The global oncology market was valued at $107 billion in 2015, an increase of 11.5% over 2014, according to the IMS Institute for Healthcare Informatics.¹ This activity is driving demand for High Potency APIs (HPAPIs). Grand View Research estimates the market for HPAPIs will be valued at $25.86 billion by 2022.2 The high investment necessary to establish and maintain cost-effective production sites has led many sponsor companies to turn to contract development and manufacturing organizations (CDMOs) with established track records in the successful development, scale-up and commercialization of highly potent small-molecule APIs and biologic drug substances.

Expanding market
The market for HPAPIs continues to expand at a healthy rate due to the development of highly targeted drugs for the treatment of cancer and chronic diseases such as diabetes and heart disease, which are affecting growing numbers of people worldwide. Sophisticated facilities, designs, advanced containment technologies and highly skilled and trained operators are required to safely manufacture HPAPIs. The largest percentage of HPAPIs, which are defined as APIs with occupational exposure limits (OELs) of < 1 μg/m3, including antibody drug conjugates (ADCs), are intended for the treatment of cancer.

In fact, Transparency Market Research estimates that there are nearly 290 small-molecule targeted therapies in development for the treatment of cancer, with a large number of highly potent biologic drugs—including antibodies and ADCs, among others, also in the pharmaceutical industry pipeline.3 Hormones, narcotics, and retinoids are examples of non-cancer HPAPIs developed for the treatment of other health problems including diabetes, cardiovascular disease and central nervous system and musculoskeletal disorders.⁴

The overall HPAPI market is predicted to be growing at approximately 10% per year, with about 25% of drugs already on the market today formulated with HPAPIs.⁵ Small-molecule drugs currently account for the largest percentage of sales, the biologic segment, including ADCs, is the most lucrative and will grow at a high compound annual growth rate (CAGR) of 14.7% from 2015 to 2022.² Regionally, North America currently accounts for the greatest percentage of sales—$4.5 billion in 2014—but the highest growth rate (14%) will be seen in Asia Pacific. Increasing numbers of generic HPAPIs are expected to boost the market value as well.²

Need for expertise
The manufacture of highly potent compounds must be achieved in a manner that protects operators and the environment from exposure to the HPAPIs and in multi-product facilities minimizes any risk for cross-contamination when switching from one product to another. Specialized facilities, equipment, operating procedures and operator skills and training are crucial. Capabilities in the formulation of very low dose drug products are also essential. For most branded drug manufacturers, and particularly small virtual and start-up companies, investment in the specialized equipment and expertise is generally not economically practical.⁶

According to Roots Analysis, there are 96 CMOs and CDMOs worldwide with more than 130 facilities that are focused on HPAPI manufacturing, and approximately 40% of these manufacturing sites are dedicated to the production of both HPAPIs and cytotoxic drugs.5 Many have recently expanded their capabilities; since 2006, the market research firm reports that more than 100 investments involving the addition of new facilities and or expansion of existing capacities have been made, and over 15% of CMOs/CDMOs have established comprehensive services in order to support both HPAPI and formulated cytotoxic drug manufacturing.

Notably, half of the nearly 600 (bio)pharma professionals responding to the recent 2016 Nice Insight CDMO Outsourcing Survey indicated that they already utilize or plan to acquire specialized, HPAPI research, development and or manufacturing capabilities from CDMOs.7 Survey participants also rely heavily on CDMOs that offer specialized technologies for enhancement of the delivery of potent compounds—BCS Class II–IV compounds including peptides—such as the development of controlled release formulations and excipients that enhance bioavailability.

Outsourcing: Finding the right partner
The right outsourcing partner will have experience assessing and understanding the potential risks associated with each individual HPAPI project. In particular, CDMOs that are successful managing HPAPI projects have a comprehensive system in place to manage the risks associated with active substances, including new chemical entities (NCEs) that lack comprehensive toxicity data. In these cases, CDMOs with extensive experience working with HPAPIs typically are better positioned to assess a compound’s potential mutagenicity, genotoxicity, carcinogenicity and teratogenicity.⁸

One approach involves comparison of the API’s properties to those of similar substances with known toxicities and assumption of a similar level of risk. Some CDMOs have in-house categorization systems for determining the required safety measures. Regardless of the method, if there is any uncertainty, it is best to assume a compound is potent, even though higher costs will be incurred. Frequent communication between the sponsor and the CDMO is then essential to ensure that necessary data can be generated and an appropriate decision on the potency of the compound be reached as early as possible. The CDMO should also be prepared to respond as needed if additional toxicity data is developed indicating that reclassification is warranted. Furthermore, CDMOs should perform additional risk assessments as an HPAPI project moves through different stages of development and commercialization to ensure the implementation of optimal procedures and practices that both protect operators and the environment but are also practical and cost effective.

Achieving a strong track record of safe HPAPI manufacturing also requires an understanding of the systems that are required to minimize the risks associated with potent compounds. Proper facility design and engineering, including the heating, ventilation, and air-conditioning system, approaches to barrier isolation and the incorporation of gowning/degowning areas are key considerations. Appropriate faculties, engineering controls and safety protocols are, in fact, increasingly imperative as newer HPAPIs under development have ever declining OELs.

Facilities must have controlled air flow—single-pass—and pressure systems with filtration capabilities and airlocks and vestibules around both laboratory and manufacturing suites. The use of closed restricted air barrier systems (RABS), isolators, automated handling equipment and disposable technologies are increasingly common as means for effectively minimizing the potential for exposure of operators and the environment to potent compounds.

The use of appropriate personnel protective equipment (PPE), comprehensive quality management systems, industrial hygiene programs, highly detailed operating procedures and extensive training programs are also essential. Expertise in synthetic organic chemistry and process development and optimization, purification capabilities, and highly sensitive analytical instrumentation and techniques, and the ability to perform these operations under conditions that minimize exposure regardless of the types of materials being used, are also required. The very low exposure levels seen today also create further challenges with respect to analysis.⁶

It is also worth noting that CDMOs that have capabilities not only in HPAPI production, but also in the development of very-low-dose formulations, have the advantage of being able to provide support to branded drug manufacturers from the initial development phase through to commercialization without any need for technology transfer. It’s also imperative that CDMOs, which by definition operate multiproduct facilities, have comprehensive cleaning protocols and advanced analytical capabilities in place to ensure that no residual potent compound remains in the equipment when switching from product to product. With many HPAPIs, even minute quantities as impurities in a different product can affect safety and efficacy.⁹

In addition to the challenges posed by the synthesis of complex HPAPIs and the need for extensive containment, CDMOs that produce potent compounds are also faced with the lack of a consistent industry-wide approach to assigning potency. The most effective outsourcing partners have strategies in place to resolve the discrepancies between compound classification systems, e.g., theirs and those of their customers. Often the best choice is to adopt the most conservative approach, despite the likelihood of longer project timelines and higher costs.⁸

The HPAPI market is predicted to experience strong growth for the foreseeable future. CDMOs with a demonstrated ability to safely develop and manufacture high-quality potent APIs will therefore continue to be in demand. 

References

1. Pharmaceutical Commerce, “Global oncology drug market was $107 billion in 2015, up 11.5%,” June 3, 2016. http://pharmaceuticalcommerce.com/business-and-finance/global-oncology-drug-market-107-billion-2015-11-5/
2. Grand View Research, Inc. “High Potency Active Pharmaceutical Ingredients (HPAPI) Market Worth $25.86 Billion By 2022.” October 2015. https://www.grandviewresearch.com/press-release/global-high-potency-active-pharmaceutical-ingredients-hpapi-market
3. Transparency Market Research, “Rising Cost of Drug Development Leads HPAPI Manufacturers to Outsource Production,” March 30, 2016. http://www.prfree.org/news-rising-cost-of-drug-development-leads-hpapi-manufacturers-to-outsource-production-240256.html
4. Gerteis Maschinen + Processengineering AG.  “Increase In HPAPI Manufacturing Highlights Need For Containment And Isolation Systems.” July 21, 2015. http://www.pharmaceuticalonline.com/doc/increase-in-hpapi-manufacturing-highlights-need-for-containment-and-isolation-systems-0001
5. Roots Analysis. “HPAPIs and Cytotoxic Drugs Manufacturing Market, (2nd Edition), 2016 – 2026.” March 9, 2016. https://www.rootsanalysis.com/reports/view_document/hpapis-and-cytotoxic-drugs-manufacturing-market-2nd-edition-2016-2026/120.html
6. Total Biopharma, “The single largest trend in the HPAPI space.”  January 22, 2014. http://www.totalbiopharma.com/2014/01/22/single-largest-trend-hpapi-space/
7. The 2016 Nice Insight Contract Development & Manufacturing Survey
8. A. Hess. “Building trust with contract suppliers to overcome the challenges of manufacturing HPAPIs.” Chimica Oggi-Chemistry Today, 33(1), pp 24-27, January/February 2015. http://www.teknoscienze.com/articles/chimica-oggi-chemistry-today-4-.aspx
9. C. Wooge. “Playing it Safe.” Innovations in Pharmaceutical Technology 49, pp. 54-57.  June 2014.

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Dr. Stephen Munk is president and chief executive officer of Ash Stevens, a full service contract pharmaceutical manufacturer offering comprehensive small-molecule drug substance development and cGMP manufacturing services. Founded in 1962 and headquartered in Riverview, MI, Ash Stevens has extensive experience developing and manufacturing active pharmaceutical ingredients (APIs) including high potency APIs (HPAPIs) for commercial clients in the life sciences industry developing innovator small-molecule therapeutics. Since Dr. Munk joined the company in 1997, Ash Stevens has received 10 FDA approvals to manufacture innovator drug substance and won four NIH research contacts, including two competing renewals. Prior to joining Ash Stevens, Dr. Munk worked at Allergan initially as a drug discovery scientist and subsequently as co-team leader of the adrenergic drug discovery team.