Ash Stevens

HPAPI

Oncology

Process Development

Q1 2016

Small Molecule

<h3>Although many reports have focused on growth in the biopharmaceutical sector, small-molecule drugs continue to account for the vast bulk of drugs on the market and in development. New classes of increasingly potent small-molecule therapeutics are addressing more unmet medical needs with fewer side effects, often at a significant cost advantage compared to biologics.</h3>
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<p>In many cases, contract development and manufacturing organizations (CDMOs) play a critical role in facilitating the successful development of innovator smallmolecule drug candidates, since these important development activities are often achieved through outsourcing partnerships with CDMOs. CDMOs can vary significantly with respect to the services they offer, from one-stop-shops offering a myriad of services to those with expertise focused exclusively on the development and manufacture of innovator Active Pharmaceutical Ingredients (APIs). Regardless of the breadth of CDMO services offered, CDMOs today are seeing increased demand for drug substance development and GMP manufacturing services for innovator small-molecule drug development projects. Some areas of increased demand for CDMO services are discussed herein.</p>
<h4>Demand for Small-Molecule Drugs Remain Strong</h4>
<p>Small-molecule drugs accounted for 84% of pharmaceutical industry revenues in 2014.<sup>1</sup> In addition, small-molecule drugs still account for approximately two-thirds of the candidates in the current robust pharmaceutical industry pipeline.<sup>2</sup> Contract manufacturers that focus on the development and production of small-molecule APIs are experiencing significant growth as a result. According to PharmSource, the revenues of publicly traded contract manufacturing organizations (CMOs) and CDMOs that are involved only in the development and production of small-molecule drugs increased by 15% in the first half of 2015, with some companies achieving revenue growth of greater than 20%.<sup>2</sup> Both biopharmaceutical and small-molecule approaches have established track records for providing valuable therapeutic benefits to patients. Both approaches also have their inherent advantages and disadvantages and will remain as complementary strategies for drug discovery for the foreseeable future.</p>
<h4>Growth In The Oncology Segment Is A Strong Driver For Small-Molecule CDMO Services</h4>
<p>All indications are that demand for innovator API manufacturing services will likely remain strong for the next few years. It is difficult to accurately assess the size of the innovator API market that is accessible to CMOs/CDMOs, since this sector data is not easily broken out from broader analyses of the overall API markets. The current strong demand for CMO/CDMO services is driven by a number of factors, which include a robust industry pipeline, the ability to raise public and private financing, and successful market approvals.</p>
<p>For example, the growing oncology drug pipeline is largely the result of significant investment in R&amp;D and innovation by the pharmaceutical industry over the last 10 years.<sup>2</sup></p>
<h4>Growing Demand for CDMOs Offering Highly Potent API(HPAPI) Manufacturing Services</h4>
<p>Another area of strong demand for innovator small-molecule API manufacturing services is in the highly potent API (HPAPI) segment. HPAPIs make up one of the fastestgrowing segments of the global API market. Grand View Research estimates the demand for HPAPIs will grow at an average annual rate of 14.4%, from $12 billion in 2014 to $25.86 billion in 2022.3 This strong demand for HPAPI manufacturing services is having significant impact on the contract manufacturing market. Companies with existing HPAPI capabilities have been busy expanding their facilities, while many without have sought to acquire existing businesses or add HPAPI capacity. HPAPI manufacturing requires millions of dollars in investment over and above that of CDMOs/CMOs providing traditional API (non-HPAPI) manufacturing services. Furthermore, CDMOs/ CMOs providing contract HPAPI manufacturing services must be prepared to adopt, improve, and/or implement new protocols, equipment, training, and technologies to meet the ever-rising bar for risk reduction and regulatory compliance in HPAPI manufacturing. Continuous improvement is essential to sustaining safe operations, mitigating risk, and attracting client opportunities.</p>
<p>APIs with occupational exposure limits (OELs) of 10 μg/m<sup>3</sup>&nbsp;or less are generally classified as HPAPIs. Increasingly, APIs of small-molecule therapeutics in development today, particularly in the oncology therapeutic area, are falling into the HPAPI category. The growth of potent new targeted therapies in oncology (e.g., kinase inhibitors) is helping to fuel the growth of this segment, with the future trending towards even more potent drugs. HPAPIs, however, present a special challenge for API manufacturers requiring appropriately designed facilities, with the necessary engineering and containment controls in place to handle these potent compounds as well as requiring highly trained and experienced staff to ensure safe and contained operations.</p>
<p>Key to Life Science companies looking to outsource HPAPI manufacturing is finding a CMO/CDMO partner with clearly demonstrated experience and expertise for both safely and effectively managing projects involving highly potent compounds. Many Life Science companies developing potent small-molecule drugs prefer to use a HPAPI manufacturer in the U.S. or Europe that has a sustained and exemplary track record for safety, regulatory compliance, and a successful audit history when working with HPAPIs. The ability to support both the development and commercial manufacture of highly potent compounds in order to avoid any need for process transfers is also often preferred by many Life Science companies that outsource HPAPI projects. The demanding nature of HPAPI manufacturing requires careful scrutiny of the potential CMO/ CDMO partner’s chemical hygiene and environmental, health, and safety (EH&amp;S) programs as well as an understanding of their commitment to HPAPI manufacturing, and continuous improvement. When it comes to HPAPI manufacturing, there is no middle ground — it is “all in” or nothing.</p>
<h4>Growing Demand For Process Development CDMO Services</h4>
<p>A growing number of small and midsized Life Science companies developing innovator small-molecule therapeutics are driving demand for more contract chemical process development capacity. These companies many times lack in-house laboratory infrastructure, expertise, and/or chemistry personnel to transition a laboratory synthesis of a development candidate to a chemical process suitable to cGMP manufacture and scale-up. Since these companies typically either license in their small-molecule assets from Universities or other research laboratories or, alternatively, use in-house or CRO Med. Chem. resources to develop their small-molecule assets, the chemical synthesis of these assets is many times not readily amenable to cGMP manufacturing without further process improvement.</p>
<p>Initial laboratory syntheses are focused on making enough of the compound as fast as possible for preclinical testing, whereas process development focuses on multiple aspects for process improvement, such as improving process yields, reducing the number of steps and operations, reducing reaction volumes and the quantities of solvents and reagents, improving safety and robustness, mitigating negative environmental impacts, increasing scalability, and eliminating time-consuming steps such as chromatographic purifications. Consequently there exists a growing gap in the API development pathway going from laboratory syntheses to cGMP processes.</p>
<p>CDMOs are best suited to address this gap since, by definition, they provide development services, which generally include process development support. Effective process development and optimization is most efficient when integrated with scale-up and cGMP manufacturing operations. CDMOs with integrated capabilities from early-stage drug substance development through commercial manufacturing can potentially effect a smoother transition from the laboratory to commercial manufacturing, streamlining the process, reducing complexity, and building process knowledge. This is particularly true when key stake holders, such as process chemists and engineers working on the project, transition with the process through the various stages of scale-up to ensure the techtransfer proceeds seamlessly.</p>
<p>Drugs with Fast-Track or Breakthrough status place even more pressure on CDMOs to rapidly scale the process to meet the deliverables of a significantly accelerated timeline on schedule, and expedite a potentially promising new therapy to patients with serious medical conditions. Here especially, a well-integrated team of engineers and process chemists are essential to bringing the process online in time to meet the accelerated timelines of the project.</p>
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<h4 class="callout-title">Small-molecule drugs accounted for 84% of pharmaceutical industry revenues in 2014.</h4>
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<h4>Growing Demand For Quality By Design (QBD) Services</h4>
<p>The growing demand for ever-higher quality pharmaceuticals by regulatory authorities and consumers is in turn driving more demand for Quality by Design (QbD) services from CDMOs. More Life Science companies developing drugs today are looking to apply the principles of Quality by Design to their manufacturing processes, to better comply with current regulatory guidelines for QbD, and with the anticipation that QbD will become a requirement at some point in the future. QbD is a statistical method employed to gain an enhanced understanding of process control and safety for a manufacturing process, ensuring consistent and robust quality.</p>
<p>Most CDMOs have been using elements of QbD for quite some time, such as “design of experiments” and understanding critical failure points. The FDA guidelines, however, provide a more structured framework anchored in statistical methods to provide accurate understanding and control of a pharmaceutical manufacturing process. Implementing QbD services can be expensive for CDMOs, requiring new equipment, statistical support, and the training and/or hiring of personnel. Not every CDMO, therefore, offers QbD services, but for those that do, it can be a draw for potential clients. In addition, since QbD remains a guideline at this point in time and not a requirement by regulatory authorities, it is not unexpected that drug developers have elected to pursue a variety of QbD strategies ranging from none at all to comprehensive QbD fillings consistent with regulatory guidelines. Nonetheless, the momentum is in the direction of more QbD work for CDMOs as drug developers try to get out ahead of the regulatory curve.</p>
<h4>References</h4>
<ol>
<li>Shanley A., “Stronger Pipelines and Approvals Drive Small-Molecule APIs and CMO Opportunities”, Pharm. Tech., March 31, 2015.</li>
<li>Miller J., “Small-Molecule API CMOs Are Thriving”, BioPharm Intl., 28(10), (2015).</li>
<li>Grandview Research, “High Potency Active Pharmaceutical Ingredients (HPAPI) Market Worth $25.86 Billion By 2022: Grand View Research, Inc.”, Press Release. October 14, 2015.</li>
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Growing Demand for Small-Molecule CDMO Services