Founded in 1962, Ash Stevens Inc (ASI) is a contract research organisation focused on low-volume, high-value APIs produced using the company’s more than 40 years experience in chemistry, process development, materials, and quality requirements of products. ASI’s corporate offices and research facilities are housed in the Detroit Research Park, Michigan, USA, and has six research laboratories and support facilities.
The company’s customer base includes both the private sector and the US Federal Government. Services include chemical research and development, support of clinical trials through synthesis of drug candidates, and manufacturing of APIs post-regulatory approval. This support has led to approvals on APIs in many areas including oncology. The company was recently approved to manufacture the active ingredients in Velcade, Vidaza and Clolar. With these approvals, it now has 11 FDA-approved drug substances in its portfolio.
“We support all facets of chemistry manufacturing and controls preparation related to APIs, including structure elucidation, specifications development, methods validation, and drug substance stability, as well as preparation of documentation for submission,” says Dr Stephen A. Munk, the company’s president and CEO.
“Ash Stevens had been a long-time Government contractor and one of the compounds that we were developing with the National Cancer Institute, Fludarabine Phosphate became interesting commercially. The company followed that drug to the market and we continue to support the brand, Fludara, 17 years after approval! That initial approval re-focused our investment programme to ensure that we continue to modernise our operations in line with current pharmaceutical and GMP thinking. That was a major driver for our 2000-2003 plant upgrade and expansion.”
Investment in process development and drug manufacture
ASI’s process development and drug manufacturing facility is located in Riverview, Michigan. The 28,000 sq ft facility now houses nine chemical drug development and production laboratories, three full-scale production areas, as well as two analytical laboratories for quality control. Projects at this facility typically involve cGMP manufacture of material for toxicological and clinical studies through to commercial production after approval of the drug product. Major production equipment includes glass-lined batch vessels (up to 500 gallons), hydrogenation and other pressure vessels, centrifugal, nutsche and Rosenmund filter-dryer equipment, and vacuum and convection tray drying ovens, plus barrier isolation systems.
Last October, ASI announced that it had recently brought two new Rosenmund filter-dryers and a 100-litre pilot plant with cryogenic capabilities online at Riverview, representing an investment of more than $2.5 million. The large filter-dryer, a 0.3 cubic metre unit, is equipped with glovebox technology to facilitate handling of air-sensitive materials and to enable safe handling of Category 3 and 4 potent materials at plant scale. The smaller filter-dryer, a 0.03 cubic metre unit, is designed to be used with the company’s new cryogenic pilot plant which has the capability of maintaining temperatures as low as -80°C and can operate seamlessly to 200°C. The new systems are modeled an ASI’s process laboratories with pocket filters and vessels using the same geometries as those found in the main plant.
“These new capabilities facilitate the rapid scale-up of processes to support product requirements throughout clinical development and post-launch,” says Munk. “It’s our mission to translate client discoveries into new products to help seriously ill people. By upgrading our facilities with scaleable systems and assuring rapid product supply, we are investing in our customers’ success in the form of faster drug approvals.
“Ash Stevens thinks in detail about specifications not only from a technical perspective but from a regulatory perspective. Often, while things might make chemical sense, specifications are inadequate from a regulatory perspective. We additionally have a real understanding of pharmaceutical needs and timelines and are able to help optimise material management issues with our clients. This allows us to be nimble and ensure that material of adequate quality is available quickly for toxicology work while we prepare for the clinical side of the programme.”
Niche product manufacture
ASI’s products are sold globally and the company has been audited by a large number of Ministries of Health including in Europe, Japan, Korea, and Australia. The company produces APIs for both large pharma clients (for Fludarabine Phosphate and Clofarabine) as well as emerging pharma clients. Munk says its flexible, robust systems allow it to work efficiently with a variety of clients:
“Many in our industry have the same physical infrastructure as Ash Stevens. What distinguishes Ash Stevens is the depth of our systems and our understanding of the needs of pharmaceutical companies in contrast to the needs and requirements of organisations focused mainly on chemicals. This is reflected in the large number of New, Innovator, and Developed Chemical Entities that we were recently approved to produce – three in a period that has seen less than 100 for the entire world.”
Munk says ASI’s capacity is well suited for niche products, as its largest vessels are 500 gallons: “This limits our ability to deliver many metric tons quickly but we are a very nimble organisation and understand the very tight timelines for ensuring the survival of our client companies. Since we also have a lot of ‘Big Pharma’ regulatory and manufacturing experience, our systems are robust enough to meet the depth and demands of larger pharma clients as well.”
Level playing field
Munk is very positive about the company’s future: “Chinese and Indian companies will ultimately need to comply with tougher regulatory standards and that will level the playing field in terms of price,” he says. “Wages are also rising in those parts of the world, but I feel the financial advantage that producers from that part of the world enjoy is largely driven by the cost of regulatory compliance.
“I think that the outlook for competent contract research and development organisations is very positive going forward. We are certainly positive for the future and continue to invest in our business. We brought low-temperature capabilities online last year and purchased new, contained isolation technology – filter-dryers with glovebox technology. We have just completed commissioning of a new 400 MHz NMR. Emerging pharmaceutical companies will continue to be formed with exciting concepts from academic laboratories as well as licensing from Big Pharma as they realise that they cannot pursue all of the great opportunities that they have before them. There will be opportunities for those organisations to realise value from products that do not fit their company objectives and that will create opportunities for new companies to take up the challenge of converting those ideas into products.
“I think that it is a great time to be in the contract R&D/manufacturing environment. Those with a good understanding of pharma needs and the financial resources to invest will thrive as outsourcing grows in importance for Big Pharma as well as new companies whose business model does not include a full complement of chemical development and manufacturing expertise,” he concludes.
FURTHER INFORMATION
Dr Stephen A. Munk
Ash Stevens Inc
5861 John C. Lodge Freeway
Detroit, MI 48202
USA
Tel: +1 313 872 3621
Fax: +1 313 872 6841
Internet Links:
Email: samunk@ashstevens.com
Web: www.ashstevens.com
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