April 19, 2021 PAO-04-21-CL-04
Several significant trends are driving interest in the development of highly potent drugs. The continued emphasis within the industry on oncology and the advancement of potent anti-cancer medicines is perhaps the strongest driver. Many of these drugs are based on highly potent or cytotoxic compounds. The desire to develop more targeted therapies is another; these treatments are designed to attack the specific site of action only and thus are often much more potent than systemic therapies. Finally, the current emphasis on patient-friendly solutions is leading to more potent drug candidates with less frequent dosing regimens.
These potent drugs are all formulated with highly potent active pharmaceutical ingredients (HPAPIs), the global market for which is estimated to be expanding at a CAGR of over 8.7% through 2027 from $17.45 billion in 2018.1
As a contract manufacturer of both drug substances and drug products, FAREVA has observed a growth in demand for our highly potent outsourcing services in line with this estimate. We have also seen changes in client projects involving highly potent APIs that directly reflect the major trends in this segment of the market.
Most of our highly potent projects involve anti-cancer and immunosuppressant therapies. However, we recently have been receiving increasing numbers of requests related to antidiabetic, blood pressure, blood diseases, and other medications that are highly potent, enabling delivery at lower dosages. Convenience and drug delivery improvement are also factors. FAREVA recently assisted a client in developing a tablet for a product that previously required intravenous dosing. The tablet proved to provide fewer side effects.
One consequence of this expansion of high potency into a broader array of indications has been the development of potent drugs for diseases that affect much larger patient populations. As a result, many of our newer projects involving highly potent APIs or drug products require far larger-scale production solutions than traditional potent projects.
An overarching trend in the pharmaceutical industry that encompasses the highly potent segment of the market is the increasing reliance on outsourcing and the growing interest in contract service partners that can provide end-to-end solutions.
The benefits of the one-stop-shop business model are numerous and include simplification, access to coordinated technical support, and enhanced safety, all of which lead to time and cost savings. The sponsor company only has to work with one outsourcing partner. Issues anticipated for the drug product can be addressed during development of the API. When development or manufacturing challenges arise, they can be rapidly addressed, because both the drug product and API groups are in close cooperation.
For example if it is determined during final product formulation that a different particle size or polymorphic form is required, there is no need to make arrangements with multiple vendors to provide additional batches of material. The issue can be rapidly addressed without significant scheduling delays, which can otherwise span many months. Furthermore, when working with a one-stop-shop partner, there are no penalties for the sponsor company if manufacturing of the drug product must be delayed due to problems that arise during API production.
If both drug substance and drug product development and manufacturing take place at the same site, there are even greater synergies. Clients only have to visit one site for inspections and meetings. Only one audit and one qualification process are required, because the same quality organization spans all operations. Drug substance does not need to be shipped to another site for final formulation and packaging, eliminating the time and cost of physical product transfer, which is often delayed owing to customs questions, reducing repetition of analytical tests, and lowering the risk of the project. Overcoming challenges can also be further accelerated if formulators are able to directly collaborate with colleagues involved in API production and processing (e.g., micronization).
True one-stop shops also provide manufacturing at all scales to support preclinical studies through early- and late-stage clinical trials, launch, and ongoing commercial production. These contract development and manufacturing organizations (CDMOs) can support everything from lab-scale process development and initial formulation development to clinical and commercial manufacture.
The benefits of this business model are magnified for projects involving highly potent APIs and drug products. Operator safety and environmental protection are primary concerns when working with HPAPIs and formulated potent drug products. With the one-stop-shop model, the customer can expect consistency with regard to facility design, engineering controls, operator training, cleaning and cleaning validation strategies, and operational procedures/protocols when working at the same facility. These are highly specialized and essential factors for safe operations involving highly potent materials.
In fact, smaller companies that have smaller CMC teams appreciate the option to consolidate multiple services at one facility, because many of these activities are highly specialized. Managing so many different activities at different vendors adds even more complexity.
As importantly, the knowledge about the HPAPI and its toxicity and other physicochemical properties is readily available to everyone involved in the project, as is information about operator protection requirements, safe handling processes, and the relevant analytics. Immediately after this knowledge is developed and updated, it is continuously shared throughout the facility/company.
The high level of investment required to ensure proper containment and safe operations when working with highly potent compounds has limited the number of CDMOs that provide outsourcing services for these projects. There are in fact very few CDMOs that can handle the most potent compounds with occupational exposure limits (OELs) below 0.1μg/m3.
Even rarer still are CDMOs that offer development and manufacturing services for both HPAPIs and highly potent drug products. And among these, very few offer HPAPI and drug product services at the same location and within the same footprint.
To ensure the success of highly potent projects, these CDMOs should not only have the technical capability to safely implement highly potent projects — including the facilities, containment equipment and skilled operators — but a track record of regulatory compliance and demonstrated experience reflected in approved products that have been distributed worldwide according to international standards.
That capability and experience is needed not only for production of clinical and commercial batches, but also in process and formulation development, with appropriately equipped laboratories (e.g., glove boxes, hoods) and expertise in analytical method development; with instrumentation and procedures in place to ensure the safety of analytical technicians.
Ultimately, customers need CDMOs offering highly potent services to have the appropriate engineering controls, equipment, and safety protocols in place for all activities that present an opportunity for operator or environmental exposure to highly potent molecules. Like other CDMOs, they must also be responsive and flexible and be committed to open communication and collaboration.
FAREVA’s Excella site has been providing potent CDMO services for both drug substances and drug products for more than 40 years, and has 25 years of experience working with highly potent compounds (down to occupational exposure band (OEB) 6). In all of our activities, operator safety and customer service are always our top priorities.
FAREVA offers support for both HPAPIs and formulated drugs at our Excella facility in Germany, as well as additional highly potent services across several other sites in Europe. With the acquisition of sterile manufacturing sites located in Idron and Saint-Julien-en-Genevois (France) from Pierre-Fabre Group and Novartis’s Unterach site in Austria in December 2020, FAREVA now also has capabilities for the aseptic production of highly potent injectables and antibody–drug conjugates (ADCs). These acquisitions provide tremendous synergies with our existing services.
At our FAREVA-Excella facility, which has capabilities in process development and optimization for HPAPIs, as well as formulation development and final drug product manufacturing for oral solid dosage forms, we have one quality unit with one set of quality standards for the entire site. We also provide all of the regulatory and analytical support required across the entire development cycle. At this site, we have completed more than 10 one-stop-shop projects, many of which have involved highly potent compounds.
Our industrial hygiene department calculates the appropriate OELs for incoming compounds and conducts all exposure measurements throughout the site, ensuring that the same standards are applied across the facility. For many years, in fact, FAREVA is the only company with Safebridge certification for both drug substance and drug product manufacturing at the same facility. This certification is not a requirement, but companies that receive are recognized as meeting criteria with respect to the management, evaluation, containment and control, and communication activities necessary to ensure safe operations involving highly potent compounds.
In addition, FAREVA has a suite at the Excella facility outfitted for micronization of HPAPIs, eliminating the need to involve an additional vendor for this highly specialized service. Micronization is particularly important for many HPAPIs because these compounds are often poorly soluble and require particle engineering to enhance their in vivo solubility and bioavailability. In these cases, it is often necessary to demonstrate the optimum particle size for the final dosage using a quality-by-design approach, which requires studies using products spanning different particle sizes. In-house access to micronization capability dramatically accelerates the development process.
With our broad range of potent and non-potent development and manufacturing capabilities, FAREVA has the flexibility to rapidly meet our customers’ needs from early-phase development through clinical and commercial manufacturing of both HPAPIs and potent drug products. Small and emerging pharma companies benefit from our specialized expertise and experience in shepherding highly potent projects from start to finish. Big pharma companies with multiple projects also benefit from our ability to support multiple chemistries and dosage forms beyond highly potent projects.
We also place a high emphasis on providing a personal touch and fostering a collaborative work environment across our internal groups and with our clients’ teams, including enabling direct access to the technical experts working on each customer’s project. Underlying all of these activities is the knowledge we have amassed over the decades, which is then combined with the knowledge we generate for each new highly potent project. That knowledge is centralized at the plant and used to establish the measures required to ensure safe chemical production using optimized processes, safe and effective analytic procedures, safe operation of our QC labs, and safe activities during drug product formulation development and manufacturing.
FAREVA is committed to supporting customers with highly potent projects from early development through commercial production as the natures of those projects evolve. The company has historically and will continue to make investments at whichever sites are appropriate whenever there is a strong business case to do so. We want to enable our clients to succeed and are willing to share some of the risk with them.
In the high-potency space, we have expanded our analytical and QC capabilities to support HPAPI and potent drug product development and manufacturing. FAREVA also made a significant and proactive investment in a top-of-the-line Gerteis roller compaction unit for very highly potent (OEB 6) substances, and high-potency micronization as well.
Currently, FAREVA is investing in the construction of a new high-containment building for the processing of highly potent drug products down to OEB 6 (OEL less than 0.1 μg/m3). Work has already begun on the suite, which is being built to the most stringent safety requirements. It is expected to be operational by mid-2023. This addition will essentially double our high-containment capacity for drug product manufacturing and development services.
With all of these investments, FAREVA is positioned to provide a broad range of capabilities to clients with projects involving the most highly potent compounds. At FAREVA’s Excella site, we support everything from HPAPI process development and manufacturing to formulation development and final drug product production, including direct tableting and encapsulation, as well as micronization, shear granulation and roller compaction prior to tableting/encapsulation, and film-coating — all from lab to commercial scale. Final products can then be packaged within isolators into blister packs or bottles. And for clients that have highly potent products that require administration via injection, we can now support their projects at our two recently acquired sterile facilities located in France.
Norbert Straub is a pharmacist, current employed as R&D Director Pharma highly Potent at FAREVA-Excella GmbH & Co. KG in Feucht, Germany, with experience in pharmaceutical solid dose drug product development and transfer projects for more than 30 years. He closely collaborated with diverse customers on five successful FDA and EMA New Drug approvals of highly potent oral solid dosage forms in the last six years, transferring the manufacturing, packaging, and testing of more than 10 mostly highly potent OSD forms to FAREVA-Excella in the last 10 years.