Many of the novel anti-cancer therapies in the pipeline are now extremely precise, conferring a selective potency against targeted diseased cells only, unlike traditional, systemic treatments. Examples of such targeted HPAPIs include small molecule cytotoxic compounds combined with a monoclonal antibody, or antibody-drug conjugates (ADCs), which can have occupational exposure levels (OELs) as low as 0.01μg/m3. ADCs are estimated to expand at nearly 20% CAGR until 2030.2 Thanks to the rapid growth of these oncology targets, the percentage of HPAPI candidates in the global drug pipeline is rising steadily. At WuXi STA, for example, we work with HPAPIs in the form of ADC payloads/linkers and small molecule HPAPI oncology therapies—some of which are in late-stage development and may go commercial shortly.
Other drivers of the HPAPI pipeline are indications for diabetes and autoimmune diseases, with both areas accounting for around 20% each of the circa 1,000 HPAPIs currently in development.3
Initially, the growth of HPAPIs in the global pipeline stemmed from the U.S. and Europe, but China’s presence in the field has blossomed in recent years due to the growing importance of its oncology market and the streamlining of the drug approval process through the Marketing Authorization Holder (MAH) program. Again, we can report firsthand that we have seen a dramatic acceleration of products for the China market in our HP pipeline in recent years.
Due to the specialized facilities and equipment, as well as extensive training required, the HPAPI manufacturing process is more resource-intensive than the manufacturing of conventional APIs. It is worth pointing out that a company is unlikely to invest in increasing its HPAPI manufacturing capacity if they only have a small number of HPAPI drugs in their pipeline.
Nowadays, the market is no longer just big pharma—in the last several years we have seen a considerable number of start-ups and virtual innovators developing novel compounds within the highly potent space. However, these new market entrants often lack the specialized facilities to develop and manufacture their innovations in-house, and therefore their only option is to outsource the projects.
In response to the growing demand, we have seen several contract manufacturers invest heavily in multi-million-dollar state-of-the-art HPAPI facilities.
Specialized facilities and expertise
The factor that makes these facilities “specialized” is primarily containment. The facilities and equipment need to be carefully designed, and are often fully enclosed systems, to ensure the safety of operators. Developing facilities to be dedicated exclusively for HPAPI manufacturing eliminates the risk of cross-contamination with other products, a cost that can be prohibitive for smaller innovators. These risks can be significant (see Figure 1).
Compounds in the 1-0.01μg/m3 band are dubbed by some as hyper potent APIs (SC) due to the potential for very severe chronic and acute toxicities with confirmed carcinogenicities. At WuXi STA, our HPAPI plants are designed to handle the upper limit (0.01μg/m3) of this OEL band but our onsite monitoring standard is <0.001 μg/m3, providing 10 times safer manufacturing environment.
Now increasingly, the industry is moving towards data-based decisions using calculations based on the toxicity risk for both patients and drug manufacturing operators, via acceptable daily exposure (ADE) and permitted daily exposure (PDE).
Beyond the facilities themselves, contract manufacturers need to develop and implement the necessary risk management strategies and training programs to ensure that employees can safely handle HP compounds and eliminate the possibility of human exposure. These training programs feature detailed information on all steps of the handling process and include clear instructions on how to operate equipment. This includes proper procedures for maintenance of HP suites, HVAC (heating, ventilation and air-conditioning systems), personal protective equipment (PPE), controls and restricted access, negative pressure rooms, correct disposal of waste, and cleaning and decontamination areas for staff. And of course, an emergency plan in the case of an unexpected event—this should include relevant emergency training and communications response, as well as knowing when to alert authorities. All of these extra precautionary programs increase the cost and complexity of developing HPAPIs, and it is why we see more outsourcing of these projects. For example, at WuXi STA we have approximately 40 dedicated scientists for the unique development needs of HP compounds.
Selecting the right partner for your HPAPI
When it comes to selecting a contract manufacturer, there is no doubt that, particularly in the case of virtual/start-up innovators with relatively few resources that cost remains the primary driver. These innovators may opt to partner with a smaller contract manufacturer with less capacity for early-stage development, to just get their drug to Phase I.
However, innovators may yet find that, without a suite of enabling technologies, projects can endure costly delays. Besides, the smaller partner may lack the necessary resources to progress the HP compounds further through the drug life cycle. So, if the innovator plans on seeing their compounds through clinical stages of development or even plans on taking it commercial then a more robust, long-term approach would be to partner with a CDMO that possesses both the capabilities and the capacity to scale-up manufacture of HPAPIs for the entire life cycle. In fact, time and money will be saved in the long haul by using one provider throughout the development process, as it circumvents the need for technology and information transfer, which can take months.
Taking this a step further, the co-location of HP labs and HP plants creates an integrated working environment for process R&D and manufacturing—so if there is a problem, the R&D team can quickly visit the plant to evaluate any issues. Further, if the innovator wants to sell their products in multiple markets they will benefit to partner with a global CDMO that has a successful record of regulatory approvals. For example, our facilities are approved by regulators from China, Japan, U.S., and Europe, and we have a proven track record for parallel approvals in these respective markets.
The technologies behind the CDMO's HP facilities should also be another key factor for drug developers to consider when selecting a partner for HPAPI development and manufacturing. The innovator needs to be able to trust that their contract manufacturer can help improve the development and manufacturing process as the drug progresses through development.
Compounds and their synthetic routes are becoming increasingly complex and we regularly have to switch between utilizing flow chemistry, biocatalysis, metal catalysis and prep HPLC for a single HPAPI. It’s important when scouting the route for HPAPIs that your CDMO be able to take a holistic, integrated approach for process optimization. To aid this, the best CDMOs often run interdisciplinary teams for process development with parallel development programs.
Another interesting component of many highly potent oncology indications is that they often receive accelerated approval designations.2 These programs are implemented for therapies that fulfill unmet needs so that they can reach patients in a substantially shorter timeframe. If an innovator receives an accelerated approval designation, the best course of action would be to then partner with a CDMO that not only possesses the relevant preclinical to commercial HPAPI manufacturing capabilities but also preferably with experience of developing compounds in shorter timelines with accelerated approvals.
In conclusion, we are seeing an increasing amount of highly potent compounds—particularly ADCs in the field of oncology—due to their increased specificity and selectivity. This comes with additional requirements for manufacturers, who will need specialized facilities and trained staff for the handling of these products due to their extremely low OELs. Currently, HPAPIs account for around 25% of the drugs pipeline,3 and they are more likely to be outsourced than other drug classes. But it must be considered that facilities are only part of the solution and your CDMO’s experience of advancing compounds through development will be a crucial factor in products making it to market successfully.