December 6, 2019 PAO-11-2019-CL-001
The percentage of drug candidates in the pharmaceutical pipeline based on highly potent active pharmaceutical ingredients (HPAPIs) is rising steadily, owing to the rapid growth of the oncology segment and a growing tendency toward a more conservative estimate of the potency of new chemical entities.
Overall, cancer drugs as a class account for the greatest share of the global pharmaceutical market, and this segment is growing rapidly. Cancer treatment garnered nearly $150 billion in 2018, an increase of nearly 13% over the year before — the fifth straight year of double-digit growth.1 In 2018, a record number (15) of anti-cancer drugs was launched, and 849 molecules were in late-stage development, an increase of 63% since 2013.2 By 2023, the global oncology therapeutics market is predicted to reach a value of $200–230 billion, according to IQVIA.2
HPAPIs are classified at an Occupational Exposure Limit (OEL) starting at < 10 μg/m³, and can often require controls of OEL of < 1 μg/m³ or even < 100 ng/m³. The purpose and specialty of an HPAPI facility is the control of exposure with regard to the plant workers and exposure of other products manufactured in the same facility. Both of these factors are of ultimate consideration for the sponsor, who is responsible for the safety of their product.
Many cancer drugs are being classified as highly potent, cytotoxic compounds. The growth in the oncology segment is, therefore, driving demand for HPAPIs. Market estimates project the value of the global HPAPI market to be expanding at a CAGR of 8.5% to exceed $28 billion by 2024.3
The safe manufacturing of highly potent compounds requires highly specialized facilities, equipment, technologies and expertise. The investment to build a commercial HPAPI facility can easily cost tens of millions of dollars and take years to properly qualify before the first commercial product can even be considered. While some large pharmaceutical companies are willing to invest in these capabilities, many do not, while small and emerging firms typically lack the resources and specifically the expertise to do so. Consequently, demand for HPAPI outsourcing services has risen dramatically, placing a strain on contract development and manufacturing organization (CDMO) capacity, despite ongoing investment in the sector.
At the same time that oncology and highly potent drugs have been expanding their share of the pharmaceutical market, the percentage of drug candidates receiving designations allowing for accelerated development pathways has also increased.
In the United States, these designations include Fast Track, Breakthrough Therapy, Accelerated Approval and Priority Review. Under these programs, which are intended to get therapies to patients with unmet needs more quickly, drugs can receive marketing authorization after successful completion of phase II studies. Larger studies must be conducted to confirm the results once the drugs are commercially available, rather than performing larger, longer and more expensive phase III studies prior to approval. The development times for accelerated approval pathways can be reduced by many months to several years.
In 2018, 73% of new drug approvals issued by the U.S. Food and Drug Administration received one of these designations — up from 38% in 2008.4 Over the last five years, more than 60% of newly approved drugs in the United States have received expedited approvals. Cancer drugs tend to receive more expedited approvals than drugs for other indications
Pharmaceutical companies looking to outsource early-phase projects involving highly potent drug substances have two options when it comes to selecting a contract service provider.
They can opt to work with a company focused on early-phase development, which are often located in emerging markets, to get material for clinical trials as quickly and cheaply as possible. This choice is attractive, because it enables the minimization of upfront expenditures, since 90% of candidates fail in early-stage clinical trials. If the drug candidate proves to have potential and moves to phase II clinical trials, production must typically be switched to a new CDMO with later-stage clinical and commercial capabilities, often in Western markets.
The second option is to work with a CDMO that has capabilities for production of HPAPIs from lab scale to commercial quantities. While this approach is often assumed to require investment of a bit more time and money up front, no technology transfer is required in later phase development, leading to greater savings in the long run. This can be described as the difference between price and cost. A low-price option may require significant investment in resources, time and reproduction of earlier activities when transferring to a commercial contract manufacturing organization (CMO), dramatically increasing the overall cost to the sponsor and significantly increasing the time to produce the important clinical batches to advance the program.
Since many HPAPIs are oncology candidates with accelerated approval designations, they often reach the commercial stage more rapidly than conventional drugs. Working with a CDMO that can take a project from early phases to commercial launch becomes even more important for these projects when considering the compressed timelines associated with positive clinical trial results.
There are many obvious factors to consider when selecting an outsourcing partner: the regulatory and quality track record, on-time delivery performance, facilities and equipment, technical expertise and capabilities, culture, price and other factors.
It is also important to consider the potential life cycle of the project and whether the CDMO can provide the necessary support. If it is necessary to switch from an early-phase CDMO to a commercial organization, there is the potential to lose data and knowledge, creating the need for redevelopment of the process. As a result, tech transfer often results in delays and added costs.
In addition, early-phase CDMOs focused on producing material as quickly as possible for an early-phase trial do not consider the later needs of the project, with respect to quantity or process implementation at large scale. These processes will often need to be significantly optimized when transferred to the late-stage/commercial CDMO, which takes time and money, and can cause significant issues for candidates with accelerated development timelines.
An integrated HPAPI CDMO has the ability to produce the full range of quantities that might be needed throughout all phases of development and can rapidly respond to changing project needs with required quantities of clinical trial materials. In addition, because they will be implementing the commercial process, they also tend to develop processes early on that are scalable and will be optimized for commercial production.
Working with an integrated CDMO also facilitates the consolidation of complex pharma supply chains. Large pharma companies currently work with many different suppliers, requiring extensive management resources. Consolidation of their supplier networks through the establishment of strategic partnerships with fewer, integrated CDMOs helps reduce the time and costs associated with supply chain management. Small and emerging pharma companies likewise benefit from limiting their CDMO partnerships to a few integrated suppliers that can support their projects from concept to commercialization.
Fareva has been involved in the production of HPAPIs for more than 10 years in our Fareva – Excella facility located in Germany. Recognizing the growing demand for CDMO HPAPI capabilities and capacity, we invested in the construction of a new, state-of-the-art building specifically designed for high-containment development and manufacturing activities at our Fareva – La Vallée site in France.
We are an integrated CDMO offering support of HPAPI projects from the earliest phases through commercial launch. We follow projects as they progress through all phases of clinical development and on to commercial manufacturing. With a process development lab, pilot plant and commercial suite all in one location, there is no need to transfer processes to another CDMO or to another Fareva site.
Products can be produced as both non-GMP and GMP material depending on what is required. The laboratory and pilot plant equipment are similar to the equipment used at commercial scale for effective scale-down modeling and rapid scale-up of optimized processes.
In addition, the same analytical instruments and methods are used at one site, in contrast to a tech transfer scenario where the second CMO has different equipment and could potentially have issues adapting the methods. This could represent a significant time and cost savings over the life cycle of the project. Long-term relationships between customers and integrated CDMOs like Fareva not only ensure no loss of process information, but more robust process documentation, leading to smoother regulatory audits and increased likelihood of success of IND/IMPD and NDA filings.
Streamlining of process, analytical and regulatory knowledge is particularly important for fast-tracked HPAPI projects. In many cases, with accelerated development projects, the site producing clinical batches is not inspected by the FDA or other regulatory bodies. When pharma companies work with CDMOs that have a long history of producing commercial products, such as Fareva, they benefit from the track record of inspections already established with regulatory agencies. Based on our track record with the agencies, customers know that Fareva produces high-quality products according to GMP requirements, which can facilitate IND/IMPD filings and final drug approvals.
Our approach to project management also supports accelerated projects by enabling the rapid development and scale-up of optimized processes. We emphasize open and transparent communication within our project team and between the team and our customers. Importantly, the same project management team stays with a project as it moves through the various development phases.
In addition, both R&D and production personnel are involved in a project from the start. Operators provide input to process development and pilot plant experts on any potential issues that might arise in the commercial equipment for processes that are currently under development. Similarly, R&D and pilot plant personnel are involved in the demonstration runs, so they can confirm that the process behaves as expected and advise the commercial operators if any questions arise. This approach ensures smooth transitions from one scale to another.
It is also worth noting that, because Fareva has multiple API production sites with overlapping capabilities, different sites can serve as second suppliers, which is an added benefit when considering contingency planning. In addition, each site has complementary synthesis and final processing capabilities. We leverage these capabilities when a project involves numerous synthetic steps with a wide variety of chemistries and/or the need for highly specialized processing technology, such as micronization.
One of the key differentiators for Fareva as an integrated CDMO offering HPAPI development and manufacturing services is our family ownership. As a family-run business, we have no outside shareholders or private equity firms involved in the company. As a result, we can operate more strategically, consider both the long and short term decisions and make investments that enable us to adapt and grow with our customers.
The recent investment in the new HPAPI building at the Fareva – La Vallée site is a perfect example. Fareva has been involved in HPAPI production for over a decade. A few years ago, it became apparent that capacity constraints existed in the highly potent manufacturing space, with most established CDMOs at or above capacity. We responded quickly to the market needs, establishing new capacity.
The new building at Fareva – La Vallée was designed based on our experience at our Fareva – Excella facility in Germany and with expansion in mind; the existing capacity at Fareva – La Vallée can be rapidly doubled as part of a predesigned expansion to meet growing customer requirements, if needed.
Fareva is a family-owned holding company headquartered in Tournon, Ardèche, France. Fareva produces drug substances and drug products at our 15 plants, including three European facilities (Valdepharm, Excella, La Vallée) focused on API manufacturing. In addition to expertise in HPAPI production, the company has capabilities in spray drying, sterile crystallization, cryogenic reactions, high-pressure hydrogenation, wet milling and steroids manufacturing (dedicated equipment).
HPAPI production takes place at Fareva’s Excella and La Vallée sites. Excella is SafeBridge® certified for both highly potent drug substance and solid oral dosages. Fareva – La Vallée is currently undergoing the SafeBridge® certification process. Our highly potent capabilities include containment up to occupational exposure level of 10 ng/m3, process and analytical development, and laboratory, pilot and commercial-scale manufacturing, including high-potent micronization up to 100 ng/m3.
We have invested more than € 33 million in the last two years to expand high-containment capabilities for highly potent R&D, API and oral solid dose activities.
The La Vallée facility was built in 1985 by Merck & Co. and was acquired by Fareva in 2015. It produces lab- to commercial-scale quantities of branded and generic APIs and intermediates, including highly potent compounds, for a wide range of customers. This work is supported by extensive process and analytical development capabilities and regulatory support.
In 2018, using the knowledge gained in high-containment manufacturing at our Excella site, we added a new 3500-m2 flexible facility specifically designed for manufacturing of highly potent compounds with OELs as low as 0.1 μg/m3 that includes R&D and QC labs and pilot and commercial units at Fareva – La Vallée. Three separate bays house the commercial (3 × 4,000L) and pilot-scale (100–400 L) production and drying operations.
At both Fareva – Excella and Fareva – La Vallée, high containment is provided by advanced engineering solutions, including the use of air locks, pressurized air flows, specialized vapor extraction technology, glove boxes and more, supported by intensive training of our operators and, when necessary, by the use of personal protective equipment.
References
George Hlass is the Senior Director of Business Development for Active Pharmaceutical Ingredients (APIs) at Fareva. He has 20 years of experience in the pharmaceutical and biotech industries and has been the head of business development in North America for Fareva’s drug substance business for the past eight years. Previously, he worked for 10 years at two other chemistry-focused contract development and manufacturing organizations (CDMOs) that offered services in discovery, development and commercial manufacturing of small molecule APIs. He began his career in biotechnology, with three years of experience in the field of gene therapy.
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