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Article / Nov 01, 2015

In-depth Process and Product Expertise

Pharma's Almanac – A Nice Insight Supplement, Q4 2015 Edition

In-depth Process and Product Expertise – This is Key to CDMO Support of Orphan Drug and Breakthrough Therapy Development & Commercialization

As older blockbuster drugs lose patent protection and generic competition increases, many pharmaceutical companies are focusing discovery efforts on therapies with the potential to treat multiple niche populations. Increasingly, innovative small and emerging pharma firms are developing new drug candidates with orphan or breakthrough therapy status that are ultimately licensed or sold to large brand manufacturers. These companies rely heavily on contract manufacturing and development organizations (CDMOs) that can provide in-depth scientific expertise and achieve under rapidly accelerated timelines the development of cost-effective, robust, reliable processes that consistently yield high-quality products.  

Until recently, most pharmaceutical firms were not interested in the development of small-volume drugs due to fears of limited returns. With the age of the blockbuster drug now history, many drug companies are finding that niche therapies, particularly those that may treat numerous indications, not only provide patients with life-saving medications, but also realize attractive financials if developed in a streamlined and cost-efficient manner. There are over 7,000 different types of rare diseases and disorders, yet only a couple of hundred approved therapies designated as orphan drugs. According to EvaluatePharma, although the average Phase III development time for orphan drugs is not shorter than that for non-orphan drugs, the Phase III drug development costs for the former are half those of the latter, and the anticipated return on investment for a Phase III/filed orphan drug is nearly twice that for a non-orphan drug.

As a result, EvaluatePharma estimates that the orphan drug market is growing at an annual rate of 11%, more than double that of the overall prescription drug market (5%), and by 2020 will reach $176 billion in annual sales and account for 19% of the total non-generic prescription market. In 2013 alone, 260 orphan drug designations were granted. In 2014, the FDA approved 15 NDAs and seven BLAs with the orphan drug designation, along with 24 supplemental approvals.

Many companies are also pursuing the new breakthrough designation established in 2012 by FDASIA, the Food and Drug Administration Safety and Innovation Act. A candidate qualifies for breakthrough therapy designation if preliminary clinical evidence suggests that the drug may have substantial improvement over available therapies on at least one clinically significant endpoint. The development and approval times for breakthrough therapies are typically half that of the seven years for conventional drugs, and both the sponsor and CDMO benefit from greater FDA guidance and communication with the agency. FDA’s CDER approved 14 breakthrough therapies in 2014 and nine in 2015 as of August 21. 

Of the firms pursuing the development of orphan drugs and breakthrough therapies, many are small or emerging pharmaceutical or biopharmaceutical companies focused on niche, small molecule therapies. These companies often have limited resources in terms of laboratory, analytical, and manufacturing equipment (indeed, some are virtual companies in that respect) and depend heavily on service providers to perform crucial process and formulation development, validation, regulatory compliance, and manufacturing activities. The choice of CDMO can therefore have a direct impact on the success or failure of the new drug.

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In an interview with Executiva, a portuguese media outlet focused on women´s leadership, Diane Villax, co-founder and long-standing leader of Hovione, reflects on her journey and the company’s development over more than six decades. Diane Villax’s career began at a time when few women worked outside the home. At 19, she joined a trading company as a foreign languages correspondent, where she developed essential business skills — including commercial correspondence, banking and export procedures — that later proved instrumental in helping her husband, Ivan Villax, establish Hovione in 1959. From its earliest days operating in the family home in Lisbon, Hovione adopted an international outlook. The company’s first major customers were in Japan, setting demanding quality standards that helped shape its long-term position in global markets. Over the following decades, Hovione expanded its footprint with the construction of its first manufacturing site in Loures (1969), followed by expansion to Macau (1986), the United States (New Jersey, early 2000s) and Ireland (Cork). The company grew into a global organization with more than 2,500 employees — including over 300 scientists — and a reputation as a preferred supplier to leading pharmaceutical companies worldwide. Throughout the interview, Diane highlights the values that have guided the company’s development: a commitment to excellence, a strong work ethic, and a focus on quality and long-term relationships. Although she did not have formal business training, she learned “on the job” and brought discipline, precision and structure to her role — particularly in the company’s early financial and administrative leadership. Now in her nineties and an active member of Hovione’s Board of Directors, Diane Villax remains engaged with the company’s evolution and governance, reflecting a continued commitment to its long-term development. Her story reflects entrepreneurial drive, resilience and long-term leadership — and offers insight into the values that have shaped Hovione’s trajectory for more than six decades. Read the full interview at Executiva.pt (in portuguese).    

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Márcio Temtem, vice president, Strategic Business Management, Hovione, addresses molecule complexity, speed, and regionalization via integrated manufacturing. The landscape of small molecule manufacturing is rapidly evolving, according to Márcio Temtem, vice president, Strategic Business Development, Hovione, who provides an expert look into how his firm is evolving their approach as the industry changes. With 17 years of experience at Hovione, a family-owned CDMO with a 66-year legacy, Temtem identifies three pivotal trends currently shaping the industry: increased complexity, accelerated development speed, and the regionalization of supply chains. Temtem observes that small molecules have grown significantly in size and complexity, often requiring multiple chemical steps and high-potency handling. This shift necessitates a specialized "toolbox" to overcome modern bioavailability challenges. Highlighting Hovione's technical approach to these hurdles, Temtem states, "We use a platform called amorphous solid dispersions, produced by spray drying to address this challenge of bioavailability.” This platform represents a core area in which Hovione maintains global leadership, utilizing innovative tools to scale processes efficiently while minimizing the use of APIs. Temtem also mentions the increased influence of AI in drug discovery and deployment, which requires CDMOs to bridge the gap from grams to tons at a much faster pace than in previous years. He further addresses the trend of regionalization, noting the rise of countries such as the US and China prioritizing regional supply chain strategies. He explains that Hovione is uniquely positioned to navigate these new challenges with supply chains through its FDA-inspected sites across three continents. Central to Hovione’s competitive advantage is their integrated manufacturing offer, which combines drug substance and drug product expertise at a single location. Temtem emphasizes the value of this model, stating, “The company… has been investing in an integrated offer, bridging the problems of chemists and formulators all at the same shop.” To support this integration, the company continues to pioneer advanced manufacturing avenues, including continuous flow for drug substances and continuous tableting for drug products. Watch the full video interview or read the transcript at PharmTech.com  

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Hovione’s Strategy for Complexity, Speed, and Regional Supply Chains

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Hovione’s historic site in Loures has been expanded to meet demand and is now operating at full capacity. This Lisbon-based flagship company has developed innovative production techniques to serve laboratories around the world On the outskirts of Loures, in the periphery of Lisbon, a maze of multicolored pipes covers the walls of the Hovione factory. This industrial site, where signs warn of an “explosive atmosphere,” houses the production of active pharmaceutical ingredients — the core business of this company with Portuguese origins generating annual revenues of more than half a billion euros. “The products that leave here are shipped to every continent,” explains Diane Villax, the family matriarch. At 91, her voice moves effortlessly between English, French, and Portuguese — a cosmopolitan streak inseparable from the history of Hovione and the Villax family, its founders. The epic began with an exile: that of Ivan Villax in 1948. With a toothbrush in one pocket and his chemistry degree in the other, the 23-year-old anti-communist fled his native Hungary with relatives hunted by the Soviet regime. After a stop in Clermont-Ferrand, he dropped anchor in Lisbon, where he met Diane, from a family of sugar industrialists. One year after their marriage, they co-founded Hovione in 1959 with two other Hungarian refugees. The early days were artisanal: the company’s laboratory was located in the basement of the family home. “One of my earliest childhood memories is of adults in white lab coats. I knew how to use a fire extinguisher at six!” smiles Peter Villax, son of Ivan and Diane, who worked for Hovione for more than thirty years. Very early on, the duo expanded internationally, notably into Japan. The 1980s were prosperous years: growth surged at 20% annually. Then transformation accelerated with the arrival of new technologies in the early 1990s. Today, “the time required to move from test tube to industrial scale has been reduced to a few weeks, compared with six months in the past,” notes Peter Villax. The American adventure Sixty-seven years after its creation, the company — now headquartered in Switzerland — employs 2,400 people. Through medicines incorporating its active ingredients, Hovione claims to treats around an estimated 80 million patients worldwide each year. The Loures site has been expanded, and production has spread to Ireland, the United States, and Macao. The cellar at 1 Travessa do Ferreiro, where the story began, is now a distant memory. Little known to the general public, Hovione is nevertheless a key link in the pharmaceutical value chain: it develops and manufactures molecules for 19 of the world’s 20 largest laboratories. Its expansion has been fueled by favorable market conditions. “Pharmaceutical manufacturers increasingly rely on outsourcing for the production of active ingredients,” notes Loïc Plantevin, a pharma specialist at Bain & Company. “Historically, major groups chose to allocate more capital to research than to manufacturing, while biotech companies — which now drive most of the market’s growth — are not designed to build factories.” Far from resting on its achievements, the company has transformed its offering. “While the founders initially focused on generic active ingredients, Hovione has evolved toward more complex molecules and formulations, produced within exclusive partnerships with its clients,” explains Jean-Luc Herbeaux, a French national and the company’s CEO since 2022. This shift reflects a deeper trend. “For several years now, active ingredients have become a more differentiated market and less sensitive to price,” adds Loïc Plantevin. “Competitiveness is now linked to know-how and advanced production technologies, which require substantial investment.” Hovione is the world champion of spray drying, a technology enabling the production of soluble powders. With the expansion of its New Jersey site, the company aims to double its U.S. capacity — a country that accounts for 60% of its sales. Despite Donald Trump’s attacks on the pharmaceutical sector, which he claims to have brought to heel by forcing price cuts, Hovione remains confident. “We are in the U.S. to grow, and that ambition goes beyond the momentum created by the American administration,” assures Jean-Luc Herbeaux. “Our customers there are asking us to help them produce in the United States over the long term.” Commitment to cutting-edge research and the search for talent are deeply rooted in the company’s DNA. “In his later years, my father collaborated with Nobel Prize–winning chemist Geoffrey Wilkinson. Together, they would go to the Hovione lab to run experiments — just ‘for fun,’ as they put it,” recalls Peter Villax. The group is the largest employer of PhD students in Portugal and has forged partnerships with several national universities. “In some ways, Hovione resembles a university,” he continues. “Despite the sensitive nature of our technologies, we publish many academic research papers.” In search of lost sovereignty To preserve cohesion, the Villax family adheres to strict governance. “Unlike many Portuguese family businesses, most members of the third generation do not work in the company,” notes Duarte Pitta Ferraz of consulting firm Ivens in Porto. “Several independent directors sit on the board. The family’s role is to define values and long-term vision, not to manage day-to-day operations.” This responsibility is fully embraced by Jean-Luc Herbeaux. Since joining the group in 2020 as chief operating officer, sales have doubled. “My priority was to refocus the group,” says the engineer, who previously worked for German chemical giant Evonik. “We developed spray drying, invested in a new tablet-manufacturing process, and increased production speed through a new model that allows our clients to access all our services at a single industrial site.” A member of the European Fine Chemicals Group (EFCG), Hovione is actively defending European pharmaceutical manufacturing — a sector under strain. According to a study by the French Union of Organic Chemical Synthesis Industries (Sicos), Europe’s share of global active ingredient production has fallen from 48% to 30% in ten years, to the benefit of India and China. The reasons include production cost gaps — raw materials, energy — as well as the burden of European administrative and regulatory procedures, explains Maggie Saykali, director at the EFCG. “If we start a price war with our Asian competitors, we will not win it,” she admits. “It is better to compete on quality, innovation, and sovereignty over our value chain.” It took the Covid-19 pandemic and severe shortages for Europe to awaken. Last March, the European Commission proposed legislation on critical medicines. But the race against time has already begun. “China is increasingly using pharmaceutical ingredients as a tool of geopolitical pressure,” warns Maggie Saykali. “It is urgent to preserve European players like Hovione, focused on process innovation — which allows medicines to be produced with higher quality and greater environmental responsibility.” With a new site under construction in Seixal, on the southern bank of the Tagus River, the Lisbon star has not finished shining in the orbit of the global pharmaceutical industry.   (This is a translation from the original article)   Read the original article on lexpress.fr  

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