SAFC, a global supplier of a a wide range of services to the biopharm and pharmaceutical industry, has recently expanded their Madison, Wisconsin facilities to neighboring Verona to rev up their high-potency API manufacturing capabilities. The original Madison facility works in concert with the new, large scale manufacturing facility in Verona to provide customers support from the pre-clinical through commercial stages of development and manufacturing. With more than 20 years of experience in highly complex chemistry, the Madison/Verona facilities are SAFC’s primary center for high-potency development.
The original facility, located in the heart of Madison’s University Research Park, actually began it’s time in the high-potency arena as Tetrionics Inc., established in 1989, by Herb Paaren and Peter Johnson, with the help of UW-Madison Professor Hector DeLuca. The company can trace its scientific roots back to the early vitamin D work of renowned UW-Madison Professor Harry Steenbock. The company achieved great success upon the development of its vitamin D analog, later commercialized in Zemplar in the late nineties. That success solidified their place in the niche market and enabled the company to complete a 25,000 square foot expansion to support the process development and kilo lab scale, and become a general GMP CMO.
In 2004 they were acquired by Sigma-Aldrich. According to Matt Hanson, the Global Market Segment Manager, “SAFC recognized it as a real opportunity to get into the highly active business,” and has continued to see the value and growth potential in the high-potency marketplace. Just two years after acquisition, the Madison facility underwent a 38,000 square foot expansion, effectively doubling the site in size and increasing the cGMP manufacturing capabilities.
The nature of the Madison location meant that the 2006 expansion would be the limit of their ability to expand further on that site, so in 2008 the Verona land was acquired just a few miles out of town and construction there began in 2010. The scenic site just outside of Madison was completed this fall, with lab validations still in progress at the time of our visit.
Although the sites are technically located in different cities, they are both run by the same management team with site-specific individuals, as a uniform operational entity. The two sites together can handle upwards of 50 projects throughout a year period, and SAFC has produced well over 20 commercial APIs out of the Madison facility.
SAFC’s service type spans all the way from pre-clinical to commercial, doing work with high complex chemistries, APIs, GMP products, and GMP intermediates.
Hanson says, “We do a lot of different support work for clients on the regulatory side, filing DMFs, helping them navigate from a substance standpoint. Most of the drugs that we work on, because they are highly active or complex, tend to be on the mid-size to smaller scale for a contract manufacturer. We can handle large batch sizes here, but generally we focus on the more complex substances with that smaller market volume.”
The Madison/Verona facilities include nine kilo labs, eight process development labs, three GMP pilot plants, two large-scale GMP plants, and two specially designed drying rooms. Bill Honkanen, the Engineering & Facilities Services Manager explains, “We recognized that as we were running our kilo lab projects, one of the longest activities for any project is the drying step. These drying steps can take multiple days or sometimes weeks, which entailed tying up a kilo lab in a non-labor intensive way. So, we installed these drying labs for that stage of production to free up the valuable the kilo labs.”
The company handles quality control on site, doing some level of quality testing on everything that comes into the facility. The Director of Operations Pat Klipstine shares, “One of the advantages is that we are part of Sigma Aldrich. Having that as part of the supply chain is a tremendous benefit to our processes.” Additionally, SAFC can support process testing, as well as final release testing, between the facilities at the two sites.
The Madison site also includes a hydrogenation lab for chemistry that involves breaking double-bonded carbons. That versatile capability necessitated a uniquely designed lab for the process.
There are complete process development and analytical development areas at the Madison site, allowing customers to provide a technology package and have SAFC either verify or develop the process from there with the whole gamut of instrumentation for APIs at their disposal. Klipstine shares, “Having the analytical instrumentation is really important in order to have that real time support during the chemistry and at the end of production to characterize and release.”
The Verona site is primarily a GMP manufacturing site, with the newly built storage space necessary to also serve as a distribution center for any materials headed to the Madison facility. The site includes two production plants with batch sizes ranging from 150 to 300 kilograms, as well as two pilot plants and various kilo labs.
Both sites have invested in the growth of their stability testing groups, to ensure that product quality is maintained after it heads out to the customer. Honkanen explains, “We take the products and put them in various environmental chambers, simulating various storage situations. We then rerun tests to check for degradation and stability.”
FOCUS ON SAFETY
Creating high-potency compounds comes with the risk of working with more volatile materials. SAFC Madison/Verona has gone above and beyond in their quest to keep personnel safe, embracing an unmatched safety standard in their facilities.
Klipstine explains, “We will take a customer from working on a technical package that may be preclinical and we will develop that chemistry with the many areas within our two sites. We have a very team-based approach to supporting our customers. We want to stress first safety as we approach the projects, then the quality of what we deliver, and then how we collaborate with that customer. Collaborating and being successful with them is extremely important when it comes to the service we provide.”
Hanson adds, “Part of handling highly active materials is you have to protect employees and handle materials appropriately, so we embraced Safebridge – an industry consultant that has set a standard of categorization and requirements for safe handling of materials. We were the second facility in the world to be certified to their standards.”
Those safety procedures are evidenced in detailed status information found outside each lab, letting employees know the hazard exposure level for each product in each lab throughout the chemistry process. All labs are secure, protected by an air lock and pressure differentials, and personnel only have access to the labs they are directly working within. High exposure risk areas include separate ingress and egress pathways as well as careful static control.
Honkanen explains, “The first control is containment, and then the reach back system, local ventilation, and then PPE. Even though the systems are enclosed, we do surrogate testing to ensure that when we’re manipulating materials that our equipment is contained/sealed. We actually have our operators in secondary PPE – more than is necessary – to ensure safety.”
The Safebridge methodology allows SAFC to perform highly complex chemistry in any one of the eight kilo labs on the Madison site, by simply using the appropriate portable equipment and very precise labeling procedures. Process safety is also ensured by the efforts of the process development chemists, who not only find proof of efficacy, but also confirm the procedures necessary to accommodate the thermodynamics as a process is scaled up.
The core of the Verona expansion includes a vast storage area protected by a whole host of explosion protection measures. Honkanen says, “This room has fire protection system that’s quite advanced and robust, there are fire protective pipes throughout the racking systems. If an event should occur, the area can be easily isolated. We also just implemented electronic inventory controls, giving us the ability to track inventory down to the exact location.”
SAFC personnel are also kept safe by foot-thick, damage-limiting concrete walls, specially designed for the high hazard risk environment that comes with producing active pharmaceuticals with highly reactive chemicals.
THE FUTURE OF HIGH POTENCY COMPOUNDS
The highly complex side of pharma is only becoming more and more tailored with more and more growth potential. “In the highly active/highly complex sector, anti-body drug conjugates are probably the most exciting in the industry right now, and is a growth sector where we have a substantial piece,” says Hanson.
Antibody-drug conjugation technology uses monoclonal antibodies or other biologics to deliver conjugated Highly-Active Pharmaceutical Ingredients (HAPIs) to targeted cells. In conjugated form, the HAPI exhibits more selective cytotoxicity, thereby sparing non-target cells from many of the toxic effects. Customers are quickly adapting these complex technologies and employing them to develop new oncology products that are more targeted and exponentially more powerful.
“We’re a part of commercial supply chains for the linker payload portion, and having SAFC St. Louis available to do the commercial part of the conjugation is a great step in our supply chain,” Klipstine explains.
“SAFC Madison has been in that game on the synthetic side for a long time, and now, coupled with the growing conjugation capabilities in St. Louis, it’s a great place to be because that business is growing everywhere,” says Hanson.
ON THE HORIZON FOR SAFC MADISON/VERONA
SAFC has invested a substantial amount into the Madison business with the last two expansions and they will provide quite a bit of capacity for the time being. The excitement of the Verona expansion is now finished; the facility is open and the remaining validation will happen later this year. The company will continue to evolve in the original facility as well – the Madison site will continue to be the R&D core.
As we look out onto yet untouched prairie land, Hanson says, “On the site here in Verona, we’ve only built on about half the acreage, so there are eight acres left to grow on to. From a strategy standpoint we are continuing to define what that might look like. The business has been robust and we consider ourselves a leader in the area. I think there are a lot of opportunities, but it’s hard to say what they will look like.”
“There are a lot of factors that will determine the direction of our growth in the future. And a lot of that depends on our collaboration with our customers and the success of how they move through preclinical to commercial,” says Klipstine.
“Ten years ago I couldn’t have imagined this, it’s amazing how it has changed,” says Hanson.