First Commercial-Scale ADC Facility Launches In North America
By Trisha Gladd, Editor, Life Science Connect
As of last month, there are a total of 264 antibody drug conjugates (ADCs) in pharma’s pipeline. 161 of those are being developed in North America, making it the continent with the highest number of ADCs in development. Despite this, there is not a company currently offering ADC manufacturing capacity through commercial scale in North America. However, this will no longer be the case by the end of this year.
SAFC, the custom manufacturing business unit of Sigma-Aldrich Corporation, announced in May that it had completed the expansion of its St. Louis facility, which will be the first facility in North America to support commercial-scale ADC manufacturing. I recently spoke with Dr. Cynthia Wooge, global strategic marketing at SAFC, about the design of the facility and what challenges they faced preparing it for the safe handling of ADCs, a highly potent biopharmaceutical.
ADC Complexity Creates Unique Challenges
ADCs are very complex molecules. Developing and manufacturing them safely and effectively requires technical expertise in both large molecules and also in handling highly potent small molecules. Additionally, appropriate containment for handling biologics, such as ADCs, as well as the highly active materials associated with them, is required in any facility designed to produce them.
There are specific environmental controls that need to be in place in order to ensure safe handling of ADCs while also maintaining the integrity of the biologic. At the same time, it’s also equally important to protect the people working in the facility from the hazards of the highly active compound. The St. Louis facility is SafeBridge certified, which is an independent industry consulting firm that audits facilities and certifies that they meet a rigorous set of guidelines for handling hazardous or potent materials.
Wooge, who is responsible for the ADC and biologic conjugation market area for SAFC contract manufacturing services, says the costs associated with ensuring the high level of safety in a facility manufacturing ADCs can create cost concerns for any company interested in entering this market. “There is definitely a higher level of capital costs associated with putting the appropriate containments in place, obtaining qualified and trained personnel, following up with the environmental monitoring, and ensuring all of that gets implemented safely and efficiently,” explains Wooge. “It’s definitely more complex than building a mammalian cell culture facility for making monoclonal antibodies and doing protein production.”
GMP Design With A Twist
To come up with the design for the St. Louis facility, there were a significant number of people involved, including a team of internal personnel, consultants, and SAFC’s primary clients. The internal group included members of the engineering team, development groups, environmental health and safety groups, operational management, and sales. “Working with the engineering group, we came up with designs that ultimately went through several iterations,” explains Wooge. “We came upon one that seemed to satisfy the needs of both the internal people and our clients, based upon the expectations of the operations and the product that would need to be manufactured in the future.”
The final design of the St. Louis site is like a typical GMP facility, with increasing degrees of containment throughout the facility. The design of the building is strategically suited to the manufacturing process flow, with increasing levels of containment as appropriate. All rooms feature air locks specific to personnel, with separate ones for equipment. Because of the benefits of single-use equipment, such as fewer requirements for cleaning and validation and the ability to prevent cross contamination, Wooge highlighted that disposables are in use at the facility, wherever possible. In addition to the typical setup of a GMP facility, there are also specialized areas and equipment for handling the highly active components. “We have a separate room with an isolator, where we actually do the weighing of the potent solid compound, because that’s the most hazardous step of the reactions—when you’re handling the solid, highly potent compound. All of this work is done inside of a glove box, and because the small molecules tend not to be water soluble, they’re generally dissolved in an organic co-solvent,” explains Wooge. “Within that room, we have our weigh-up of the compounds. We also have an area where we can handle flammable solvents, so we can do the dissolution step safely and appropriately.”
After the materials dissolve, it goes into a production suite. This was designed as an open floor plan, so they could be flexible in terms of scale and unit operations. “That’s something where you need to be able to have some flexibility with unit operations, as we want the facility to be adaptable to the next generation of ADC technology,” explains Wooge. “When we first began conjugation, the goal was to minimize the use of chromatography because it adds complexity, cost, and time to the process. Now it is frequently used to remove aggregates or for purification.” A separate room is used for the filling of the ADC bulk drug substance into the bulk package containers, that has a Grade A isolator to allow aseptic filling.
Finally, any waste from the facility is handled in rooms separate from the production area. Everything is then incinerated offsite, so the toxic materials do not inadvertently enter the waste stream. Wooge notes, “We put a lot of thought into how the facility was laid out to ensure the safety of our operators, the safety of the environment, and most importantly, the safety of the patients who will be receiving the product.”
In terms of capacity, Wooge says the projections for the facility are around 600-liter scale volumes per conjugation. However, it will vary by product. If a client has a product that is an orphan indication, which requires only a small volume of product, there is flexibility in the facility that allows them to adjust, if needed.
Why Now?
In addition to the high number of ADCs in the North American pipeline, the ADC market itself is expected to be worth $10 billion annually by 2024. As of right now, there are only two approved ADCs on the U.S. market – Seattle Genetic’s Adcetris and Roche’s Kadcyla (Pfizer’s Mylotarg is currently only available in Japan). At the time of their approval, the ADC market was still very young, which made it very risky for companies to invest the infrastructure and capital needed to put the specialized facilities in place. For those who did take the risk, such as SAFC, what proceeded is the explosive growth in the pipeline that the industry is now seeing, which brings promise to any company with a foot in the ADC door. “Bringing any drug to market takes time,” says Wooge. “Recognizing that the average length for a product to go from preclinical studies to approval is ten to fifteen years, we’re optimistic that, with the FDA now offering some more accelerated pathways, it’s only a matter of time before we see more ADCs hit the market.”
A facility in the US offering manufacturing capacity through commercial scale helps companies, particularly in the U.S., with one of the biggest challenges the industry faces when it comes to ADC manufacturing – a risky supply chain. “The supply chain for ADCs tends to be extremely complex,” notes Wooge, “You could conceivably use up to six different CMOs to get a final product manufactured. By mitigating that risk, you eliminate multiple vendors who all need to meet a delivery date on an integrated timeframe. This can also be a burden from an administrative and project management standpoint.” Once the bulk drug substance is made, it can be shipped to Baxter, who currently has a collaboration with SAFC for ADC fill finish.