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Appropriate process design and engineering are critical for the production of small-molecule and biologic HPAPIs.
Highly potent active pharmaceutical ingredients (HPAPIs) make up the fastest growing segment of the worldwide API market, according to market research firm RNCOS, which predicts that the value of the global HPAPI market will reach $15.3 billion by 2017. Consultancy Transparency Market Research, meanwhile, estimates that the total HPAPI market will increase at a compound annual growth rate of 9.9% from $9.1 billion in 2011 to $17.5 billion in 2018.
More biologic HPAPIs
While the majority of HPAPIs have thus far been developed for the treatment of cancer (cytotoxics and cytostatics), particularly tyrosine kinase inhibitors and derivatives, newer hormone, narcotic, and retinoid-based drugs are also highly potent. In addition, HPAPIs are generally thought of as small-molecule drugs, but many biopharmaceuticals have occupational exposure limits (OELs) of 10 μg/m3 or less, a general guideline for classifying APIs as highly potent, according to Srinivas Achanta, regulatory affairs manager with Hetero. Of particular interest are antibody-drug conjugates (ADCs), which include a small-molecule, cytotoxic payload and an antibody connected with a linker and are designed to deliver the highly potent payload to targeted cells, reducing the likelihood of harm to normal cells.
Drivers of the HPAPI market, according to RNCOS, include a rising demand for cancer HPAPIs, increased private player participation, particularly in developed regions, and technological advances in process manufacturing of these challenging APIs. The number of ADCs in development has grown rapidly in recent years and is also a factor in the growth of the HPAPI market. The entrance of a growing number of competitors in the HPAPI market is, however, resulting in a highly fragmented market and may have a negative influence on growth, according to Transparency Market Research. The consulting firm also notes that a shortage of US FDA-approved manufacturing sites may act as a further restraint on growth for the HPAPI market.
North America currently accounts for the greatest share of the market, followed by Europe. The greatest growth, however, is expected in Asia Pacific, with major activity taking place in India and China due to rising health awareness, continuing expansion of these economies, improving healthcare systems, and a rapid increase in the production of generics, according to Transparency Market Research.
Importance of ADCs
Because ADCs enable the targeted delivery of HPAPIs to specific cancer cells (or other problematic cells), they have attracted significant attention, and the number of ADCs in development has increased dramatically. “The toxin that is conjugated to the antibody in ADCs has been the fastest growing segment of the HPAPI market, with demand quickly increasing in recent years,” says Cynthia Wooge, global strategic marketing manager at SAFC. With three components to manufacture and combine together under containment conditions, the production of ADCs can be a complex process, adds Achanta. In addition, Wooge notes that certain new types of ADC compounds, which may be considered the next generation of ADCs, are considered to be even more potent than existing products and are pushing the limits on current capabilities with respect to the handling of low OEL materials.
Opportunity for single-use systems
Single-use manufacturing technologies are on the rise for small-scale highly potent products such as ADCs, according to Jeff Marcoux, technical business development manager at Novasep. “Another important trend is the widespread acceptance of portable dedicated equipment, including both single-use and permanent systems for small-scale production of very highly potent compounds such as ADC payloads, which often have OELs lower than 0.1 µg/m3·8 h,” he notes. “Dedication of equipment and the adoption of single-use technologies can play an important role in controlling cross-contamination and maximum carry-over limits after cleaning (MACO) when implemented as part of a risk-based approach,” he adds.
“All high potency APIs must be produced under conditions that not only protect the operators from exposure to the compounds, but also prevent contamination and the inadvertent carryover of a different product that was previously produced or is simultaneously being manufactured. While today’s modern HPAPI facilities are meeting today’s requirements, there is a continual need to improve these technologies going forward. To accomplish this task, we need to focus on the development of production and handling methods including single-use systems and/or new technologies that can provide increased protection of the API from cross-contamination. Such protection systems must focus on the cleaning and removal steps,” observes Achanta. “The development of such new technologies is of increasing importance as the number of multiproduct facilities, which post the greatest risk of contamination of HPAPIs, are growing around the world in order to meet the greater demand for these products,” he adds.
Need for appropriate process design
Appropriate process design is in fact critical for the entire HPAPI production operation. “Most very highly potent APIs and ADC payloads require small clinical and commercial quantities, and the production of gram-scale GMP APIs and payloads can be challenging. The control of containment using flexible and small equipment, including glass equipment, is always a challenge and requires a tailored approach for each process and each unit operation,” Marcoux says. Appropriate process design at the development scale is also necessary to ensure that the process will fit the equipment and capabilities of the facility upon scale-up, according to Wooge.
Achanta believes that one of the biggest challenges at large scale is the handling of powders and solids. “Up to a scale of a few kilos, it is relatively straightforward to manage solids, because bottles with alpha–beta split butterfly valve connectors can be used for charging reactors to maintain containment. On a larger scale, however, this approach is impractical,” he explains.
Wooge also notes that appropriate cleaning methods must be implemented in order to achieve the required limits for residue levels in multi-use equipment. “The use of analytical methods that provide very low detection limits is necessary in order to confirm that the required residue levels have been achieved,” he says. He also adds that there is certainly an interest in continually achieving lower detection limits when handling HPAPIs.
Finally, Achanta points to the ambiguity surrounding the classification of HPAPIs given that different pharmaceutical companies often have proprietary systems and the fact that often the classification of new APIs is unknown due to a lack of data as issues that must be managed with appropriate process design and containment controls.