A Potent Combination
To keep up with market demands and customer expectations, CDMOs are constantly looking at new technologies, equipment and partners to increase their value and position. When all three come together and allow a company to better serve its clients and expand market reach and capabilities, you have what most would consider a “win-win” situation.
Metrics Inc., a contract formulation, development and manufacturing company of oral solid dosage pharmaceuticals, has a reputation as one of the leading Phase I-III clinical trial materials manufacturers in the United States. Recently, the company was bought through a strategic corporate purchase by Australia’s Mayne Pharma. This has given it access to global markets and additional oral solid dosage technologies.
HISTORY AND TECHNOLOGIES
Metrics, based in Greenville, N.C., was founded as a contract analytical laboratory in 1994 by current president and former Burroughs Wellcome scientist Phil Hodges and ECU professor Dr. John Bray. As often happens in this industry, the acquisition of one company by another created a glut of experienced pharmaceutical professionals and Metrics took advantage of this. Six months after the formation of Metrics, Glaxo acquired Burroughs Wellcome. This situation enabled Metrics to secure highly experienced people in a short time and expand its services to include the manufacture of Phase I clinical trial materials. In 1998, Metrics started providing small-scale manufacturing and product development.
By 2000, Metrics had grown to 55 employees, prompting it to build a 44,000-square-foot facility.
“From 2000 to 2006, our growth was focused on building formulation development relationships for Phase 1 and Phase II CTM and first-in-man development scale capabilities,” says Jeff Basham, the company’s vice president of business development. “And with those relationships came pressure to expand into larger-scale development and Phase III manufacturing.”
By 2006, the company had 200 employees and, not surprisingly, ran out of space. In 2007, Metrics completed a commercial manufacturing and analytical laboratory expansion which added 52,000 square feet. The expansion was validated in 2008. It was around this time that the company started to attract business in the potent and cytotoxic areas. As Metrics’ reputation grew in these areas, company officials realized that they needed additional capacity and added a dedicated potent and development facility.
In 2008, Metrics opened its potent and cytotoxic drug development facility – essentially a facility within a facility – at its Greenville, N.C., location.
“We built this potent facility because we had clients with chemical entities in their pipelines that had highly potent characteristics,” says Basham. “Our clients said to us, ‘If you build it, we will come.’”
For their potent facility, Metrics decided to use hard-wall isolators to protect personnel, the environment and the product itself from contamination. The use of isolators in conjunction with dedicated air handling that brings in 100% outside air with HEPA-in and HEPA-out filtration provides enhanced control and protection.
And as Basham points out, such containment is exactly what companies are looking for. “Large pharma companies are looking for these controls. They don’t want PAPR (powered air purifying respirator) equipment; they want isolators and protection for operators and product.”
Metrics spent a significant amount of time planning and designing its potent facility, which included the integration of standard equipment into multi-use isolators through a standardized 270-mm rapid transfer port. This port allows for completely contained product transfer from isolator to isolator, or to safely export the final product or waste product from the facility.
The two potent compound processing rooms also feature one-way traffic flow of materials, personnel and equipment. Currently the facility can accommodate Phase I through III projects up to 10 kg in size. Containment at levels of 30 nanograms per cubic meter of room air is achieved.
THE MAYNE PARTNERSHIP
Toward the end of 2012, Metrics began to look for a corporate partner, something that would benefit both parties involved.
“Metrics needed to have a global footprint,” says Basham. “We have European and Japanese clients – we were not a purely North American based company – but we looked that way because we didn’t have facilities outside the US.”
Mayne’s acquisition of Metrics in October 2012 could be described as a “strategic purchase.”
“What was interesting about Mayne is that they had sold off all of their sterile product development capabilities, which had given them some US presence, so they needed a US presence and we needed a global presence,” Basham said. “Overall, the strategic situation was a perfect match. We integrated our financing and human resources functions, but everything else has been complementary.”
ANALYTICAL, DEVELOPMENT AND CTM MANUFACTURING
As what began as an analytical services company, Metrics still offers a wide range of these services and also believes that a large and well-run analytical services department is a key driver of success. As Basham explains, “Metrics is different. We started as an analytical company; hence, we have a thorough support system for formulation and CTM activities. We have four to five chemists on staff for every formulation scientist or commercial manufacturing person, so there is no backlog here. It (analytical services) is a key component of our support structure, whether it’s commercial or development work.”
Metrics boasts that of its 330 employees, 130 are analytical chemists. The company also adheres to a team concept in that every senior formulator is supported by a senior analytical chemist.
In the formulation development/clinical trial manufacturing area, Metrics has 15 scientists – eight of whom have more than 15 years of industry experience.
Metrics relies on a project management system with a slight twist. Each project is assigned to a senior formulation scientist and that person runs with the project no matter where it starts. The project manager stays with that project – even as it transfers into commercial manufacturing – in order to maintain consistency with the client. “The thing that the client likes is that the technical lead is always the same person in case there are any questions,” says Basham. “This person is intimately involved with all aspects of the product life cycle. This system is a differentiator for us.”
For clinical trial manufacturing (CTM), Metrics offers 12 GMP manufacturing suites, including five suites for potent actives (OEL at or above 1mcg/m3 room air). It offers two additional suites for highly potent actives, with 100% contained equipment (OEL at or above 30ng/m3 room air). Three packaging lines complement the aforementioned manufacturing suites. Metrics' facilities are regularly inspected and meet DEA guidelines for Schedule II-V controlled substances.
To offer a better idea of Metrics’ CTM and commercial batch capacities, it can process batch sizes up to 450 kg. Basham says that Metrics’ capacities are ideal for smaller patient populations and companies that have “niche” quantity needs – as compared to larger CMOs.
EXPERTISE AND SPECIALTIES
While Metrics is quite adept at formulation development and manufacturing CTM for many dosage forms, Basham notes that their specialties lie in the areas of scale-up and bioavailability enhancement. “We have particular expertise in handling compounds that have poor bioavailability,” says Basham. “We’ve done well with those materials.”
The company has developed intellectual property in the oral drug delivery area – a matrix system that mimics the action of an osmotic pump. Tablets with an osmotic pump feature a very fine hole that absorbs water and pushes API out of the hole. Metrics uses a matrix combination of excipients and API together with a functional coating to achieve the same concept.
Metrics now offers two other technologies to make oral solid dosage forms perform better – both of which have come from its alliance with Mayne. SUBA™ is a novel drug delivery technology for enhancing the bioavailability of poorly water-soluble drugs, and Cleantaste™ is a proprietary technology to mask the taste of API in liquids and tablets. This technology enables polymer coating of individual drug crystals to produce fine, non-gritty particles sized 25 µm to 125 µm (see sidebar for more detail).
FAST TRACK FORMULATION DEVELOPMENT
Sometimes a client comes to Metrics needing formulation help in a hurry. Metrics has developed a fast track program that can deliver Phase I clinical lots to a client in approximately 12 - 16 weeks.
"If someone brings us a NCE (New Chemical Entity) and it hasn't been in a 'first in man' clinical trial yet, we can provide them with solutions," says Basham. “We characterize it and can do a conventional capsule formula – or a neat API - pure API not mixed with excipients - in a capsule or bottle."
“Of course, all analytical methods have to be in place and validated,” he adds. “We will do 30 days of stability testing, the manufacturing, put it all in a package, put it in their application and off they go.”
LOOKING TO THE FUTURE
As Metrics looks to the future, its goal is to continue to build on its current strengths and further benefit from its relationship with Mayne.
Metrics plans to expand its potent and cytotoxic capabilities. “We have land available and part of the site development plan with Mayne is to expand our capability in that area,” says Basham.
Additionally, the relationship with Mayne has given Metrics the financial foundation to expand other areas of their business. For example, the company is adding a segregated development facility with equipment separate from its GMP area. The area includes five manufacturing suites and a large analytical lab. "Our clients have been pushing us to move through the early phases of development and proof-of-concept without having to keep GMP standards," says Basham. “You can do those things quickly without the cleaning verification requirement."
“It’s an exciting time for us and our clients,” concludes Basham.