How Sigma-Tau PharmaSource’s personal approach to liposome process development and commercial production has fueled their emergence as a CMO.

A wholly owned subsidiary of the Italy-based Sigma-Tau Pharmaceuticals, Inc., Sigma-Tau PharmaSource is a contract manufacturing arm for the global company. The Indianapolis location is the only manufacturing facility. Sigma-Tau focuses its efforts on complex drug developments that treat rare diseases. Everything the company markets and produces carries an orphan drug designation.

Sigma-Tau PharmaSource has made a name for itself by specializing in the manufacture and process development of liposomes. Liposomes are generally spherical molecules comprised of lipids (fatty acids, sterols, etc.) that can be loaded with active pharmaceutical compounds.

They provide a mechanism for transport of the actives that can both reduce the inherent toxicity of the active and deliver more active to the targeted cells. This composition is more easily broken down by the body and allows for a more targeted approach than other delivery molecules. Essentially, the use of liposomes can result in a more controlled way of delivering medicine. In addition to its current uses, it is being investigated as a treatment option for many aggressive diseases, including several forms of cancer.

The company, and the facility from which it now operates, has a rich history with these complex molecules. Originally owned by The Liposome Company in the mid-90s, the building was used for the initial scale-up and launch of Abelcet. In 2010, the Sigma-Tau Group acquired the drug and facility. In the process, the company assumed a role as the industry’s primary manufacturer of this antifungal pharmaceutical.

Additionally, of the 10 commercial PEGylated products currently available, three of them are produced at STPS’ Indianapolis facility. PEGylation refers to the process of attaching polymeric ethylene oxide chains to molecules. The typical benefits can include a more controlled absorption rate, lower toxicity levels, and, ideally, increased drug stability. STPS provides a full complement of GMP-certified PEGylation services, including formulation analysis.

The ability to provide liposomal and PEGylated formulations, as well as the associated testing systems for these molecules, and use them to produce sterile drug products, has been a key differentiator. Combining this knowledge with the ability to provide commercial, clinical and early stage development expertise in such a specialized area offers current and potential customers a unique option when searching for a CMO.

“People know Abelcet because of its applications, and people know Sigma-Tau because of its global footprint,” offers Matthew VonEsch, Senior Director of Manufacturing at Sigma-Tau PharmaSource. “What they don’t always know is that we have CMO offerings for these complex molecules. We’re one of maybe 10 pharmaceutical companies producing liposomes, and most of those are Big Pharma companies utilizing these delivery molecules for their own products. We feel our proven track record in this highly specialized area will allow us to really grow our CMO business.”

Special Deliveries

“We specialize in sterile bulk processing—something not many can do as a CMO,” offers VonEsch. “These molecules are particular because they don’t like heat and can’t be put through sterile filtration. So each excipient has to be separately filtered prior to creating the larger molecule.”

Rigg explains that this affords STPS the ability to either scale up or down, according to customer needs. “It’s interesting,” he states, “because this process essentially allows our clients to re-brand existing products. The drug is the same but by incorporating the use of the liposomes, the delivery method is very new.”

STPS’ intimate understanding of liposomes and PEGylated formulations has led to the implementation of processes and testing procedures that can deliver higher quality results more quickly. These attributes are obviously well received. “We really don’t want to be a high-volume, commodity-based CMO. That’s a good business for some, but it doesn’t really fit our model. We’ll continue to focus on complex formulations and building the relationships that accompany these types of projects,” states Rigg.

“We’re always up-front about our capabilities,” continues VonEsch. “We work to be flexible in building a long-term partnership. Customer interactions usually begin with technical conversations to help us better understand the materials, development stage and deliverables. We then have the customer come back to us with some additional information, but we usually know very early in the conversation if it’s a good match, and if so, what the production flow will look like.

“We’ve found that by being very open right up front, we can more easily demonstrate our expertise.  This leads to a greater sense of ‘ownership’ of the product, which resonates very strongly with customers, regardless of what stage they’re at.”

As STPS has continued to grow their knowledge of liposomes and PEGylated formulations, they have also been able to expand the scope of their partnerships. “Some bigger customers might bring us something that is in need of refinement or to prepare for scale-up,” offers Rigg. “Some smaller companies might only have the concept, so they need us to help improve processes and fill in the development gaps.”

Riggs, VonEsch, and Gwyn Murdoch, Senior Director of Quality Operations at Sigma-Tau PharmaSource all agree that meeting such demands as recently as three years ago might not have been an option.

“We would have sent these customers somewhere else or told them to come back later in the development process,” states VonEsch.

“Now we can work with them. In the past those working with liposomes could only work with developers, now they can work with the manufacturer, too,” adds Murdoch.

Down the Line

Complementing the aseptic filling being performed for liposome and PEGylated formulation customers, STPS also handles some legacy high-margin, low-quantity fills. In addition to sourcing the vials, STPS offers contract packaging services that cover the labels, secondary packaging, lot coding, bulk packaging, and serialization—which has become a hot topic throughout the pharmaceutical industry.

Because STPS ships globally and deals with unique FDA, EU and other regulatory requirements, the company had to implement the appropriate software and product coding at a pace that was not disruptive to production or fulfillment. “Our approach was to fully understand all of the requirements before rushing to make changes that might need additional adjustments down the road,” VonEsch states.

As the company grows, one of the biggest challenges facing Murdoch and STPS is developing a uniformed quality control approach for all customers, regardless of the product’s development or commercialization stage. “We don’t want to have two quality systems for late and early,” she explains. “Our current systems are based on commercial GMP standards, but we’re working to develop a more analytical approach that provides the flexibility we need when applying it to development stage projects. We’ve never had a sterility issue, and preserving that record calls for us to constantly improve our quality systems and processes.”

In developing their new SOP, Murdoch, VonEsch, and Rigg can build on some current practices and investments that have established a strong quality track record:

• QBD (quality by design) is worked into the production process, but the attributes of this approach are dictated by the characteristics of the finished product. This leads to a more scalable design having a more precise impact on capital equipment or additional automation investments.
• Although the nature of liposome production does not always lend well to single-use technologies (due to the use of heat and alcohols), these products are used when applicable. The ability of these products to cut the costs and time associated with cleaning has helped preserve product quality and improve output.
• The investment in new automated visual and container closure inspection equipment will help improve lot inspection times by days per batch.
• “We have raw materials that cost tens of thousands of dollars per gram,” state VonEsch. “So while improving efficiency is important, we also focus on improving yield. We have one customer that was happy with an 80 percent yield rate. We optimized and implemented processes that improved that rate to 97 percent. So efficiency is great, but if the technology can result in less waste, that leads to real gains for us and the customer.”

Currently, STP is running their single fill suite and three formulation rooms 16 hours/day, five days/week. So there is room for growth in terms of capacity, and their current facility could be built-out to accommodate additional production. Right now the company is working with design and engineering firm IPS to construct plans that will support a new formulation suite and additional filling capabilities.

“Ideally, we can leverage some of our existing capacity to fund such expansions,” offers Rigg.

The contract manufacturing marketplace continues to grow and expand to meet new and exciting demands. This growth may result from new pharmacological advancements, quantity demands from an aging populous, or by simply capitalizing on an understanding of how to produce a product quicker, better or less expensively. By continuing to listen to its customers, empower its employees and refine its approaches, Sigma-Tau PharmaSource has the opportunity to realize all of these competitive advantages and the growth potential accompanying them. 

This article can also be found in the November/December 2015 edition.