The value of the global market for highly potent active pharmaceutical ingredients (HPAPIs) is estimated to be expanding at a compound annual growth rate of 6% and predicted to reach $24.9 billion by 2025.1 This healthy growth is driven, in part, by advances in clinical pharmacology and oncology research. The development of targeted therapies such as antibody-drug conjugates, which contain highly potent cytotoxic payloads, has also been a key contributor.
While oncology remains the dominant indication, APIs across the board are becoming more potent as well, including those for the treatment of diabetes, cardiovascular diseases, central nervous system disorders, and musculoskeletal diseases. There is a shift in the pharmaceutical industry from general blockbuster drugs to more targeted therapies that are often more potent and provide more directed treatment to smaller patient populations. The higher potency enables greater efficacy at lower doses, often with reduced side effects. In addition, the loss of patent protection for branded drugs based on HPAPIs is creating further opportunities for contract manufacturing of potent compounds.2
Many HPAPIs are not only potent, but also highly complex. As such, contract development and manufacturing organizations (CDMOs) that seek to offer support for HPAPIs must have state-of-the-art engineering capabilities, facilities, and equipment that will protect plant workers and the environment plus sophisticated synthetic chemistry and process development expertise.
Indeed, it is essential for CDMOs that routinely handle highly potent compounds to take further steps to manage safety from the perspective of containment and industrial hygiene. They must ensure that products coming through the pipeline can be safely produced at high quality and within the appropriate time constraints.
Assessment of a CDMO’s ability to truly handle highly potent compounds in a safe manner can be challenging. Currently, the industry standard threshold for potency is 1 μg/m3 of airborne particulates, and any compounds with occupational exposure limits (OELs) below that are considered highly potent. However, many pipeline candidates have OELs 10 times lower than that. It is absolutely essential that CDMOs operating in the HPAPI space continuously update their capabilities to ensure the safe handling of even the most potent compounds.
How can a customer know if the technology and engineering systems employed by a CDMO are appropriate? How can they tell if glove boxes and isolators address the needs of current highly potent compounds or whether they are installed, set up, and used correctly?
Most reputable CDMOs have addressed these questions by adopting some type of qualification program. The most effective approach is to use a third-party certification agent. One of the most well known in the highly potent space is SafeBridge Consultants, Inc., a subsidiary of Trinity Consultants, Inc., that focuses on occupational health and safety for the pharmaceutical, biotechnology, and fine chemical industries.
Since an increasing percentage of pipeline candidates are becoming more potent, players in the high-potency CDMO space must have a broad range of manufacturing capabilities and be able to implement them at small to large scale.
For early clinical trials, highly potent drugs are typically required in very small quantities, and therefore containment systems suited for small-scale operations are necessary. It is essential, however, to be prepared to support successful programs as they move through later clinical phases and on to commercialization. As such, facilities, equipment, and engineering systems must also be in place to allow for the safe production of larger volumes of HPAPIs.
At Albany Molecular Research Inc. (AMRI), the majority of HPAPI projects fall in the realm of treatments for blood cancers, including leukemia and lymphoma. In addition to this large pipeline of programs, we are seeing increasing interest in potent steroids as older products in the steroid world are being revisited for potential new applications. We are one of a select few CDMOs that can offer support for steroids and hormones in a full-fledged facility with an established track record.
Recent emphasis on developing new, nonaddictive pain killers has created outsourcing support for the production of highly potent compounds also considered to be irritants, such as capsaicin and its derivatives. We are also involved in the development of HPAPIs with dermatological applications. Such compounds can be tremendously potent — perhaps with application via a droplet at the end of a toothpick. As such, they pose significant challenges from an industrial hygiene perspective.
The chemistries of these HPAPIs vary considerably and require expertise in organic synthesis, many different purification technologies, and wide-ranging analytical capabilities, all implemented under appropriate containment conditions. Many pharmaceutical companies looking for specific technologies will bring their projects to AMRI to leverage our ability to perform reactions under pressure, such as hydrogenations, within a high-containment environment; our expertise in chromatographic separation of potent compounds; and our capabilities in the lyophilization of HPAPIs and formulated products containing them.
We also support smaller and emerging pharma companies that require physical potent compound handling capabilities. We help ensure their projects move seamlessly through the development cycle, including those with accelerated development designations.
Many of the targeted, highly potent compounds in the pipeline are inherently unstable and extremely complex.
This fragility creates challenges for production and delivery. It is important to understand the nuances of the chemistry with respect to impurity profiles. Advanced analytical capabilities in the form of state-of-the-art instruments and techniques that can be implemented in a contained environment are essential to successful process development.
To address this need, AMRI has developed a center of excellence around analytical capabilities, marrying our process R&D group with highly functional analytical assets in our West Lafayette, IN, facility. Mass spectrometry, high-performance liquid chromatography, NMR, and other advanced technologies enable us to tackle very difficult problems and provide high-level structural characterization, stereochemistry, and other detailed information required to quickly establish impurity profiles.
These capabilities also ensure that AMRI can respond rapidly when manufacturing issues arise. Having such a high-tech support team available immediately enables AMRI to identify problems rapidly and then quickly develop and implement solutions so that project timelines can be maintained.
Indeed, success that is built on a diversity of capabilities and offerings provides great value. A CDMO like AMRI that clearly has a commitment to working with highly potent compounds is a more reliable partner. We have the breadth of capabilities, including advanced analytical technologies, to enable the development of CMC sections without the need to use subcontractors and the ability to quickly adapt to keep programs on track.
AMRI has several facilities with expertise in HPAPI development and manufacturing. We have worked with highly potent compounds at our Rensselaer, NY, facility for over 25 years. At our R&D center, we provide process development and ancillary services (i.e., stability studies, impurity characterization) for even the most potent compounds, enabling efficient scale-up and technology transfer to our clinical and commercial manufacturing sites.
In April 2020, the Rensselaer manufacturing facility was designated an “Industry Leader” by SafeBridge as part of its recertification under the SafeBridge program for “Potent Compound Safety Certification.” It is the first facility in the pharma industry to receive this designation. This certification confirms that AMRI not only meets the standards identified to be an industry leader for the safe handling of HPAPIs, but currently holds the top position for potent compound safety in the industry category for this classification.
With the acquisition of our steroid/hormone facility in Valladolid, Spain, we provide these unique capabilities as well. In addition, our Burlington, MA., and Glasgow, Scotland, sites offer high potency fill-finish services designed to support the processing of highly fragile, complex HPAPIs into formulated products. Having expertise in drug product manufacturing enables us to further support our customers as their projects move through clinical phases and into commercial production.
AMRI’s ability to support customers from the discovery stage through final product manufacturing for highly potent products is a differentiator. Often, the discovery and manufacturing world do not overlap. With our strong discovery group, which is located at our Buffalo, NY, facility, AMRI is able to support customers beginning at the early discovery phase and as they move projects into R&D.
We provide an effective bridge between the two that enables a seamless transition, after which process development and scale-up can occur as an HPAPI candidate moves through preclinical to early- and then late-phase clinical development and, ultimately, to approval. It can be very powerful for customers to have AMRI shepherd a program using all of the resources in our network. This approach provides greater speed and helps to avoid the often lengthy delays associated with technology transfer.
Importantly, corporate environmental, health, and safety (EHS) standards are applied across all AMRI facilities to ensure that everyone is operating under the same rules with respect to containment, toxicology, and industrial hygiene. In addition, a single project manager serves as the point of contact, ensuring that all of the relevant disciplines are involved in projects from the outset, thus enabling projects to move at an optimal speed. This combination of corporate structure/standards and strong project management teams at each site underlies AMRI’s success as a reliable and trustworthy HPAPI and drug product outsourcing partner.
With the nature of potent compounds evolving at a fairly rapid pace, it is essential to build flexibility into our systems. AMRI works closely with equipment manufacturers and constantly tests our procedures — from isolator operation to containment technology integration — to ensure that they remain relevant. As compounds become increasingly potent, we often find that the existing equipment is capable of meeting stricter containment requirements. We need to modify the way in which we use the equipment to achieve those lower levels.
One of the hallmarks of this approach is detection, and thus our ability to test for compounds or surrogate compounds is crucial. As our analytical capability improves, we are able to measure lower and lower levels of compounds. We marry the capabilities of the equipment to our ability to detect, measure, and monitor highly potent compounds. By taking this approach, AMRI is prepared to meet future needs.
There is also a recognition in the industry that the equipment required, particularly in drug product facilities working with highly potent products, is extremely expensive and challenging to qualify and run. To address these issues, our Glasgow facility is at the forefront of the application of single-use containment solutions. For each manufacturing campaign, a new, disposable, preconfigured containment system is rapidly set up and ready to operate. This can lead to a dramatic reduction in the risk of contamination when changing from one product to another. This approach also helps to mitigate the cost of containment infrastructure.
With respect to specific product technologies, AMRI is investigating capabilities for antibody production to enable full support for clients with ADC candidates. We already have expertise in cytotoxic payloads and can perform conjugation steps in the discovery space. We are excited to be adding capabilities for the production of antibodies and other biologic products and to expand our conjugation capabilities beyond the discovery phase. In the process area, we are investing in equipment and technologies necessary to implement flow chemistry for highly potent compounds. This technology can not only reduce the cost and time of process development and scale-up, it can also enable the implementation of chemistry that is too hazardous to be performed in a batch setting, opening up opportunities to access novel molecular entities and simplify synthetic routes to complex highly potent compounds.
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