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Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.
Demand for highly potent APIs continues to rise.
Highly potent APIs (HPAPIs) are an increasingly important segment of the API market. While there are many contract development and manufacturing organizations (CDMOs) that claim to have potent compound production capabilities, few have the facilities, equipment, and trained personnel needed for the production of highly potent compounds with occupational exposure levels (OELs) of 10 µg/m3/8h. CDMOs with established expertise are investing in expanded capabilities to meet the growing need for HPAPI production capacity.
Global demand for HPAPIs is estimated by various market research firms to be approximately $17 billion in 2018 and expanding to about $26 billion by 2023, according to Claudio Salvagnini, director of CDMO API and HPAPI activities at Minakem. The rapid growth is driven largely by the global oncology market, as many highly potent compounds are used for the treatment of cancer. This market has already surpassed $100 billion in global sales and is expanding at double-digit rates, according to intelligence reports reviewed by Minakem.
Maurits Janssen, head of commercial development, API development, and manufacturing with Lonza Pharma & Biotech, adds that the percentage of HPAPIs that are cancer treatments has grown from more than 50% in 2015 to approximately 60% in 2018, with the rest found in hormonal treatments, central nervous system treatments, and all other therapeutic areas. There are also many rare diseases under focus, and many of these conditions are being treated with highly active compounds according to Marko Salo, vice-president of marketing and sales with Fermion.
Three-quarters of HPAPIs are novel compounds. In particular, the growing focus on precision and personalized medicines such as antibody-drug conjugates (ADCs) that treat specific patient subgroups or conditions is driving development of novel APIs. Innovation is therefore another important factor in the growth of the HPAPI market, according to Salvagnini. He adds that despite the increasing number of biologic drugs in the pharmaceutical pipeline, the HPAPI market remains dominated and is foreseen to continue to be dominated within the next five years by small-molecule, chemical APIs.
Lonza also expects the generic HPAPI market to see strong growth over the next few years due to patent expirations of some branded HPAPI products, according to Janssen. Another driver for the growth of HPAPI capacity demand is the additional knowledge being obtained for existing compounds that previously were not considered to be HPAPIs. As new toxicity data are generated, some of these compounds are being reclassified as HPAPIs, according to Salo.
Outsourcing of HPAPI production is also expected to expand faster than the overall HPAPI market, according to Janssen. “This growth is due to the fact that the majority of innovation is taking place in smaller emerging biotech companies with no in-house manufacturing capabilities and therefore the need to outsource,” he explains.
The number of companies advertising highly potent manufacturing capabilities is quite high, according to a recent survey conducted by Minakem. “In a market analysis, approximately 100 [contract manufacturing organizations (CMOs)]/CDMOs were identified as claiming to focus on high potency and making numerous investments in the past 10 years, so what was once a niche segment appears to be more crowded,” Salvagnini notes.
Upon closer look, however, Minakem found that classification of highly po.tent manufacturing capability comes down to how each company defines potent vs. highly potent. Many of these companies are capable of processing compounds with OELs down to 10 µg/m3/8h, but only a handful of active CDMOs have the capability of handling highly potent intermediates and APIs with OELs of 0.10–0.01 µg/m3/8h and lower, Salvagnini says. This HPAPI business is highly concentrated in West.ern countries, according to Janssen.
Salo adds that many of these recent investments have involved smaller capacities. Janssen notes that the majority of HPAPI equipment for commercial manufacturing is mid-scale (4–6m3), where there is the highest de.mand. “Only a few companies, including Lonza, can cover the full range of reactor scales along the drug lifecycle from 2–10m3, allowing customers to access phase-appropriate equipment for their individual needs,” he says.
“Entry into this segment of the market is limited by the high initial investment required to install containment systems, glove boxes, proper air flow and conditioning systems; develop effective processes; and train operators,” observes Salvagnini. He adds that having a solid reputation for success in HPAPI manufacturing is probably more important than in other segments of the pharma industry, given that the safety of operators, the environment, and patients is a key concern. “We have seen that clients looking for HPAPI services conduct more thorough audits and risk assessments when evaluating potential outsourcing partners,” Salvagnini says.
There are currently no indications of overcapacity in the market, according to Janssen, but increasing competition may lead to a lower perceived market growth of the segment in the future. Continued investment will still be needed, however; as manufacturing and handling technologies for HPAPIs continue to improve, older facilities will require upgrading from time to time to prevent becoming sub-standard.
Minakem recently expanded HPAPI capabilities at its Louvain-la-Neuve plant in Belgium, which it acquired in 2015 from Ajinomoto OmniChem. “We acquired high-containment technology with this site and set as a goal to become a leader in high potency development and manufacturing,” notes Salvagnini. With available space for expansion within the building and on the site, it was possible for Minakem to revamp existing facilities and add new equipment and production trains. In addition, the company has access to talent due to its location near universities and pharmaceutical companies.
“The HPAPI segment is a high-technology market that requires continuous investment to ensure state-of-the art capabilities,” Salvagnini asserts. Not only is the HPAPI market expanding, highly potent compounds are becoming increasingly complex and more potent. “We need to be certain that we have the broadest range of synthetic and containment capabilities to meet the evolving needs of the marketplace,” he adds.
The new closed-controlled, high containment laboratory facility was opened in August 2018 and extends Minakem’s capacity to develop and manufacture HPAPI compounds from small-scale development to full GMP batch releases. In addition to nine fume hoods, a double-barrier of protection in the form of new-generation glove boxes in a room dedicated to dry powder handling and weighing, air locks, HEPA air filters, and cascading flow, the facility includes a preparative chromatography system for the isolation and purification of target molecules from milligrams to hundreds of grams for analysis and production applications.
The current production suite enables production of gram, 1–10 Kg, 20–50 Kg, and 100–150 Kg batches of compounds with OELs down to 0.1 µg/m3/8h. Minakem has also installed 5-, 50-, and 300-mm preparative high-performance liquid chromatography (HPLC) columns, according to Salvagnini. The company is also looking to invest in additional hydrogenation equipment under containment.
Fermion’s three-year project to expand HPAPI production capability at is Hanko, Finland plant reached its conclusion in the summer of 2018, with first batches and regulatory inspection completed. Unit 4 consists of a fully automated, completely closed HPAPI unit of more than 50 m3 capacity for the production of highly potent compounds with occupational exposure bands (OEBs) 4 and 5, according to Salo.
The facility can be run by just three operators due to a high level of automation. As a result, Fermion is able to produce HPAPIs cost-competitively, Salo adds. A bar-code system is fully integrated into the automation system, preventing charging of the wrong materials and avoidance of paperwork.
The project was commissioned in response not only to the growing demand for HPAPIs, but also because Fermion was finding that some older generic APIs that were previously categorized as OEB3 are today considered to be category OEB4 or OEB5 compounds. “We want to protect our operators to the highest possible degree and would rather overprotect our employees than take any risks even for lower OEB class products,” asserts Salo. He adds that it is Fermion’s point of view that operator working conditions with modern containment protection systems such as isolators are better than those that rely on old-fashioned personal protective gear.
One factor contributing to Lonza’s continued investment in HPAPI capacity and capabilities is the growth of oncology as a focus of biopharmaceutical research and development, according to Janssen. “Since these products use increasingly complex and toxic molecules, the companies that develop them more frequently seek external partners like Lonza Pharma & Biotech with the facilities and track record and expertise to properly handle HPAPI formulations,” he says. As an example, he points to ADCs and their use of highly toxic molecules to specifically target and kill cancer cells as representing a step up in oncology treatment that would neither be possible nor effective without extremely potent payload molecules and the capabilities required to handle them.
The company’s HPAPI investments have focused on providing agile manufacturing solutions for the wide range of product volumes required by biopharma companies’ increasingly specialized and pharmaceutically potent products, according to Janssen. Lonza Pharma & Biotech’s Visp, Switzerland Center of Excellence in HPAPI Development and Manufacturing has multi-purpose facilities designed to efficiently and safely manufacture multiple products simultaneously at various scales. Lonza currently has active HPAPI projects with OELs ranging from 5 to 0.04 µg/m3.
In February 2018, the company announced expansion of its HPAPI capabilities in North America, including the addition of two commercial-scale processing suites for the handling and encapsulation of HPAPIs using drum-dosing technology for powder-in-capsule filling at its Tampa, FL site.
In late 2017, Cambrex announced a $24-million investment in a new facility to manufacture HPAPIs at its Charles City, IA plant in the United States. The 4500-sq.-ft. production area will operate to an OEL of 0.1 µg/m3 and have a total reactor capacity of 2200 gallons and be able to manufacture batches from 50 to 300 kg. The small-scale manufacturing area at the site is also being reconfigured to provide a single high-containment building to support early stage development and manufacturing. Construction and installation of all new equipment is expected to be completed by Q1 2019.
The investment is in response to the growing number of highly potent, small-molecule APIs in the pharma pipeline, according to Shawn Cavanagh, COO of Cambrex. It is also part of an ongoing strategic campaign to invest in small-molecule API development and manufacturing across Cambrex’s global network of facilities.
Implementing new HPAPI development and manufacturing capabilities presents multiple challenges that must be addressed within a limited timeline, according to Salvagnini. “Multiple departments are involved, so cross-functional teams with representatives from environmental health and safety, program management, R&D, production, etc., must collaborate with external consultants and project design and construction companies. Having solid internal experience in containment technology and working efficiently together in close collaboration on a daily basis is essential for keeping such types of investment projects on track,” he says.
Previous experience with the addition of HPAPI units is also highly beneficial for successfully completing new projects on time and without major issues, according to Salo. Janssen agrees: “Considering Lonza’s 20 years of experience in handling HPAPIs and in maintaining the required facilities, the construction of new capacity was supported heavily from past experience, and progress was demonstrated by the short realization timeline and absence of critical challenges,” he observes. He also notes that Lonza has found it extremely valuable to build on a stable team of specialists and to keep everyone pointed in the same direction.
In addition to the expected healthy growth of the HPAPI market that is expected to continue in the coming years, significant changes in manufacturing and logistics are anticipated in response to changing market dynamics. “The move into personalized and specialized medicines means that large numbers of molecules will be produced at small scale, which is quite a massive change from the way the supply chain operates today,” asserts Salvagnini.
There is also a movement toward higher containment protection levels, according to Salo. Molecular complexity will increase further as well and present ongoing manufacturing challenges, according to Salvagnini. In addition, many HPAPIs in the pharma pipeline face bioavailability challenges and/or require modified-release technologies, according to Janssen. “As a result, HPAPI production and manufacturing today requires more specialized capabilities than ever before,” he says.
In addition, many drug formulating companies are closing their in-house production facilities and shifting toward contract outsourcing as a more cost-effective approach to HPAPI manufacturing. “These companies are looking for external CDMOs that offer integrated services and can tailor their enhanced technology platforms and supply-chain solutions to specific companies’ needs to facilitate development and reduce time to market,” Janssen comments. Outsourcing, he adds, is strongly driven by emerging and mid-sized pharmaceutical companies, which account for most of the innovations in the pharma industry today.
“CDMOs will need both flexibility and agility to accommodate the broader range of chemistries, toxicities, delivery technologies, and product volumes for highly potent intermediates and products that will exist in the near future,” asserts Salvagnini. Responsiveness will also be important, as increasing numbers of projects are designated as accelerated approval programs. “Minakem is preparing by adapting both its facility and internal organization, building dedicated supply-chain and building project teams in order to rapidly proceed through increasingly complex processes and stay on the critical path for shortened timelines,” Salvagnini says. He adds that its ongoing investments are made with this new future in mind, including investments in analytical capabilities and skilled and talented workforce.
Vol. 42, No. 11
When referring to this article, please cite it as C. Challener, "Building Capacity for Potent API Production," Pharmaceutical Technology 42 (11) 2018.