The global high potency active pharmaceutical ingredient (HPAPI) contract manufacturing market is poised to reach $14.65 billion by 2030 and is expected to grow at a compound annual growth rate (CAGR) of 9% over the forecast period. The main drivers of the market, according to a report by Grand View Research, are rising demand for oncology drugs, advancements in manufacturing technology, and a rise in capacity to meet the increasing demand. In addition, a rise in target therapies to cure chronic diseases will continue to drive industry growth.

According to a white paper by Roots Analysis, Business Research & Consulting, more than one-quarter of all drugs manufactured worldwide are considered highly potent and 60% of oncology drugs contain HPAPIs.²

While the first half of the COVID-19 pandemic impacted demand for HPAPIs with the disruption to the supply chain and reduced research-based activities, in the second half, the industry started to gain importance due to a rise in demand for vaccines. This in turn increased demand for raw materials and product intermediates of API molecules. Furthermore, the growing demand for HPAPI molecules during the COVID-19 pandemic has led to the price hike of the same, thus boosting revenue growth in 2020 and 2021. In turn, there has been a rise in outsourcing activities for HPAPIs as it removes the need for investment in expensive infrastructure for containing it.

According to the report, the innovative segment of the market accounted for the largest revenue share, 72% in 2021, while based on applications, the oncology segment dominated the industry with more than 64.5% in 2021 due in part to a rise in research on new cancer therapies. The oral solids dosage form segment is expected to witness the fastest growth rate during the forecast period.1 Meanwhile, the biotech segment is estimated to witness a significant growth rate from 2022 to 2030.

Over the past several years, key industry players have been expanding facilities, collaborating, and engaging in partnerships, mergers, and acquisitions. For example, in late 2021, Flamma USA, completed the re-commissioning of its HPAPI suite. In June of 2022, MilliporeSigma, the U.S. and Canada Life Science business of Merck KGaA, doubled its HPAPI production capacity with the expansion of its facility in Verona, near Madison, WI. Lonza also completed the expansion of its HPAPI multipurpose suite in Visp, Switzerland, in September 2022. The expansion added development and manufacturing capacity for ADC payloads, supporting the entire development and manufacturing pipeline from feasibility studies to commercial supply.

According to industry insiders, the current market landscape for cytotoxic drugs and HPAPI manufacturing and development remains strong and is rife with opportunities. “There appears to be a shift that is moving towards biologics and large molecules (antibodies, ADCs, protein-drug-conjugates) which are making small molecule CDMOs start to broaden their offerings,” said Curia’s senior director, global technical operations, Brian Haney. “This expertise can be difficult to develop so it’s a change for some providers.”

Maurits Janssen, executive director, strategic business development, small molecules, for Lonza said the continued interest in antibody-drug conjugates provides an additional driver in the high potency arena. He noted that 12 of the 15 currently marketed ADCs were approved in the past six years. Each of these approvals contributed to developments in toxins used as the payload, as well as in the development and manufacturing of bioconjugates. “These ongoing advances continue to increase the demand for HPAPIs and drive significant new investments by CDMOs in specialist equipment and facilities to keep up with that demand,” said Janssen.

Louise Carpenter, head of formulation development at PCI Pharma Services, characterizes the current market landscape for cytotoxic drugs and HPAPI manufacturing and development as “Dynamic.”

“Reports estimate that around 40% of all drugs in development are classed as highly potent, and around 60% of those are targeted towards oncology,” said Carpenter. “The increased demand for novel anti-cancer therapies are therefore a huge driver in terms of industry R&D.”

HPAPIs are an increasingly important part of today’s drug development pipeline driven by the rise in treatments that focus on specific targets, particularly in oncology. “HPAPIs are important in small molecule cancer treatments that target specific parts of the cell such as kinase inhibitors. The increasing demand for HPAPIs is creating a great opportunity for companies that manufacture and provide clinical support for these drugs,” said, Dietmar Reichert, director strategic marketing drug substance, Evonik Health Care.

The market for small molecule cytotoxic and HPAPIs is still growing, alongside biologics molecules and other modalities, according to Adam Kujath, executive vice president and site head at Sterling Pharma Solutions’ Germantown, WI, facility. “Small molecules of this nature are still key for use in new drug research, as well as for new drug delivery technologies and combination treatments. The number of CDMOs offering “standard” high potent handling and manufacturing services has increased significantly, meaning there is now sufficient capacity in the market and more options for innovators seeking CDMO services,” said Kujath.

Recent trends

Regarding recent trends in HPAPI manufacturing and development, PCI’s Carpenter said that a noticeable trend in the formulation development space is the use of a Design of Experiment (DoE)/Quality by Design (QbD) approach at earlier stage of the product lifecycle. She noted that DoE is a systematic, statistical approach with the aim of optimizing the product and the process by understanding the relationship between various factors (input variables) and responses (output variables). “This method helps identify the most influential factors, determine their optimal levels, and establish robust and efficient processes while minimizing the number of experimental runs,” said Carpenter.

Lonza’a Janssen added, “In addition to many well-known CDMOs investing heavily in expanding their existing capabilities, smaller players are increasingly making investments to enter the HPAPI space, too.”

Additionally, new delivery technologies are breathing new life into the market, according to Sterling Pharma Solutions’ Kujath, and previously un-dosable products are finding clinical success as a result. Now that more antibody-drug conjugate (ADC) therapies are getting their clinical readouts, there is also significant renewed interest in innovation in this area. “These molecules require containment in manufacturing to handle the cytotoxic warhead, but it offers improved safety of the drugs with a more targeted delivery. We are also seeing increased work around the linker technologies that bind the cytoxins to the monoclonal antibody, but also to peptides and secondary small molecule modalities,” said Kujath.

Challenges

The key challenges faced by HPAPI CDMOs are not much different from standard CDMOs, according to Curia’s Haney. “There is a need to deliver high quality materials as fast as possible to enable developmental milestones. HPAPI CDMOs have the additional challenge of managing the containment of the products, but they are also often working at smaller scales where the equipment and operations can be managed within that containment,” said Haney.

Carolina Bonifacio, head of R&D at Siegfried’s site in Barbera del Valles, Spain said, “These substances not only require particularly sensitive handling in the manufacturing process; the employees who work with them also need special skills, knowledge, and protection to handle them. Therefore, for HPAPIs, a thought-out risk and hazard assessment is needed throughout.”

“The key challenges faced by CDMOs in the highly potent arena typically arise from uncertainty in the actual toxicity of the compound,” said Lonza’s Janssen. “For early-phase clinical compounds, it is rare for all the required toxicology data to be available at the outset, so the default is to treat them as if they were highly potent.”

Meanwhile, Evonik’s Reichert noted that HPAPIs are a double-edged sword. “Their potency makes them extremely effective in targeted therapeutics, but their impact even at low concentrations can make them very dangerous to handle.”

Additionally, when developing early-stage new chemical entity (NCE) drug candidates, the lack of available data with which to accurately assess the true potency of these molecules is a challenge, according to Stephen McQuaker, director of drug development consulting, candidate development, Quotient Sciences. “This occurs particularly for first-in-class medications where comparisons to known species aren’t reflective of the drug. There is also an important link between potency and toxicity that needs to be made. With continuing developments in disease-targeted treatments (e.g., kinase inhibitors or antibody-drug conjugates), a molecule that may have displayed high potency may also exhibit a good toxicology profile,” McQuaker said.

Growth and demand

Industry insiders see growth and demand in the oncology space, particularly for ADC and oligionucleosides along with small molecules. “In oncology, in particular, the mechanism of action often leads to highly potent drugs, and the number of large and small molecule drugs that fall into this category continues to increase,” said Janssen of Lonza. “With oncology having the lowest likelihood of approval – only 5.3% of compounds entering Phase 1 trials will ultimately gain market approval from the regulators – pipelines will need to grow further in order to respond to the unmet medical need.”

“We see strong demand for scale appropriate protein production for ADC candidates and we see growth in aseptic fill/finish, especially lyophilized ADC formulations,” said Curia’s Haney.

Sterlings’s Kufath said the highest demand continues to be in oncology, with 60% of drugs being developed in this therapeutic field involving highly potent ingredients. “However, we are also seeing a significant growth in immunotherapy drugs, which, due to their potential for sensitization or low-dose pharmacology, requires high containment. Additionally, the renewed interest in psychotropics in microdosage formulations has seen a spike in the market,” said Kufath.

There is an increasing need for CDMOs in the cytotoxic drug domain, “With markets and therapeutic options increasing, the need for cytotoxic and HPAPI development and manufacturing capabilities will continue to rise,” said Lonza’s Janssen. “CDMOs should, therefore, offer various capabilities and capacities for both HPAPI and non-HPAPI development and manufacture. In addition, global programs for EHS should be in place to ensure a safe working environment, minimize exposure to employees, and ensure EHS compliance.”

Special requirements

When it comes to what special requirements and capabilities are needed for high potent compounds, Lonza’s Janssen said there are many. “The list includes contained handling at the right level, occupational health experience and experts to maintain containment levels, EHS toxicologists to support the accurate classification of compounds, a diligent and experienced operations team, a global EHS program ensuring a safe working environment, minimizing exposure to employees, and ensuring EHS compliance.”

Quotient Science’s McQuaker added, “Working with HPAPIs presents a number of challenges in ensuring a safe working environment for operators while guaranteeing the highest drug product (DP) quality and safety standards. “HPAPI facilities require extensive planning to establish the highest level of containment and monitoring controls, with a tightly controlled flow of people, materials, and environmental elements.”

According to Curia’s Haney, CDMOs need to have expertise in assessment of toxicological hazards and the understanding to create the appropriate safety controls to keep their team safe. “Having the best technology and equipment is only a part of that puzzle. The expertise to create, implement and test their solutions is critical to success,” said Haney.

Industry experts assert that the realm of high potency demands unwavering precision. “Containment measures, analytical capabilities, and rigorous risk assessment protocols are essential to ensure both safety and efficacy throughout the development and manufacturing journey,” said Stu Needleman, chief patient centricity officer and chief commercial officer, Piramal.

CDMOs keep pace with demand

To keep pace with evolving trends in the HPAPI space, Curia is looking to expand its capabilities in some of the niche operations, such as chromatography, micronization and lyophilization. From the perspective of therapeutics, Curia is looking to add bioconjugation as an offering to complement the company’s expanding antibody and cytotoxic API development and manufacturing capabilities.

At its site in Barcelona, Siegfried recently opened a new global development center for HPAPIs in spring 2023. The Development Center demonstrates Siegfried’s commitment to invest in technologies and to development capacities in this area for its customers. Bonifacio said that highly qualified specialists are working there closely with Siegfried’s customers in modern, purpose-built laboratories to transform their innovations into commercial products. In addition, state-of the-art laboratories have been built on an area of around 1,500 square meters, where 40 employees are working in product development.

Piramal also recently completed production of a plant featuring new reactor suites at its facility in Riverview, MI. It represents a capital expenditure of $38 million in equipment and construction costs. The facility covers approximately 25,000 square feet of space and includes production, warehousing and supporting utilities, and is readily scalable to accommodate additional reactor bays. The featured technology in the new facility is 10 kl of reactor capacity accompanied by a pressure dryer filter. The reactors are capable of producing high potency APIs with low Occupational Exposure Levels (OELs) of >1μg/m3.

In summary, as demand for HPAPIs continues to increase, it has never been more important to choose the CDMO that is best placed to deliver, from the very early stages of development to the manufacture of drug product, according to Lonza’s Janssen. “A CDMO with extensive capacities and capabilities, combined with a portfolio of solubility and bioavailability solutions, should be able to provide support across the full range of scales, processes and containment needs, making for a seamless service,” said Janssen.