CDMOs see a huge leap in outsourcing activities related to the development and manufacturing of high potent active pharmaceutical ingredients (HPAPIs) in the coming days as prescription drugs go increasingly potent and targeted.

The global HPAPI market size is expected to expand at a compound annual growth rate of 6.2% from 2023 to 2030 from an estimated $25.17 bn in 2022, due to factors such as the growing applications of HPAPIs, increasing prevalence of cancer, and growth of targeted therapies, according to a report by Grandview Research.

As much as 31% of all global launches of novel active substances have been for oncology indications in the past decade, shows Global Trends in R&D 2023 report by IQVIA.

Highlighting the fact that the increasing demand for HPAPIs is largely driven by the expanding oncology drug sector, industry leaders find several key drivers fueling the demand.

“Firstly, prescription medications are becoming increasingly potent,” comments Dietmar Reichert, director, strategic marketing drug substance at Evonik, Essen, Germany. “This reflects a broader trend across various therapeutic domains, including pain management, mental health, and oncology.”

Reichert adds that personalized treatment modalities, which use highly potent drugs tailored to individual needs, are also a significant factor driving demand.

Additionally, stringent regulations and guidelines governing drug efficacy and safety have been instrumental in the development of more potent medications, as these drugs must adhere to the highest standards to ensure patient safety and compliance with GMP.

Axel Zimmermann, director, research and development, pharma services, Thermo Fisher Scientific also shares the view that the increasing preference for targeted medicines will heighten the demand for HPAPIs. “The shift towards targeted therapies that aim to address the underlying molecular mechanisms of disease will continue to drive the need for potent compounds.”

Highly potent cytotoxic chemotherapeutics used as payloads of site-specific antibody-drug conjugates (ADCs), hormonal drugs, and highly potent ligases (PROTACs) for targeted protein degradation are a few examples of ultra highly potent active pharmaceutical ingredients now entering the pharmaceutical market, he adds.

Thermo Fisher Scientific, with annual revenue exceeding $40 billion, is one of the leading contract development and manufacturing organizations (CDMOs) offering end-to-end services to pharma and biotech companies.

Targeted therapies fuel outsourcing

Even as the quest for precisely targeting drugs with higher therapeutic index becomes a dominating trend across therapeutic domains, outsourcing in the development and manufacturing of HPAPIs has become increasingly common.

Around 30 percent of pharmaceutical projects now focus on HPAPIs, reports indicate.

Given the wide range of potential uses of HPAPIs, CDMOs hone their skills in improving highly potent therapeutic targeting using small and large molecule approaches.

Today, CDMOs capable of handling HPAPIs have an advantage over those without these capabilities, says Matthew Jones, senior manager, head of crystallization/solid state, pharma services, Thermo Fisher Scientific. But, alerts Jones, as more HPAPIs enter development, CDMOs must evolve to meet market demand.

Currently, the demand is increasing for particle size control and novel formulation technologies enabling targeted delivery.

“We continue to see diversity in methods of form-giving and formulation. As HPAPIs must reach their target in the body of a patient with precisely defined timing and concentration to maximize efficacy and minimize side effects, methods of form-giving and formulation will continue to grow in importance,” informs Jones.

Novel formulation technologies aimed at the targeted delivery of APIs encompass nanovesicle-based formulations and ADCs. Nanovesicles can be designed to carry both water-soluble and fat-soluble APIs and can be modified to target specific cells in the body by incorporating receptors specific to these cells.

While small molecule anticancer drugs look to increase their selectivity, ADCs, which combine the effective killing power of small molecule cytotoxins (payloads) and the highly specific tumor-targeting ability of monoclonal antibodies (mAbs), seeks to deliver their payloads in the proximity of the cancer cells to reduce systemic toxicity and maximize their activity.

Expertise and capabilities, however, in handling HPAPI molecules are scarce, so the role of specialized manufacturers is becoming more crucial, observes Reichert of Evonik.
According to him, not only the bigger players, but smaller companies are also playing an increasingly important role in the development of innovative medicines and products, particularly in the field of oncology. To shorten development timelines and reduce supply chain risks, such companies require access to flexible and sophisticated manufacturing facilities to bring their innovative products to market and to patients. Due to the high potency of these molecules, safety, and containment are critical components of effective HPAPI manufacturing. Collaborating with a qualified CDMO that ensures flexibility and safety can help pharma companies advance HPAPI projects quickly and with low risk.

Moreover, personalized medicines usually require the production of HPAPIs in much smaller quantities, necessitating specialized equipment.

“Traditional large-scale production methods, like those used for antineoplastic agents or kinase inhibitors, require extensive facilities and equipment. However, with a move towards personalized medicine and the introduction of ADCs, we can see a shift towards producing HPAPIs in much smaller quantities. This requires smaller, more specialized HPAPI equipment,” Reichert points out.

Bolstering capabilities

In response to the growing demand for sophisticated HPAPI manufacturing, CDMOs are investing in specialized equipment and facilities.

In July, Evonik announced a collaboration with Heraeus Precious Metals, Hanau to expand the range of services for HPAPIs.

Heraeus, which is the leading supplier of platinum HPAPIs worldwide, focuses on producing highly potent small molecules such as payloads including linkers and toxins for ADCs.

One of the world’s largest process developers and manufacturers of HPAPIs for more than 20 years, Evonik’s factory in Tippecanoe, Indiana can manufacture six different HPAPIs in parallel and has a total capacity of 170 m3. Its Hanau, Germany facility has process and analytical laboratories to develop and optimize HPAPIs requiring containment down to an occupational exposure limit (OEL) of 5 ng/m3, according to a company release.

Evonik is developing flexible, integrated capabilities dedicated to HPAPI development from preclinical to commercial production, says Reichert. “These programs focus on safe procedures, from equipment start-up to handling, cleaning, and decontamination. This is especially important as outsourcing of HPAPI production is increasing at a rapid pace.”

HPAPI makers also focus on building higher containment capabilities to handle newer APIs which are becoming increasingly complex.

The production and handling of these new APIs requires, in some cases, the use of a high level of containment during their manufacturing that must guarantee an OEL below 10 ug/m3 or even 1 ug/m3, says Paolo Tubertini, CEO, Olon Group.

This strategy for high containment is also required to avoid the risk of cross-contamination during their handling.

For this reason, building on the long experience of handling HPAPIs, Olon has heavily invested in the last years to increase the capacity in several sites to guarantee the production of HPAPI anticancer drugs even at a large scale, up to hundreds of kg as batch size.

“Thanks to recent investments in its integrated manufacturing network, today Olon offers the capacity to develop and produce highly potent APIs, from very small to large scale, along the entire development chain,” Tubertini maintains.

This is because Olon relies on all types of reactors regardless of required size, as well as its experience in managing high containment production processes which are among the most extensive worldwide.

A global leader in APIs, Olon has completed the new extremely high containment production line with reactors that allow the CDMO to produce HPAPIs in large-scale product batches ranging from 30 to 150 kg. This expansion enables the company to serve the customer along all the stages of the scale-up, in conjunction with Olon’s other sites, says Tubertini.

Other notable recent expansions and deals in the HPAPIs space include Agilent Technologies’ acquisition of Biovectra, a Canadian CDMO specialized in HPAPIs and other molecules for targeted therapeutics and ADCs besides biologics, in July.

Aenova bolstered its Regensburg site for the development and production of HPAPIs with an investment of around €25 m last June, enabling up to occupational exposure band 5 (OEB 5) and, in particular, of cancer drugs. The Aenova site in Regensburg has been developing and producing tablets and capsules with HPAPIs such as methotrexate, hydroxycarbamide, azathioprine, imatinib, etc. since the 1950s.

MilliporeSigma expanded its CDMO HPAPI and ADC linker-payload production capacity last May. The expansion has doubled the company’s HPAPI production capacity, positioning it as one of the biggest single digit nanogram OEL CDMO providers in the world, according to a company release.

Piramal Pharma Solutions started production from its new API manufacturing plant in Riverview, U.S. in February 2023. This state-of-the-art facility specializes in the production of APIs and HPAPIs.

A month ago in the same year, Sai Life Sciences completed the construction of a new HPAPI manufacturing facility at its API manufacturing site in Bidar, India.
The year 2022 witnessed some major expansions such as Cambrex’s completion of a $50 million upgrade and the opening of new high potency capabilities in the US and Wuxi STA’s expansion of its HPAPI facility in China.

Continuous manufacturing techs to cut OE risk

According to Reichert of Evonik, CDMOs face a multitude of challenges when it comes to developing and manufacturing highly potent drugs. A CDMO must have sufficient and appropriate capacity in production, research, development, and innovation (RD&I), QA, and QC to support customer projects from the clinical phase to commercialization at an attractive price.

Manufacturing and development of HPAPIs mandate heightened emphasis on containment. OELs for HPAPIs, as mentioned, are extremely low. This is essential to ensure personnel safety, environmental protection, and regulatory compliance.

In addition, the regulatory requirements for containment facilities are getting increasingly stringent.

“On the manufacturing side, the ongoing trend towards HPAPIs will further drive the implementation of even more advanced containment technologies and stringent safety measures to ensure maximum protection for personnel and the environment,” points out Zimmermann of Thermo Fisher Scientific.

In this aspect, continuous manufacturing methods are gaining traction in the production of ultra HPAPIs. Continuous flow chemistry and continuous crystallization techniques offer advantages such as reduced risk of exposure during the manufacturing process in addition to improved control over reaction conditions and enhanced yield.

Meanwhile, Peter Poechlauer, principal scientist, pharma services, Thermo Fisher Scientific, drives home the point that containment is essential not only for small-volume HPAPIs but for those facilities where high potent intermediates are used for the synthesis of large-volume APIs, as well. “While the actual HPAPIs are mostly used in small-volume applications, it should not be disregarded that highly potent intermediates are also used in the synthesis of large-volume APIs. Therefore, it is important to provide appropriate containment even in facilities with reactor volumes significantly larger than 1 m3.”

Thermo Fisher Scientific has implemented protective measures and technology solutions that allow the CDMO to isolate all potential sources of exposure and contamination, such as filling stations. The company has also implemented procedures to avoid cross-contamination between raw materials, intermediates, and products such as routine swab tests, Poechlauer adds.

Above all, the greatest challenge is the CDMO’s ability to handle and process HPAPIs in a way that keeps operators and the environment safe.

Employee and environmental safety are not realized through technology alone, remarks Rajiv Grover, head of strategic business development, Aspen Oss B.V, The Netherlands—the API services arm of Aspen Pharmacare, a global specialty and branded pharmaceutical company. “Safety training, which is an integral part of the qualification protocol of every employee, is repeated periodically [at Aspen] and is maintained by continuous learning-on-the-job.”

Typically, new NCEs are designed to interfere in biological pathways in the body and are therefore more complex and difficult to synthesize, “Small molecules and peptides are a growing portion of the HPAPIs. At the same time, the market demands sustainable manufacturing methods at affordable costs. Aspen is uniquely positioned to be the contract development and manufacturing partner of choice in the field of medium and long peptides (like GLP-1) and small molecules,” explains Grover.

Here newcomers fear to tread?

ADC manufacturing, which is currently high in demand, is yet another domain that presents significant challenges. Many manufacturers hit a wall when it comes to the development, manufacturing, and safer supply of high-demand ADCs as they require specialized know-how and high containment capabilities.

“ADC class is highly promising and extremely challenging as well, as they require specific capabilities to handle different modalities with strict containment regulations,” avers Tubertini of Olon.

This required high level of control ensures the safest environment for ADC payload-linker production and product integrity, which can only be reached by leveraging decades of expertise in containment for cytotoxic anticancer production, focusing on full control of cross-contamination, operator protection, and extensive training.

On top of that, the handling and manufacturing of these compounds require not just new facilities, but the availability of an integrated system in which all the activity done on the site must be controlled, starting from the storage of either incoming material, intermediate, and final product, their dispensing and handling and finally the treatment and disposal of all the wastes. All the systems must be also challenged with Failure Mode and Effect Analysis (FMEA) to guarantee the high containment even in case of any deviation from the standard practices.

For these reasons, adds Tubertini, it is not easy for a newcomer to enter in business guaranteeing the assurance of supply of ADC products.

In 2003, Olon acquired the sites and inherited the know-how and experience of the former Farmitalia, a pioneer in cytotoxics, which successfully developed and commercialized the anticancer drug doxorubicin – the first member of the anthracyclines class.

Recently, Olon has announced the acquisition of GTP Bioways, a French CDMO specializing in R&D services, process development, and production of mAbs, enzymes, proteins, nanodrugs, ADCs, and F&F.

Leveraging over four decades of expertise in containment for cytotoxic anticancer production, Olon stands at the forefront of ADC payload-linker manufacturing with unparalleled safety and efficiency, according to Tubertini.

Olon’s new, €22 million facility dedicated ultra-high-containment production line, reaching containment level OEB6, will produce high-potency and toxic products, such as cytotoxic payloads and payload-linker system supporting the development and the commercialization of new ADCs.

Soman Harachand is a pharmaceutical journalist based in Mumbai and a regular contributor to Contract Pharma. He can be reached at harachand@gmail.com.