The old adage, “If you want something done right, you should do it yourself” can be applied to many situations. Perhaps nowhere is it more appropriate, at least in the pharmaceutical industry, is at Acceleron Pharma in Cambridge, Massachusetts.
Acceleron was established in 2004 to focus on growth and differentiation factors in the TGF beta super family. The company’s main purpose is to develop biologics that modulate the growth of bone, muscle, fat, and the vasculature in order to treat patients with diseases with high unmet medical needs – many of which are know as “orphan diseases” for which there are no other available treatments. As the biology is complicated, a substantial number of novel proteins are required as tools for in vivo experiments. Due to the complex biology, Acceleron has developed numerous protein antagonists as tools to understand the biology initially and has developed similar molecules as therapeutics.
Doing It All In-House
Early in the company’s history, management compared production at Contract Manufacturing Organizations (CMOs) to “in-house” protein production. Based on several factors including the difficulty of expressing these proteins, the internal knowledge and insight of the properties of the members of this protein family, and the more favorable economics for the internal production of many reagents projected to be needed, Acceleron made a decision to internalize protein production. The initial production and purification of the proteins was done by the company’s own personnel in development labs.
This initial facility was a simple, 1600 ft2 facility which was designed and constructed in a relatively short period of time, minimizing capital and validation costs, and allowed the company to adopt a ”pay as you go” approach to the costs associated with pre-clinical and clinical production.
As the company got closer to the need for making preclinical and clinical material for its first product, the question of whether to outsource its product or do it internally resurfaced. Again a number of CMOs were contacted and asked for quotes for the work to make the initial development candidate. As the quotes came back the company realized that the cost of outsourced production would limit the number of projects which they could pursue into Phase I clinical studies. In addition, given the aggressive timelines critical to creating value for existing investors by showing the utility of these molecules in the clinic, company management had a strong desire to have better control of the timelines for production. Bob Steininger, SVP Manufacturing at Acceleron Pharma explains the company’s thought process at the time, “My goal here was to figure out a way to get a small company to control their destiny, which is really tough and frustrating when you have a great idea and you can’t act on it fast enough and you can’t learn along the way.” He continues, "we are making relatively complicated molecules. It is more difficult for an outside firm to deal with these. We had the expertise in house. Whenever it was sent out it took longer and more times to do the process, and it wasn’t clear when we would get into a CMO. For a small company like ours, for us to get data as quickly as possible, it was necessary to have control of the timeline.”
Based on the first facility's success and the company’s desire to control their destiny and costs – the decision was made to build a larger, second generation facility. The result is a 12,000 ft2 facility with approximately 4500 ft2 of processing space.
In order for Acceleron to make the facility as cost-effective and as nimble as possible, the company relies heavily on single-use technologies. The heavy reliance on what many might consider a “new” technology, was actually based on years of experience, as Steininger explains, “I was previously at Millenium, and technology was being developed to use single use – and I accepted that technology and made it work for a process that we had. It appeared to be reasonable. We probably did the first Phase 1 material made in bags. We put together a facility very quickly and made material – everything was delivered and made in single-use bags – which is very similar to what we do here.’
He adds, “The facility here and our whole effort; development, production, pilot production and GMP production has been based on the use of single-use technology from the get-go. It has really helped us by enabling us to make material quickly, particularly the complicated material we make.”
Large Cell Culture Production Area
Addition By Subtraction
While many companies are exploring single-use technologies and realizing the benefits that this technology provides, Acceleron needed to push the envelope a bit more with their new facility. As the facility is based in a rather crowded urban environment with little space to expand, and considering the company’s desire to contain costs as much as possible, the company came up with the revolutionary idea to eliminate in-house production of water and steam.
Steininger explains how they accomplished this, “In order to do this you have to be very confident that your media and buffer suppliers have a very good system to provide water and buffers appropriately.”
“Its very much like the Japanese auto industry – a very close relationship with your suppliers. All the parts have to fit together and fit together well with the appropriate tolerances. That’s not any different from what we are doing here. The companies that supply us with media and buffers have to do that well and as accurately as possible. That’s a dependence that most people have not taken a risk with, but it can be done given that there are a number of companies that will supply you liquid and plastic, etc."
The large purification production area.
And Acceleron has found those suppliers. “There are three reputable suppliers of buffers and there are lots of people who will supply you with media,” says Steininger. “Our media comes from California and our buffer comes mostly from Maryland. We are transporting water over a distance which doesn’t seem to be a limiting factor.”
Facility Design Input
As mentioned, Acceleron sought to keep the process, and perhaps more importantly, the process knowledge as much as possible, in-house. This knowledge, which isn’t stored on a computer, is found in the experience and talent of their personnel. “To a certain extent, we have called them manufacturing (personnel) but they are in fact scientists,” says Steininger. “In this early phase, you really want people who can understand how the process works, how it can translate into a larger scale, and how to adapt equipment from a vendor to what we are doing. That is in fact, I think what Acceleron has tried. We have manufacturing scientists who can adapt the single-use technology, the connectors, etc. and make it work. Many of these people worked in our first facility, they then transferred that technology into our new facility and made it run. That has worked well for us.”
A Small-Scale Flexible Future
With the success of Acceleron's facility, the question that needs to be asked is this the wave of the future? Are small-scale, flexible facilities, using predominantly single-use technologies the nail in the coffin for older facilities and technologies? “I think it is certainly one of the ways,” says Steininger. “One of the aspects that have come clear over the last few years is that there hasn’t been a lot of big stainless steel facilities built recently. This is because expression levels have gone up and there are more than enough plants in the area. You are seeing a lot of old and new companies using this technology. (In our case we used it) to see how we can minimize our capital costs and maximize the utility of what we have and if we need to add more (capacity) lets use this technology (single-use) rather than another way. It is enabling us to use capital more effectively – especially on the smaller scale. For a small company, it’s a very big advantage.”
Steininger and the folks at Acceleron have designed, built and are operating a very unique facility and one which they are rightly very proud of, “I think the ability to set it up where you actually made a facility that could depend upon, at least initially, other people supplying all your liquid and designing a gray space in a way that helps keep a lot of the "junk" out of the process (is what I’m most proud of)," says Steininger. “This design also allows us to think about the future - to build out our facility so we can make our own water and buffers.”
With their facility operating the way they want it to, Acceleron is planning for the future, as Steininger explains, “We have four drugs that will be in the clinic from Phase 1 – 2b in the next few years. Depending on how the trials go some we will make ourselves, some we might use a CMO. If it has to be done real fast we will make it here. If it gets too big, too fast, we will transfer it. We will have to focus on how we can make clinical supplies and make sure our products move through the clinical process. We will expand if need be depending on the clinical data.”