How Ash Stevens’ approach to their business—focusing on their API manufacturing expertise—has helped the company grow in prominence as a CMO.

Founded in 1962 by chemists Arthur Ash, Ph.D., and Calvin Stevens, Ph.D., and headquartered in Riverview, Michigan, Ash Stevens Inc. is a privately-held, full service contract manufacturing organization (CMO) with over five decades of experience manufacturing active pharmaceutical ingredients (APIs).

Ash Stevens’ services, spanning from early-stage development through registration and commercial manufacturing, specialize in high-quality drug substance development and API manufacturing services for Life Science companies that are developing innovator small-molecule therapeutics.

“We make APIs, but we can do anything in the small molecule API sector of the business,” said Stephen A. Munk, Ph.D., CEO and President of Ash Stevens. “We can take a chemical structure on a piece of paper and deliver a ready-to-approve CMC section of a new drug application (NDA) in a technical document format—ready for review by the FDA.

“We offer a wide-range of platform of services that include process development, optimization and scale-up services, safety and hazard assessments, quality by design (QbD) services, and comprehensive analytical and regulatory support—so, really, we do the whole small molecule package.”

Ash Stevens facilities include capabilities from a recent plant expansion, including vessels as large as 4,000 liters with a capacity to produce batches as large as 250 kilos.

The Foundation

Having originally been founded to provide contract research services to the federal government, the company has now shifted its business model to primarily providing commercial contract drug substance development and API manufacturing services to the Life Sciences industry; though, they do still maintain a presence in federal government contract services.

“The company was founded out of Wayne State University in the very early 60s by Professor Calvin Stevens and Dr. Arthur Ash,” said Dr. Munk. “The company was initially founded to do contract government research—a process the founders were both familiar with from their academic training. For the first 29 years in business, that was the bulk of Ash Stevens’ business.

“We still have two government contracts and the work is being conducted at our Detroit facility, which is really more of a laboratory site than a manufacturing plant.

“In the early years, they [the founders of Ash Stevens] worked on anti-malarials for the World Health Organization (WHO) and potential drug candidates for the National Cancer Institute (NCI).”

Their research for the NCI on potential drug candidates led to the company’s first drug approvals (the first of which was in 1991), and transitioned the business toward commercial API manufacturing endeavors.  

The state-of-the-art, GMP manufacturing facility in Riverview, Michigan—the headquarters of Ash Stevens—houses both process laboratories and large-scale plant equipment. At this location, process research is performed.

What They Do

Spanning a number of areas and various capacities in commercial manufacturing, Ash Stevens:

• Works in all therapeutic areas
• Develops and manufactures highly-potent APIs
• Manufactures grams to 200-250 kg batches of APIs
• Has a range of clientele from virtual start-ups and biotechs to large pharma

“We do everything related to the API,” said Vince Ammoscato, M.Sc., Vice President of Operations at Ash Stevens. “But we don’t put it in any kind of dosage form.”

“Ash Stevens’ business is to develop chemical processes for making the active ingredient (API) in a new drug and manufacture the API needed for the drug’s clinical trials and (if successful) for commercial distribution,” explained Dr. Munk. “After leaving Ash Stevens, the API goes to a fill-finish or drug product company to be formulated into a dosage form, such as tablets or an injectable for administration in humans.”

Ash Stevens, not limited to the development side of manufacturing, also manufactures APIs post-approval.

“For many of these products, we can manufacture throughout the lifecycle of a product,” said Dr. Munk.

“We work mainly with innovator drugs, and we do not work with generics,” said James M. Hamby, Ph.D., Vice President of Business Development at Ash Stevens. “When an innovator drug goes off patent, we suffer from that as well.”

Ash Stevens offers services supporting the development, registration, and commercial manufacturing of innovator APIs. Some of the company’s services include:

• Process development and scale-up
• cGMP manufacturing
• Commercial API manufacturing
• Development and cGMP manufacturing of highly-potent APIs (HPAPIs) using barrier-isolation technology
• Analytical capabilities, including method development and qualification, stability studies, and qualification of reference standards
• Regulatory support for all phases of drug development and manufacturing

Mastering Development

Being a CMO facility, Ash Stevens’ research and operations focus largely on the development of drugs, rather than the finding of them.

“We don’t discover the drugs,” said Dr. Hamby. “Usually the drugs come to us at the point where a clinical candidate has been identified by the sponsor company. At this point, the sponsor company developing the drug is looking to partner with a contract manufacturer like Ash Stevens to develop and manufacture their API for clinical trials.”

One challenge for CMO companies is to industrialize the process of drug manufacturing. Rarely is the initial laboratory synthesis amenable to scale-up for clinical trials and ultimately commercial manufacturing without further development of the manufacturing process.

“We have to take the initial process [from the laboratory] and develop it,” Dr. Hamby explained. “We have to industrialize it so that it can be scaled up, repeated consistently, and yield the quality that is necessary.”

Ash Stevens aims to maximize the yield and efficiency in order to be as green as possible—using minimal amounts of solvents, increasing the cycle time, etc.

“The discovery process really is one where the architecture of the molecule is designed,” said Dr. Munk. “Once that architecture is defined, we get involved and construct the molecule on an industrial scale and industrialize the chemical process.”

According to Dr. Munk, it takes an average of 10 to 12 years from the discovery of a molecule to commercialization, with each clinical batch taking several months to manufacture.

“Typically, I would say, from the first time we put our hands on it [the drug molecule] to the time it is approved is typically five to seven years,” said Dr. Munk.

Once a drug has been approved by the FDA, the commercial production process begins. At this point, the manufacturing process has been validated, and making changes at this point in the process is often difficult. As a company, Ash Stevens is experienced with the commercialization of new drugs—with thirteen FDA manufacturing approvals for innovator (NCE) drugs.

“Once you have a good manufacturing process, it’s very hard to make changes,” said Dr. Munk. “You can, but that involves revalidation of the process, conducting more stability studies, and filing update supplements with the FDA for approval.”

Distinguishing & Differentiating

As a company, Ash Stevens strives to differentiate itself from its competitors, particularly in:

• Regulatory compliance
• Experience (50+ years)
• QbD approvals
• High-potency work (APIs)
• EH&S program (safety)
• Track record (13 FDA approvals)
• Scientific excellence
• Forming partnerships with their clients (customer satisfaction)

“I would say high potency is a strength of ours,” said Ammoscato.

“Driven by the National Cancer Institute Interaction for many, many years, we learned how to handle very potent compounds,” Dr. Munk explained. “We had one of the first barrier isolation systems in the late 90s and continue to add barrier isolation technology over the years and have had that as a focus for how we conduct our work.”

“We can handle potent materials from the gram scale all the way to hundreds of kilos,” said Ammoscato. “And we have data to support that we can do that safely.”

Ash Stevens has also utilized a number of advanced technologies, which have helped to minimize the need for moon suits.

“It’s interesting engineering technology,” Dr. Munk said. “The advantage of a lot of engineering installations that we have is that it minimizes the need for the moon suits. Some people still use moon suits in addition to the barrier isolation technology, but the whole purpose of the barrier isolation technology is that it is the barrier.”

FDA Manufacturing Approvals: Innovator APIs

To date, Ash Stevens has received over a dozen FDA manufacturing approvals for innovator APIs. These include four fast-track manufacturing approvals for the active ingredients in the drugs:

1. Millennium Pharmaceuticals and Takeda Oncology Company’s Velcade® (bortezomib)‎
2. Celgene’s Vidaza® (azacitidine for injection)
3. Genzyme Corporation’s Clolar® (clofarabine)
4. ARIAD Pharmaceuticals’ Iclusig® (ponatinib)

Other approvals include:

• Cerus Inc.’s INTERCEPT Blood System™ (amotosalen)
• Takeda Pharmaceuticals’ Ninlaro® (ixazomib)

Hard Work Rewarded

In 2014, Ash Stevens received the Eli Lilly Supplier of the Year Award, and in 2015 the company received a worldwide CMO leadership award in all five categories (productivity, quality, innovation, regulatory, and reliability)—the latter of which was based on outside market research by Nice Insights from consumers of CMO services and sponsored by Life Science Leader.

In December, the company also received a national performance improvement honor. Recognized for exemplary efforts in improving its environmental, health, safety, and security (EHS&S) operations by the Society of Chemical Manufacturers and Affiliates (SOCMA), Ash Stevens accepted a Bronze Performance Improvement Award at SOCMA’s 94th Annual Dinner.

Another of Ash Stevens’ strengths, they believe, is the size of their company. 

“As a company, we are a nice size,” said Dr. Hamby. “We are small enough to be interactive and communicative with our clients and able to solve problems quickly, but we are big enough to have most of the capabilities that most clients require, as well as the technical expertise that most projects require.”

“If you look at the calendar year of 2014,” said Dr. Munk, “the most drugs that any company got approved in a twelve-month period was three. And I believe AstraZeneca and one other company got three. A few others got two, like Merck and Novartis. In the last twelve months, Ash Stevens has had two manufacturing approvals for NCE drugs, which I think is pretty remarkable.

“We get a lot of approvals, which I think is a distinguishing factor for a contract manufacturer.”

To date, the company has received a total of thirteen FDA manufacturing approvals for innovator APIs. These include four fast-track manufacturing approvals for the active ingredients in the drugs Velcade®, Vidaza®, Clolar®, and Iclusig®.

In November, the FDA approved Ash Stevens’ facility in Riverview, Michigan for the manufacturing of the API, ixazomib, an oral proteasome inhibitor indicated in combination with leanlidomide and dexamethasone for the treatment of patients multiple myeloma who have received at least one prior therapy.

As a testament to Ash Steven’s commitment to its core values of Integrity, Service, and Dedication, the company is experiencing robust repeat business and very low employee turnover.

“I think clients like that stability,” said Ammoscato. “Projects last up to 10 years and they like to know that that expertise is still going to be here—not having to deal with different people two years down the road.”

“Our success is tied to their success,” said Dr. Hamby. “We want our clients to succeed.”

Focused on core competencies, Ash Stevens continues to thrive on what they do best: chemistry.

“We would rather do one thing very well than do a bunch of stuff mediocre,” said Ammoscato.

“For us, the focus is organic chemistry,” said Dr. Munk. “We have trademarked our founder’s favorite expression: ‘It begins and ends with chemistry.’”

This article can also be found in the January/February 2016 edition. 

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