In recent years, the increase and interest in the development of highly potent APIs (HPAPIs) has led to more than 25% of drugs on the market today being classed as highly potent.¹ The global HPAPI sector is one of the fastest growing areas in the pharmaceutical industry, and the annual revenue from these drugs is expected to reach a value of $40 billion by 2025.² The contract manufacturing market for HPAPIs is expected to grow at a CAGR of 10.1% through to 2027.³

Growth drivers

The reason for this growth is that HPAPIs can enhance therapeutic efficacy by delivering highly pharmacologically active treatments, which require much lower doses than other therapeutics. They can be used across a range of disease areas and have shown promise in treating serious and chronic conditions such as asthma, diabetes, and cardiovascular diseases, but they are most commonly associated within the field of oncology. Nearly one in three new drug approvals over the past several years have been for cancer,⁴ and 60% of oncology drugs in development today involve highly potent ingredients,¹ emphasizing the importance of the sector’s ability to handle and manufacture these drugs. Alongside biologic therapeutics, small molecules are vital in the industry’s response to the needs of oncology patients, and highly potent payloads are also utilized in antibody-drug conjugates (ADCs), which often focus on cancer treatment.

Classification

The potency of an API is determined by its toxicity and dose range studies that determine critical values such as no observable effects limits (NOEL), which are then used to derive a risk-adjusted occupational exposure level (OEL) that indicate the limits considered to be safe for chemical substances in a workplace environment. An occupational exposure band approach based on OEL is often used to determine the appropriate containment measures, and although the specifics of banding and levels vary, any API with an 8-hour average OEL under 10 µg/m³ is generally considered to be potent.

However, when determining containment strategies, organizations should not consider OEL alone. It is also important to factor in the physical nature of the API—such as whether it is a powder—the steps that need to be undertaken in the process to manufacture the API, and the level of employee exposure when working with the material. With so many variables and potential unknowns to consider, it is common for organizations to be conservative when designing a containment strategy.

In addition, the advances that have been made in toxicological assessments, such as the use of high-throughput screening, computational biology, and advances with in silico structural activity relationship analysis, have enabled more efficient and effective classification. As such tools have improved and become more commonly used, more and more APIs in development have been considered highly potent.

Successful outsourced manufacturing

Because HPAPI development and manufacturing require substantial capital investment in multiple means of containment, specialized expertise and extensive training on proper handling and containment measures, the complexity, as well as cost and time commitment, means that these services are often outsourced to contract manufacturers. This has led to a rise in the number of companies offering HPAPI manufacturing and the sector becoming competitive, meaning innovators must look beyond purely the service offering to find a suitable partner.

There are several factors that need to be considered when drug developers are selecting outsourcing partners to ensure the greatest potential for a successful collaboration and minimize the risk to a program’s progression.

With the growth in opportunities for contract manufacturers in the HPAPI field, capacity to handle materials is vital, but it is also important to find a partner with purpose-built facilities at the necessary scale rather than facilities that have been retrofitted to be suitable for handling HPAPIs. Specifically designed facilities are more likely to employ a fit-for-purpose, multi-layered approach that ensures that HPAPI operations are as safe and controlled as possible.

As well as the layers of containment, having these specialized facilities offers asset flexibility to handle a range of process requirements, and a facility-wide awareness of safety measures. For example, if controls within glove box isolators fail unexpectedly, these isolators should be migration controls to prevent highly potent materials from entering the GMP suite that houses them. On top of that secondary measure, airlocks within the containment suites themselves should be in place to prevent the ingress of potent materials into the wider facility.

In addition, it is important that a manufacturing facility can support a range of potencies and levels of containment. As a project progresses, additional studies may be run on the potent material that may determine whether it is more or less potent than originally anticipated, requiring a change in the level of containment necessary. The ability to support the full range of potency and containment, if any new information alters the containment strategy, is crucial to avoid time and cost delays that may otherwise occur in having to transfer the project to a different partner.

Even with the appropriate controls in place within the facility, it is important to remember that there is no “one-size-fits-all” approach to containment. Failing to use sufficient levels of containment creates significant risk for operators working with highly potent materials, as well as the facility. Conversely, using high levels of containment when it is not necessary based on the material’s potency can create added costs and project delays.

As well as physical assets, specialized teams and processes are integral to the success of any HPAPI project. Equipment is only as effective as the people operating it, and anyone working with HPAPIs should have extensive training in containment, controls, and cleaning, as well as how to respond appropriately in the event of any issue or emergency.

Ongoing testing and monitoring are also critical throughout any HPAPI project to ensure that target containment levels can be achieved and maintained. Containment verification testing of the suite should be carried out as a part of the initial qualification of the suite before any work with highly potent material begins, using a surrogate material such as naproxen sodium. This will affirm that the suite can properly contain the HPAPI, and that the operators have received proper safety training.

Product-specific performance qualification and hygiene monitoring should then continue as the project progresses, including surface and air monitoring. This helps to ensure that the equipment and processes perform as anticipated over the course of the entire project, and that any changes can be addressed proactively.

As well as tailoring the containment approach for a given project, asset flexibility is also key to supporting a variety of process considerations. HPAPI projects often involve a range of other process requirements, such as cryogenic capabilities, milling, high pressure reactions, chromatography and lyophilization. A facility should have the ability to handle HPAPIs safely in conjunction with these other key requirements, as well as to continually support a project as it scales up.

The future of HPAPIs and ultra-high potency APIs

The ongoing demand for better, more targeted treatments and therapies for cancer and other diseases is pushing not only the growth for services, but also the nature of HPAPIs to become ultra-high potency APIs. Some therapeutics, including ADC toxins and certain medicinally used psychedelics, can have extremely high levels of potency based on clinical microdosing. This requires especially high levels of containment and, in the case of psychedelics, the additional security infrastructure, systems, and licensing necessary to handle controlled substances.

Containment for these ultra-high potency APIs can go down to the single-digit nanogram or picogram levels, much lower than those of typical mid-range HPAPIs. Outsourcing is even more prevalent for these materials, as even organizations that are equipped to handle typical HPAPIs may not have the high levels of containment required to support these compounds.

The typical compounds that fall into this level of potency can usually be classified as either cytotoxic or and genotoxic, and when handling such materials, it is important to recognize that there are specific guidelines regarding acceptable limits of exposure.

Manufacturing of ultra-high potency APIs takes place either in dedicated suites, or with the use of additional fully contained nanogram level primary containment within existing HPAPI suites. This adds the necessary level of extra control within room controls and migration controls such as interlocked unidirectional entries, pressure cascades and downflow booths.

Where possible, to avoid cross contamination, product contact equipment is either single-use or dedicated to a product. When this is unfeasible, carefully designed cleaning processes must be used to ensure the removal of the target compound, with verification using validated analytical techniques. All solid handling must be performed within isolation chambers to minimize the risk of migration of material within the suite. These solid handling operations and the associated engineering controls are also validated as a part of the suite/equipment qualification, to demonstrate that migration does not occur. Additionally, it is also common for destructive cleaning methods—such as oxidation—to be used, which decomposes the active compound. However, this can be more complicated and requires additional clearance studies/testing.

For operators, any need for additional personal protective equipment will be based on a risk assessment and will depend upon the design of the manufacturing suites, and the built-in engineering controls.

Because of their nature and small dosages needed for patients, manufacturing of ultra-high potency APIs is on a typical scale of 1-200 grams. This makes process development more challenging, as it must be carried out at the milligram scale due to the high cost and limited availability of key materials. Processing of final product would then typically involve purification by column chromatography, which requires specialized equipment across a range of scales to support the potential for medium and high-pressure chromatography requirements. Lyophilization is commonly leveraged for final isolation and drying of product, with methods such as crystallization/filtration and traditional drying more rarely used.

For analysts, the challenges are chiefly associated with cleaning validation, but for product testing, standard characterization is not always deployed because of the low volume of material. High volume destructive testing such as residue on ignition, and others require special instrumentation to perform on the micro scale.

Conclusion

For CDMOs, having the capabilities to handle HPAPIs has almost become a standard in the industry, as an increasing number of molecules in development are classified as such. Proper risk assessment is paramount for companies working in this space, and regulatory compliance, alongside validated procedures, and specialized facilities, allow manufacturing to take place safely and routinely.

The growth of ultra-high potency APIs emphasizes the need to contain materials for worker safety, and a structured regimen for cleaning and avoiding cross-contamination in multi-purpose facilities. These challenges are further magnified because of the smaller quantities of materials involved, and the necessary limits of detection of analytical methods to ensure not only product quality, but cleanliness of equipment and facilities.

If the trend for innovators to look towards ultra-high potency APIs, as well as ADCs and psychedelics that require specialized facilities continues, then CDMOs must adapt accordingly to meet the needs of the industry, making the necessary investments to allow for the safe handling and manufacturing of such materials. As with all industry trends, those companies that are flexible and offer a tailored approach to development and manufacturing partnerships can benefit by securing long-term partnerships with customers while building valuable experience throughout the entire product lifecycle.

References
1. Rees, V. Research finds 25 percent of drugs contain highly potent compounds. European Pharmaceutical Review, 25 September 2020. https://www.europeanpharmaceuticalreview.com/news/129187/research-finds-25-percent-of-drugs-contain-highly-potent-compounds/
2. High Potency APIs/HPAPI Market by Type. Markets and Markets https://www.marketsandmarkets.com/Market-Reports/high-potency-api-market-36582475.html
3. High Potency API Contract Manufacturing Market Size. Research and Markets. https://www.researchandmarkets.com/reports/5649397/high-potency-api-contract-manufacturing-market
4. Pavlovich, J. Classifying Potent and Highly Potent Molecules. Pharmaceutical Technology [Online] 2018, 2018 Supplement, s18-s20, s33 https://www.pharmtech.com/view/classifying-potent-and-highly-potent-molecules