then back to the main loop. Controls allowed operators to initiate a call for warm WFI for the media flow, then shut off the flow and heaters when the process was complete. Some warmed WFI passed the POU valves and returned to the main WFI loop. This warming side loop would have been needed regardless of the sanitizing approach. The difference was the higher cost of the electric sanitary heater compared to a steam-fired sanitary heater, which is more widely available and less expensive.
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- 50% reduction in the size of the facility’s process cooling system
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- $1 million saved on construction costs
Reducing Costs, Eliminating Emissions
The use of ozone sanitization and an electric sanitary heater for the WFI generation process yielded significant advantages, helping reduce the estimated $10 million construction budget by approximately $1 million. This reduction allowed the project to move forward. The design changes ultimately:
- Eliminated the need for a plant steam system.
- Reduced the process cooling system size by 50%, from 150 to 75 tons.
- Removed the need for insulating the WFI loop.
- Reduced the size of the building's mechanical yard.
- Decreased the time to perform the sanitization cycle by eliminating the need to account for warm-up and cool-down times of the WFI Loop, increasing overall throughput of the facility.
An additional, unintended benefit of using ozone and electric-based methods was the creation of a process that produced zero on-site carbon emissions. This is significant because low-carbon options are currently limited for projects that need steam and can be costly to install and operate.
In the past, natural gas-fired boilers have been the method of choice to produce steam due to their low installation and operating costs. Natural gas boilers have a coefficient of performance (COP) of 0.8 for the direct generation of carbon at the site of steam generation. Compression/refrigerant-based steam sources are also currently being developed, but they are years from being introduced to the market. These sources have the potential to achieve a COP of 2 and use electricity. Some may utilize waste heat sources.
Electric boilers may be the lowest-cost option to install, though this depends heavily on the building’s electrical system capacity. From an efficiency standpoint, an electric boiler has a COP of 1. One unit of electricity in an electric boiler generates one unit of steam.
However, the grid from which power is pulled may be generating carbon to produce that power, with emissions levels varying widely. In a worst-case scenario, the grid may generate so much carbon that a natural gas boiler on site may have a lower overall carbon footprint than an electric boiler.
For full disclosure, the heating hot water system used in this project was powered by natural gas and had sufficient capacity to meet the building’s HVAC needs. Thus, it cannot be claimed that the project eliminated the entire building’s carbon generation. However, the fact that carbon emissions were eliminated in one process by simply changing a sterilization method shows there is great potential for other solutions to help reduce the environmental impact of pharmaceutical manufacturing facilities.
Safe, Sustainable Manufacturing Processes are Possible
As environmental concerns become more pressing, designing pharmaceutical manufacturing facilities that incorporate new technologies and sustainable practices is vital. This project demonstrates that even with the implementation of energy-efficient processes that reduce the carbon footprint, such as ozone sterilization, it is still possible to maintain the quality and safety of pharmaceutical products. Moreover, with thoughtful planning and collaboration, operational efficiency and budget considerations can be balanced with a commitment to sustainability, ultimately contributing to a healthier future.