Press Room

Guy Villax spoke for the EU API industry at the EU Pharma Strategy Structured Dialogue that the EU Commission launched today. He said: EFCG members make Active Pharmaceutical Ingredients, the core of medicines. The EU has not been in control over its generic medicines for some time – we face frequent shortages and a geostrategic fundamental dependence on APIs and precursors from India and China – where serious accidents, government policies and market failures make us vulnerable.   We have ended up in this untenable situation due to i) unbridled market forces and globalization and ii) 30 years of EU regulations that did not consider that pharma is an intensely globalized and highly competitive industry.  Europe was once the cradle of pharmaceuticals. Today price pressure has driven the generics supply chain to prefer to buy 74% of APIs and precursors from low cost countries with limited regulation. These production locations have low regulatory oversight therefore present higher risk to patient, often cause environmental and antimicrobial resistance because of poor control over wastes, and have a high frequency of deadly accidents – EU industry cannot compete with such low cost operations.   EFCG was founded to level the playing field, this need remains. An EU patient centric pharmaceutical industry needs a EU centric pharma supply chain with a sustainable EU manufacturing base, this requires deliberate and careful regulation to compensate for market forces and to correct the playing field. The US and Japan have already launched countermeasures, we must work with our allies and not independently. European citizens deserve medicines that are Affordable, Accessible and most importantly Available. EFCG knows the issues well and is ready to help, count on us in this partnership. Pierre Luzeau will next list the needed solutions.     The meeting gathered representatives of pharma industry (generics and innovators), patients, hospital pharmacists as well as addressed Minister Marta Temido, MEPs Dolors Montserrat and Nathalie Colin–Oesterlé, Commissaires Kyriakides and Breton, Vice President Schinas.    About the Structured dialogue on Security of Medicines Supply   About EFCG    

News

Guy Villax spoke for the EU API industry

Feb 26, 2021

    好利安藥廠火警疏散演習 Fire and evacuation simulator at the pharmaceutical factory “Hovione”   Firefighters fought the fire by the storage tank. The Fire Brigade (CB) held on the morning of February 24th this year, a fire and evacuation simulator with dangerous chemical substances in the pharmaceutical factory “Hovione” together with Hovione FarmaCiencia SA, with the intention of intensifying the measures contingency and the coordination and communication mechanism between both parties in case of incidents. The exercise simulated that a worker discovered that the leak occurred at the connection point of the methanol solution storage tank, thus causing a fire. The employee immediately sounded the fire alarm, the pharmaceutical factory's emergency and contingency team immediately proceeded to the internal contingency action, called the CB to ask for assistance and adopted security measures to evacuate the employees to the evacuation and meeting place. During the evacuation period, there was 1 worker who was injured. After becoming aware of the occurrence of a fire at the pharmaceutical factory “Hovione”, the CB immediately dispatched 9 emergency vehicles and 38 firefighters to the site to fight the fire, carry out the evacuation and search according to the defined plan, as well as provide nursing care for the injured and simulate transport to the hospital. The simulation lasted almost 1 hour. CB and the pharmaceutical factory “Hovione” sent around 160 people to participate in the simulation, whose main purpose is to test the responsiveness and the communication mechanism between the relevant parties in case of incidents. The respective process went well, after the simulation, both parties held a review meeting, whose objectives and expected results were achieved. [Translated from the original]       好利安藥廠火警疏散演習 為加強與好利安藥廠在發生事故時的應變措施及協調溝通機制,消防局於本年2月24日上午,與好利安製藥科學股份有限公司在氹仔好利安藥廠聯合舉行化學危險品火警及疏散演習。 演習模擬工作人員發現一個含有甲醇溶液的儲存缸接駁口出現洩漏並發生火警,工作人員隨即按動火警警報,藥廠緊急應變隊伍即時啟動內部應變計劃,同時致電消防局求助,以及採取安全措施疏散員工到逃生集合點,於疏散期間有一名員工不慎受傷。消防局接報好利安藥廠發生火警後,立即派遣9架緊急車輛及38名隊員趕赴現場,按照既定計劃進行滅火及疏散搜救行動,並對傷者進行即時護理及模擬送院,演習過程歷時約1小時。 消防局和好利安藥廠合共派出近160名人員參與是次演習,主要目的是測試發生事故時雙方的應變能力及溝通機制,演習過程順利,事後雙方進行檢討會議,並達到預期目的及效果。     Simulacro de incêndio e evacuação na fábrica farmacêutica “Hovione” Os bombeiros combateram o fogo junto do tanque de armazenamento. O Corpo de Bombeiros (CB) realizou na manhã do dia 24 de Fevereiro do corrente ano, um simulacro de incêndio e evacuação com substâncias químicas perigosas na fábrica farmacêutica “Hovione” em conjunto com a Hovione FarmaCiencia SA, com o intuito de intensificar as medidas de contingência e o mecanismo de coordenação e comunicação entre ambas as partes em caso de incidentes. O exercício simulou que havia trabalhador que descobriu que ocorreu a fuga no ponto de ligação do tanque de armazenamento da solução de metanol, acontecendo assim um incêndio. O empregado tocou imediatamente o alarme de incêndio, a equipa de emergência e contingência da fábrica farmacêutica procedeu logo à acção de contingência interna, ligou ao CB para pedir auxílio e adoptou as medidas de segurança para evacuar os funcionários para o local de evacuação e encontro. Durante o período de evacuação, havia 1 trabalhador que ficou ferido. Depois de ter tido conhecimento da ocorrência de incêndio na fábrica farmacêutica “Hovione”, o CB enviou de imediato 9 veículos de emergência e 38 bombeiros ao local para combater o fogo, executar a acção de evacuação e busca conforme o plano definido, bem como prestar os cuidados de enfermagem junto do ferido e simular o transporte para o hospital. O simulacro durou quase 1 hora. O CB e a fábrica farmacêutica “Hovione” enviaram cerca de 160 pessoas para participar no simulacro, cuja finalidade principal é testar a capacidade de resposta e o mecanismo de comunicação entre as partes pertinentes em caso de incidentes. O respectivo processo correu bem, depois do simulacro, ambas as partes procederam a uma reunião de revisão, cujos objectivos e resultados esperados foram alcançados.   Read the article at News.Gov.MO        

Press Clipping

Fire and evacuation drill at the pharmaceutical plant “Hovione”

Feb 25, 2021

  3 FEBRUARY 2021 - Belem Cultural Centre - CCB, LISBON - (online event)   The Case for Sustainable Accounting Standards When the planet faces big issues, scientists are the first to flag them, the first to understand them, the first to design solutions – sadly science is seldom at the table when business decisions are taken. When the issues are simple, such as the ozone hole above Antarctica, scientists can get decision-makers to understand and act and we have Science to thank for the Montreal protocol: 20 years elapsed from discovery to inverting the trend – this speed is possible when the problem is simple: a single chemical reaction -ozone and chlorine- and a single culprit – man-made CFC gases. Climate change is very complex, there are multiple causes, the magnitude of change needed is massive and therefore cannot be solved without a transversal approach. Scientists are not able to influence decision-making because they do not speak the language of business. Companies, CEOs, asset managers, shareholders, funds march to the tune of profitability, their language is that of financial performance – today’s accounting standards ignore externalities and measure business profit not accounting for the good and the bad impacts of business on society and on the environment. Sustainable accounting standards that measure profitability adjusted for social and environmental impact is the necessary new common language if we are to ensure scientists, business and other stakeholders understand each-other. If we do not measure, we cannot manage. CFOs don’t know what is a mole of a newton, as much as most people in this room might not know what is EBITDA or an impairment. We must measure unambiguously the true and complete value of business. This measure of value added corrected for sustainability can connect to a measure of sustainable GDP of a city or of a country, which in turn can connect with the value of the world's ecosystem services and natural capital. Tracking this performance over time will allow to assess the trajectory of the health of our planet. Sustainable accounting standards will drive business to hire new skills. Finance and controlling areas will recruit scientists, engineers, anthropologists, sociologists... Over time the Chief Financial Officer will see its role evolving to that of a Chief Value Officer. If business adopts sustainable accounting standards, executives and shareholders will know the complete extent of their impact and the liabilities they face from exposure to climate change. No one can then plead ignorance. Taxation can take into account social benefits and environmental costs thereby driving desired behaviors. No amount of Science Based targets and Mission Oriented R&D projects can ever come close to the impact on Climate Change that Business harnessed by the right accounting standards can deliver by doing its day-to-day work in a manner that considers the people and the planet. Sustainable accounting standards will allow the market forces to drive decisions in the right direction. Putting a man on the moon by the decade’s end, may be more inspiring than making every company in the EU to comply with Sustainable Accounting Standards. This may come across as a small step for the EU Commission to take, but it would be a giant leap for the planet. How could Horizon Europe spur the innovations necessary not only to embrace sustainable accounting practices, but also make it possible for economic, business and investment actors to evolve the underlying logic of market capitalism to value natural, social and human capital on par with financial? Could the EU lead the world in this evolution during next 10 years?”   Guy Villax Lisbon, 3rd February 2021 PDF version       Find more about this virtual event at 2021portugal.eu  

News

The Case for Sustainable Accounting Standards

Feb 03, 2021

  Lisbon, Portugal, 12th January 2021 – Hovione, the leader in Pharmaceutical Spray Drying, today announced the launch of ASD-HIPROS, a proprietary screening service for spray dried dispersions. This platform is the most advanced and most accurate tool to identify optimal and commercially viable Amorphous Solid Dispersions formulation by Spray Drying (ASDs). During drug development, it is crucial to quickly find the optimal formulation assuring fast progress to clinical supplies and minimal formulation changes till commercialization.   ASD-HIPROS, the Hovione Intelligent PROprietary Screening methodology, is able to rapidly screen for the best combination of polymers, drug loads, surfactants and solvents by using an advanced computational tool followed by producing scale-independent representative samples of the most promising formulations, which are evaluated for performance and stability.   “ASD-HIPROS is a multiple-step screening service that was perfected in the last 15 years and is able to provide an accurate assessment of Spray Dried Dispersion, in less than 2 months and requiring as little as 5-g of API.” commented Dr. Filipe Gaspar, Hovione’s Chief Technology Officer. “Our accumulated experience and expertise in Spray Drying were used for the development of this platform. It offers a rational formulation definition using a combination of in silico computational modelling and high throughput formulation testing, maximizing the chances of identifying a winning formulation based on outputs obtained from Spray Drying prototypes”.   “We offer a seamless experience, for our customers, and a secure path for their drugs to clinical supplies and commercialization, thanks to our unmatched experience, know-how and manufacturing capacity.” stated Dr. Jean-Luc Herbeaux, Hovione’s Chief Operating Officer.     About Hovione Hovione is an international company with over 60 years of experience as a Contract Development and Manufacturing Organization (CDMO) and is currently a fully integrated supplier offering services for drug substance, drug product intermediate and drug product. With four FDA inspected sites in the USA, China, Ireland and Portugal and development laboratories in Lisbon, Portugal and New Jersey, USA, the company provides branded pharmaceutical customers services for the development and compliant manufacture of innovative drugs including highly potent compounds. For generic pharmaceutical customers, the company offers niche API products. Hovione also provides proprietary product development and licensing opportunities for drug products. In the inhalation area, Hovione is the only independent company offering a complete range of services.     Contact Isabel Pina | Director External Communications ipina@hovione.com |Tel.: 0035121 982 9362    

Press Release

Hovione Launches ASD-HIPROS

Jan 12, 2021

As the European Commission prepares a new pharmaceutical strategy, manufacturers seek financial support and technology investment by Rick Mullin NOVEMBER 27, 2020 | APPEARED IN VOLUME 98, ISSUE 46   When the COVID-19 pandemic exposed weaknesses in the pharmaceutical supply chain in the US—in particular its dependence on products outsourced to Asia—the government responded forcefully. The Trump administration led with an initial grant of $354 million, with a possible $458 million to follow, for a newly formed company, Phlow, dedicated to manufacturing critical active pharmaceutical ingredients (APIs) domestically. Next came a letter of intent for a $765 million loan to Eastman Kodak to convert a specialty chemical plant at the company’s headquarters in Rochester, New York, into an API manufacturing complex dedicated to “reshoring” pharmaceutical chemicals from China and India. Now it’s Europe’s turn. The European Commission (EC) has been studying the global supply chain, setting itself a year-end deadline for delivering a drug and health-care strategy. Proposed road maps solicited by the EC from manufacturers of APIs and finished drugs illustrate differences between the US approach and Europe’s possible path to self-sufficiency in pharmaceutical manufacturing. In a meeting in April with the European Union conference of presidents, the EU’s health and food safety commissioner, Stella Kyriakides, raised the matter of supply chain vulnerabilities exposed by the COVID-19 pandemic. Kyriakides cited “structural weaknesses in the EU’s medicines supply chain and a high dependence on non-EU countries for active pharmaceutical ingredients” and recommended that supply chain issues be addressed in an EU strategy. The EC solicited public comment on the proposed strategy in June. Judging from the recommendations put forward by European associations representing drug and pharmaceutical chemical firms, the commission’s approach will differ significantly from the tack taken by the outgoing Trump administration. Rather than spending millions of euros launching made-in-Europe ventures, the EC will likely leverage a sizable established manufacturing base. Likewise, industry guidance for Europe’s plan places greater emphasis on making its supply chain more secure rather than less global, while maintaining and expanding the region’s manufacturing footprint. Adrian van den Hoven, general director of Medicines for Europe, an association of generic-drug and API makers, stresses that reshoring cannot be viewed as simply resuming the manufacture of products that have been outsourced to China and India. “It’s a question of making it sustainable to invest and continue to invest in Europe,” van den Hoven says. “We still have a pretty robust industrial footprint in Europe, with a lot of capabilities.” But growth has flattened in recent years, he adds, as manufacturers in countries like India have taken market share.     Medicines for Europe’s proposals to the EC include a change to generic-drug pricing, which individual countries currently set at the lowest possible levels to reduce the cost of subsidized health care. The association proposes a scheme that would allow prices to be negotiated from the bottom up based on a supplier’s cost of goods, regulatory costs, and other considerations. For hospital and retail purchases, van der Hoven says Medicines for Europe favors “multi-winner tenders,” in which buyers are required to purchase from several suppliers as opposed to awarding contracts to the lowest bidder, a practice that has fueled consolidation among drug suppliers. The group also advocates government support for technology development. Van den Hoven points to Europe’s almost $900 billion COVID-19 recovery package, “The commission has made it clear that some of the funding will be available for technology investment by our sector,” he says. Medicines for Europe also advocates global coordination of drug supply as opposed to rampant reshoring. “It is important that we maintain critical technologies in Europe,” van den Hoven says. “That said, we don’t believe we can or should produce everything in Europe.” That view is seconded by Luis Gomes, senior vice president of operations at the Portuguese API firm Hovione. He’s also chairman of the Pharmaceutical Activities Committee of the European Fine Chemicals Group (EFCG), an industry association. “I think the commission has an understanding that it needs to strengthen the production of pharma products in Europe in order to reduce the dependence and vulnerability of the supply chain,” Gomes says. “I think regulators need a kind of road map to pursue what I would call meaningful pharmaceutical production reshoring in Europe. That starts with priorities.” The EC must arrive at a list of critical APIs that need to be manufactured in Europe, Gomes says. Those no longer made in Europe can be reintroduced, thus increasing the domestic manufacturing base. “And it’s not only APIs one cares about,” he says. “You are also dependent on supply of intermediates and building blocks. You need to look at the supply chain from an end-to-end perspective.” Pharmaceutical chemistry presents a significant hurdle given that many of the reactions involved have disappeared from Europe in the wake of the region’s Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) legislation and other environmental tightening over the past 2 decades. For example, REACH required expensive environmental controls on reactions such as nitration, fluorination, and bromination, which are critical to making certain drug ingredients. “I think REACH created an incentive for production of these chemicals to move to other places, especially Asia, but that doesn’t mean they cannot be manufactured again in Europe,” Gomes says. Like Medicines for Europe, EFCG sees a need for the government to invest in green technology. Financial support will also be needed to establish European production of critical drugs and drug ingredients now made exclusively overseas. Maggie Saykali, director of resins and fine chemicals at the European Chemical Industry Council (Cefic), says in an email that her trade association also has been in discussions with the EC regarding vulnerabilities in the pharmaceutical supply chain. Cefic is preparing a report with recommendations at the commission’s request. “One of the pillars of our roadmap is selective reshoring of the critical technologies needed for the molecules for which long-term supplies must be guaranteed,” Saykali writes. “In order to be sustainable in the long run, this selective reshoring needs support for process innovation, expansion of existing EU production facilities and enforcement of a level playing field for the highest-quality safety, environmental, and social standards.” Sources agree that continuous manufacturing technology will play a role in developing efficient and green manufacturing. They also agree that the Research Center of Pharmaceutical Engineering’s Center for Continuous Flow Synthesis and Processing (CC Flow) initiative at Graz University is the center of continuous technology development in Europe. C. Oliver Kappe, scientific director of CC Flow, says that his lab is not communicating directly with the EC on the development of a reshoring strategy but that several of its partners are contract manufacturers and members of associations such as EFCG. Kappe says the lab plans to set up a facility near Graz, Austria, that will pilot the manufacture of both APIs and finished drugs in a fully continuous fashion. Continuous manufacturing could help avert crises such as drug shortages during pandemics in Europe, Kappe argues. He notes that CC Flow has worked on a process for manufacturing remdesivir, a COVID-19 treatment developed by Gilead Sciences. It also has collaborated with a similar center in the US, the Medicines for All Institute at Virginia Commonwealth University. Medicines for All is a partner in Phlow, the company launched by the Trump administration to repatriate generic drugs. While Europe has taken a few pages from the US response to the COVID-19 pandemic—the EU recently announced it would create a biomedical research agency comparable to the Biomedical Advanced Research and Development Authority, the US government agency that launched Phlow—the European path will inevitably differ. Observers note that Brussels is coordinating 27 independent countries’ efforts, ensuring a more protracted process than experienced in Washington. One EU country has floated a Phlow-like venture with a view toward securing domestic supply of acetaminophen. The government of France is sponsoring a partnership with the French drug firms Sanofi and Upsa and the French API maker Seqens to establish domestic supply of the analgesic, which currently comes mostly from China. Seqens manufactures bulk acetaminophen there. Upsa and Sanofi manufacture most of the finished drug used in France, but they source API from China. The plan, still at a preliminary stage, would have Seqens add capacity for the API in France. Van den Hoven at Medicines for Europe likes the hospital and health-care-facility purchasing strategy adopted by Phlow and its partner Civica Rx, a nonprofit launched in 2018 to help manage generic-drug prices and prevent shortages for member institutions. But he questions the US government’s decision to spend up to $800 million establishing a new company to foster domestic manufacturing of APIs. “It’s an incredible amount of money,” he says. “In Europe, we can do it for a lot less.” He points to Sandoz’s deal with the Austrian government to invest more than $175 million at its site in Kundl, Austria, Europe’s last large antibiotics plant. “This is really small change for a production site that supplies half of Europe with penicillin,” van den Hoven says. On Nov. 25 the EC issued its Pharmaceutical Strategy for Europe, which outlines a raft of initiatives the commission will put forward for approval by the European governing bodies. The strategy, which is not finalized, addresses many of the manufacturing issues raised by industry associations, including pricing policies and investment in green technology. But it lacks details on regulatory changes impacting the use of continuous process manufacturing, and it does not suggest the creation of a list of critical APIs. Van den Hoven says the commission is still fielding input from industry pending a finalized plan. Europe’s drug manufacturers are awaiting further direction from the EC just as the world braces for a surge in COVID-19 infections that may reignite supply chain anxiety. Van den Hoven notes, however, that the first wave of the pandemic was marked by a cooperative response globally. For instance, Europe expedited the export of drugs used in intensive care units to the US despite crisis-level demand for the same drugs at home, he says. “The political climate is a little tense right now,” van den Hoven says. “But at some point people are going to have to go back to cooperation again.”   Read the full article on C&EN website  

Article

Europe’s drug supply chain gets ready for a makeover

Nov 27, 2020

Experts Share Their Opinions on How the Custom Manufacturing and Research Industry can Tackle the Impact of the Covid-19 Pandemic and a Demanding Economic Climate   20.10.2020 - The coronavirus crisis caused by the Covid-19 pandemic has uncovered problems that have been smoldering beneath the surface of the pharmaceutical industry — including CMOs/CDMOs and CROs — and need to be addressed. That supply chains are vulnerable to disruption when major development, production and transportation hubs are blocked or shut down has become painfully obvious. The ongoing pandemic is putting pharmaceutical R&D strategies to the test and also challenging manufacturing planning and supply chain management. Particularly in this industry segment, the supply chain is global, complex and interconnected. Each link must be strong enough to ensure that the road from lab to final drug product is as smooth as possible, even under the most difficult circumstances. In addition to the pandemic, the growing threat of a no-deal-Brexit amid old and new trade conflicts and increasing protectionism, is putting even more stress on companies operating in the pharma sector. In cooperation with Wombat Capital*, a cross-border investment bank, CHEManager asked executives and experts of CMOs, CDMOs and CROs operating in the pharmaceutical sector to share their opinion on current challenges for their industry and how these challenges may influence changes in their market and opportunities.   Expert Interview: Jean-Luc Herbeaux       16.10.2020 - So far, the pharmaceutical industry — including CMOs/CDMOs and CROs — has responded well to the outbreak of the Covid-19 pandemic. However, the coronavirus crisis has uncovered problems that have been smoldering beneath the surface and need to be addressed. That supply chains are vulnerable to disruption when major development, production and transportation hubs are blocked or shut down has become painfully obvious. The ongoing pandemic is putting pharmaceutical R&D strategies to the test and also challenging manufacturing planning and supply chain management. Particularly in this industry segment, the supply chain is global, complex and interconnected. Each link must be strong enough to ensure that the road from lab to final drug product is as smooth as possible, even under the most difficult circumstances. In addition to the pandemic, the growing threat of a no-deal-Brexit amid old and new trade conflicts and increasing protectionism, is putting even more stress on companies operating in the pharma sector. In cooperation with Wombat Capital, a cross-border investment bank, CHEManager asked executives and experts of CMOs, CDMOs and CROs operating in the pharmaceutical sector to share their opinion on current challenges for their industry and how these challenges may influence changes in their market.   What in your opinion and from your perspective are the main impacts of the coronavirus pandemic on the drug supply chains? Jean-Luc Herbeaux: While Covid-19 placed some strain on global supply chains and logistics, the pharma industry overall showed surprising resilience considering the severity of the situation. The pandemic highlighted the strong reliance and dependence of drug and medical product supply on China and India and the limitations of such a supply model. It caused governments to look at pharmaceutical manufacturing in a more strategic manner, including potential repatriation, to guarantee access to life-saving medicines to cater to the most extreme demands. A new type of “nationalism” promoting preferential (or even exclusive) access to therapies and vaccines has emerged in the meantime and it has the potential to greatly disrupt the established global manufacturing and supply models.   Many Western CDMOs have already shifted operations back to the USA and Europe as intensive business activity in China has driven up labor costs. In addition, national policies, trade-related developments such as Brexit and the US-China dispute and impacts of pandemics are likely to require repatriation of at least part of the supply chain in many countries. Could CMOs/CDMOs be beneficiaries of restructured supply chains? J.-L. Herbeaux: CMOs/CDMOs have a chance to benefit from the repatriation trend, which already started some years back. The first wave of relocation, which started some 4 or 5 years ago, stemmed from quality and regulatory considerations. This repatriation was very beneficial to CDMOs with assets and quality systems in good standing as they were able to gain access to business which had escaped them up to that point. The new wave seems to be driven by countries and their citizens coming to terms with the fact that most of their medical supplies are from foreign countries and entities. The recent Covid-19 crisis has revealed the limits associated with reliance on third party country supplies and the ongoing Covid-19 vaccine and therapy “nationalism” further exacerbated the sentiment that repatriation of pharma assets is now a strategic priority. We ought to recognize that the Covid-19 pandemic is extreme in terms of impact and medical supply needs. It has overwhelmed the global supply chains in unprecedented ways and no economically sound supply strategy could have prepared us for an event of such global proportion. In these special times, there is a risk of overheating and of wrong capital investment decisions. Investments need to make sense not only for the short term (i.e. in Covid-19 times) but also for the long haul (once the world returns to a more normal reality). In this overheated environment, experienced western CDMO´s with flexible assets and operating models and with meaningful engineering capabilities are probably the best bet for this industry. They know how to ramp up and run assets in an effective and nimble manner and make best use of these assets now and in the future thanks to their ability to accommodate an ever-changing portfolio.   What do you think the impact of the repatriation of the drug supply chain will have on the M&A activity in the CMO/CDMO industry? Do you think that this would create an impact on valuations? J.-L. Herbeaux: The pharma industry is very likely to weather the Covid-19 crisis better than other sectors and accordingly, one can expect valuation to go up at a time when investors may be looking for safe heavens. The demand-supply balance for M&A candidates in the USA will also drive multiples. One can foresee that the high availability of cash and short-term hype may result in some misguided investment decisions in parties and/or assets, which do not represent mid to long-term value. In the pharma CDMO space, assets are important but not sufficient. The right-to-win stems from established competencies in quality, regulatory and manufacturing service excellence and these attributes take time to develop.   Has the inability to hold face-to-face meetings with prospective clients and conduct client visits to sites affected your new business development since the outbreak of the coronavirus pandemic? J.-L. Herbeaux: New business development has become more difficult as travel restrictions have curtailed opportunities for face-to-face interactions. Physical closeness is known to help individuals (or groups of individuals) form interpersonal relations and develop trust. Proximity and face-to-face communication are therefore particularly important for first-time interactions. We see this clearly in our commercial activities: it is a lot easier to maintain or even further established relationships than to develop new ones. Add to this the need for pharma companies to audit new partners and you will understand why existing partnerships are preferred to new ones at this moment.   The CMO/CDMO industry has managed to support efforts to develop vaccines and therapeutics for Covid-19 despite already being at a high level of utilization. What made that possible? J.-L. Herbeaux: From what is published, there is significant cash being deployed to ramp up vaccine production and capacity repurposing or reactivation is also on the agenda. Some of this cash came from governments and public organizations to secure supply. As for Hovione, we are involved in several steep capacity ramp-up exercises and these have been made possible by very strong partnerships with our clients and suppliers. Everyone understands that these are extraordinary times, and all agree that only shared commitments can result in success. The rest is fueled by a sheer desire to save lives. We push our organizations, systems, and processes to new levels of speed and productivity relying on decades of experience, expertise and best-in-class practices. Under these extreme conditions, CAPEX, resources, and associated capacities are deployed faster and products become available in record time. This is what leading and agile CMOs do for a living: deal with the cross-functional and cross-discipline complexity associated with production ramp-up and compress timelines.   For the biopharma CMO/CDMO industry, the pandemic crisis has created great opportunities. What is your opinion on whether and to what degree the CDMO industry will enjoy long-term benefits from its role in tackling the current crisis? J.-L. Herbeaux: One may assume that the public opinion of the pharma industry will have improved during the last months and that any company, including CDMOs, which contributed to solving or alleviating the Covid-19 humanitarian crisis, would have a chance to boost its image externally but also with its own staff. There is little which can compete with being a contributor to tackling a global health crisis and saving lives. Leading CDMOs have certainly showed that they can be trusted and that supply chains supported by CDMOS/CMOs are robust. Moreover, their demonstrated ability to step up and make capacity available on short notice, absorbing much of the complexity associated with reaching new levels of supply, has positioned CDMOs at the core of the industry’s journey to provide therapies and vaccines to billions of individuals. The co-dependence between CDMOs and Pharma companies is stronger than ever, and this should increase the propensity of pharma to outsource.   One of Hovione’s facilities is located in Macau, China. How was the site in particular and your business in China in general affected by the outbreak of the coronavirus pandemic? J.-L. Herbeaux: Macau is a good example of Hovione’s success in controlling the risks associated with Covid-19. Extensive measures were quickly put in place to protect the team members and to ensure the continuity of our manufacturing operations. Many of the raw materials for Macau come from mainland Chinese suppliers and the site was also able to secure its supply chain. The site was even able to adapt to repair specialized equipment with its own staff as technical visits from suppliers were not possible. Our other sites, which have also been running without interruption or disruption, learned from the Macau response and organization. Best practices were quickly rolled out globally under the leadership of a global task force. All our sites are now operating safely according to this new reality. One of our most important decisions has been to offer free testing to our employees with an elevated risk profile, e.g. as they return from holiday.   The race is on to develop treatments and vaccines against Covid-19, and so is the need to assure supply of these potential drugs and vaccines. Pharma companies are leveraging their internal manufacturing networks but also partnering with CMOs/CDMOs. What supply and manufacturing strategies/alliances are in play? J.-L. Herbeaux: The Covid-19 pandemic has engendered an all-out search for treatment options. Many hundreds of compounds for prophylactic and therapeutic use have been tested in the race against this deadly disease. No drug candidate or route of administration has been neglected and innovative formulation concepts are given due consideration under the assumption that regulatory authorities will likely grant accelerated approval to treatment options which show positive clinical outcomes. The patient population is considerable, and the urgency is absolute. The manufacturing capacities for the few treatments that have demonstrated some efficacy (or promise of efficacy) to date are being ramped up to scales and with speeds which transcend anything the industry had seen so far. Pharma companies have sought the help of their partners to ramp up raw material supply and custom manufacturing services to help them deal with this colossal challenge. In times of pressing requirements, strong partnerships are key and unsurprisingly pharma companies have tended to reach out to their existing partners – especially those who demonstrated the ability to meet complicated supply challenges involving new asset deployment and commissioning. We, at Hovione, are part of this select group of CDMOs working closely with partners on both new formulation concepts and steep upscaling of industrial production capacities.   “Emerging”, “virtual” and other small (bio)pharmaceutical companies are driving the discovery and development of new drugs but are mostly dependent on the availability of financing – which could become more restricted due to the economic downturn cause by the economic and epidemiologic disruptions to the global economy. As emerging biopharma companies are important customers of CMOs/CDMOs, how is this going to affect your business? J.-L. Herbeaux: As a leading CDMO known for helping pharmaceutical companies of all sizes bring new and off-patent drugs to market, Hovione is of course dependent on the health of the biotech industry and its pipeline. So far, our business has remained extremely vibrant as our customers do not appear to be short of cash and pipeline projects are progressing as per plan. The last 3 years have been good in terms of biotech financing (the biotech sector in NASDAQ is at an all-time high). So, one may contend that biotech companies’ strong cash positions will allow them to weather the storm as long as the crisis does not perdure and investments do not stop abruptly. After a few months of increasing disruptions in clinical trials due to Covid-19, data now suggest that clinical trial disruptions have started to recede. Most trial disruptions appear to be due to suspension of enrollment – not financials.   Read the full article at CheManager      

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The Coronavirus Crisis: Challenges and Opportunities for CMOs, CDMOs and CROs

Oct 20, 2020

Over the coming months, Hovione will be hiring for positions in quality control, quality analysis, warehouse operations and production operations. Hovione, a contract pharmaceutical manufacturing and particle engineering company, has announced 48 new jobs for its base in Cork. The expansion follows a partnership agreement between Hovione and biopharma company Ligand to ramp up production of Captisol, a product that can improve the solubility and stability of drugs. Captisol is used in the Covid-19 treatment Veklury, which is produced by US pharma company Gilead. New hires will be based at Hovione’s site in Ringaskiddy, Co Cork, which has been in operation for more than 10 years. It was acquired from Pfizer in 2009 and currently employs around 200 people. According to the company’s talent acquisition specialist, Michelle Ahern, the vacancies will span quality control, quality assurance, process engineering, project management, engineering, warehouse operations and production operations. Recruitment for the roles is underway and the team plan to fill them by the end of 2020. Founded in Portugal in 1959 by Diane and Ivan Villax, Hovione helps to bring new and off-patent drugs to market. The pharma manufacturing company has 1,600 staff members around the world, with facilities in the US, Ireland, China, Portugal, India, Japan, Switzerland and Hong Kong. Jean-Luc Herbeaux, COO of Hovione, said that increased demand for Veklury has meant that Hovione will soon be producing in a month the amount of Captisol it normally produces in a year. “This sudden spike in demand has required unique mobilisation efforts across the Hovione network to secure additional raw-material supply, execute major capital-expenditure projects at our sites, maximise operational efficiency, hire additional talent and identify external partners to expand our overall capacity,” he said. Ligand’s president and COO, Matt Foehr, added that Captisol is a “critical component for a number of life-saving medicines”. Hovione Cork’s general manager, Paul Downing, said that the opportunities are for people “who want to join a fast-paced, dynamic, empowering, diverse, inclusive and exciting organisation”. To learn more about working at Hovione, visit the company’s careers portal here.   Read the article at siliconrepublic.com    

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Pharma manufacturer Hovione announces 48 new jobs for Cork

Oct 02, 2020

Continued clinical progress of Captisol-enabled drugs affirms the value of the proprietary technology   SAN DIEGO--(BUSINESS WIRE)--Ligand Pharmaceuticals Incorporated (NASDAQ: LGND) announces that recent new contracting with partners and investments in manufacturing capacity have contributed to its Captisol business operating at the highest levels in the history of the technology and position Captisol for major growth. Significant new clinical and regulatory developments with Evomela and Kyprolis, among other drugs, are reinforcing the role the proprietary technology serves in enabling important medicines. During 2020, Ligand has facilitated the successful installation of equipment to allow production at significantly higher levels to support anticipated demand. In addition to manufacturing at partner Hovione’s facilities in Ireland and Portugal, Ligand has now added final step processing capacity for Captisol in both the United States and England. Ligand also introduces guidance for 2021 Captisol material sales of approximately $200 million. “The global medical need for Captisol-enabled drugs has never been higher,” said John Higgins, Chief Executive Officer of Ligand. “Our recently expanded operating team has successfully positioned our Captisol technology for the substantial growth we now expect in 2021 and beyond. There is significant ongoing investment by our partners for over 30 Captisol-enabled medicines in clinical development. We have entered into more contracts this year than any other year and are proud to be working closely with Gilead under our recently extended 10-year supply contract. We continue to be pleased with the momentum relating to Captisol, as it is a critical component in multiple life-saving medicines.” Recent Captisol technology business highlights include the following: To date in 2020 Ligand has entered into more than 120 Captisol research use agreements and eight clinical and/or commercial license agreements. This is the highest number of use agreements to be signed in a single year since the invention of Captisol. Captisol is utilized in the formulation of Gilead Sciences’ Veklury® (remdesivir), which has received emergency use authorizations or regulatory approvals for the treatment of moderate or severe COVID-19 in over 50 countries and is included in more than 30 ongoing clinical trials. Ligand is supplying Captisol to Gilead and the company’s voluntary licensing partners who are supplying generic remdesivir to 127 low- and middle-income countries. Ligand expects Captisol orders into 2021 and beyond to Gilead and its partners to help countries around the world manage the pandemic. Ligand recently extended its Captisol supply agreement with Gilead until September 2030. The contract defines terms and conditions for forecasting, supply, order commitments and price. Ligand’s manufacturing partner Hovione announced today that to meet Captisol demand associated with Veklury, Hovione will soon be producing more Captisol per month than it usually produces per year. “This spike in demand has required unique mobilization efforts across the Hovione network to secure additional raw material supply, execute major capital expenditure projects at oursites, maximize operational efficiency, hire additional talent and identify external partners to expand our overall capacity. The pharmaceutical supply chain is working together in an unprecedented fashion to treat patients and save lives. Hovione is privileged to be part of this truly global rapid response,” said Jean-Luc Herbeaux, Chief Operating Officer of Hovione. Recent clinical data have been announced including publication of a study from the Medical College of Wisconsin that compared safety parameters for Captisol-enabled Evomela® versus Alkeran® in patients undergoing autologous stem cell transplantation for the treatment of multiple myeloma. The study of 294 patients demonstrated a statistically significant reduction in 30-day re-hospitalization rates for patients treated with Evomela (6.8% for Evomela vs. 17.9% for Alkeran, p=0.04)a with a similar safety profile to Alkeran. Evomela is marketed by Acrotech Biopharma in the U.S. and by CASI Pharmaceuticals in China. Partner Marinus was recently awarded a BARDA contract by the U.S. government to develop Captisol-enabled IV ganaxolone for the treatment of refractory status epilepticus caused by nerve agent exposure. Ligand’s pivotal trial for Captisol-enabled Iohexol (CE-Iohexol) is planned to initiate in December 2020. CE-Iohexol is an iodine-based contrast agent for hospital-based imaging procedures. The market for iodinated contrast agents is substantial with approximately 20 million imaging procedures per year in the U.S., representing an estimated $1.5 billion in sales. The objective of the clinical trial will be to demonstrate a reduction in the incidence of contrast-induced acute kidney injury and an equivalent image quality compared to GE’s Omnipaque®. The trial is expected to enroll approximately 500 patients and results are expected within two years. Ligand’s forecast for 2021 Captisol material sales of approximately $200 million is based on information it has on anticipated demand from its major partners given growth in existing and new markets, clinical requirements for Captisol-enabled development programs and binding orders from certain commercial or pre-commercial partners. The 2021 Captisol outlook compares with the Company’s guidance for 2020 Captisol material sales of approximately $90 million.   About Captisol® Captisol is a patent-protected, chemically modified cyclodextrin with a structure designed to optimize the solubility and stability of drugs. Captisol was invented and initially developed by scientists in the laboratories of Dr. Valentino Stella, University Distinguished Professor at the University of Kansas’ Higuchi Biosciences Center for specific use in drug development and formulation. This unique technology has enabled several FDA-approved products, including Gilead’s VEKLURY®, Amgen’s KYPROLIS®, Baxter International’s NEXTERONE®, Acrotech Biopharma L.L.C.’s and CASI Pharmaceuticals’ EVOMELA®, Melinta Therapeutics’ BAXDELA™ and Sage Therapeutics’ ZULRESSO™. There are many Captisol-enabled products currently in various stages of development. Ligand maintains a broad global patent portfolio for Captisol with more than 400 issued patents worldwide relating to the technology (including 37 in the U.S.) and with the latest expiration date in 2033. Other patent applications covering methods of making Captisol, if issued, extend to 2040. About Ligand Pharmaceuticals Ligand is a revenue-generating biopharmaceutical company focused on developing or acquiring technologies that help pharmaceutical companies discover and develop medicines. Our business model creates value for stockholders by providing a diversified portfolio of biotech and pharmaceutical product revenue streams that are supported by an efficient and low corporate cost structure. Our goal is to offer investors an opportunity to participate in the promise of the biotech industry in a profitable, diversified and lower-risk business than a typical biotech company. Our business model is based on doing what we do best: drug discovery, early-stage drug development, product reformulation and partnering. We partner with other pharmaceutical companies to leverage what they do best (late-stage development, regulatory management and commercialization) to ultimately generate our revenue. Ligand’s OmniAb® technology platform is a patent-protected transgenic animal platform used in the discovery of fully human mono- and bispecific therapeutic antibodies. The Captisol platform technology is a patent-protected, chemically modified cyclodextrin with a structure designed to optimize the solubility and stability of drugs. The Vernalis Design Platform (VDP) integrates protein structure determination and engineering, fragment screening and molecular modeling, with medicinal chemistry, to help enable success in novel drug discovery programs against highly challenging targets. Ab Initio™ technology and services for the design and preparation of customized antigens enable the successful discovery of therapeutic antibodies against difficult-to-access cellular targets. Icagen has established deep biological expertise focused on ion channels and transporters and has a strong track record in ion channel drug discovery from screening to lead optimization. Ligand has established multiple alliances, licenses and other business relationships with the world’s leading pharmaceutical companies including Amgen, Merck, Pfizer, Sanofi, Janssen, Takeda, Servier, Gilead Sciences and Baxter International. For more information, please visit www.ligand.com. Follow Ligand on Twitter @Ligand_LGND. Forward-Looking Statements This news release contains forward-looking statements by Ligand that involve risks and uncertainties and reflect Ligand's judgment as of the date of this release. Words such as “plans,” “believes,” “expects,” “anticipates,” and “will,” and similar expressions, are intended to identify forward-looking statements. These forward-looking statements include, without limitation, statements regarding: Ligand’s expectation that Captisol demand will increase significantly in 2021 and beyond (particularly for sales to Gilead and to partners in Gilead’s consortium) and Ligand’s ability to supply Captisol to Gilead and other partners, including Ligand’s ability to increase supply capacity; the timing of initiation, enrollment and expected results with respect to the planned clinical trial of CE-Iohexol; and guidance regarding Ligand’s 2020 and 2021 Captisol material sales. Actual events or results may differ from Ligand's expectations due to risks and uncertainties inherent in Ligand’s business, including, without limitation: Ligand may not receive expected revenue from Captisol sales; the COVID-19 pandemic has disrupted Ligand’s and its partners’ business, including delaying manufacturing, preclinical studies and clinical trials and product sales, and impairing global economic activity, all of which could materially and adversely impact Ligand’s results of operations and financial condition; Ligand may not achieve its Captisol material sales guidance for 2020 and/or 2021; remdesivir may be later shown to not be effective or safe for the treatment of COVID-19 and/or the FDA (and/or equivalent agencies in other countries) may revise or revoke its emergency use authorization for remdesivir for the treatment of COVID-19 in patients hospitalized with moderate or severe disease if the FDA (and/or another such agency) determines that authorization no longer meets the statutory criteria for issuance; alternative COVID-19 therapies or vaccines may be approved or the risk of coronavirus infection could significantly diminish, any of which could materially and adversely affect the commercial opportunity for remdesivir; Gilead may terminate the supply agreement without cause upon 30 days’ prior written notice; Ligand may be unable to scale-up the supply of Captisol or at acceptable prices; Ligand is currently dependent on Hovione as a single source sole supplier for certain Captisol manufacturing functions and failures by such supplier may result in delays or inability to meet the Captisol demands of its partners; Amgen, Acrotech Biopharma or other Ligand partners may not execute on their sales and marketing plans for marketed products for which Ligand has an economic interest; Ligand or its Captisol partners may not be able to protect their intellectual property and patents covering certain products and technologies may be challenged or invalidated; Ligand's Captisol partners may terminate agreements or development or commercialization of products; Ligand may not generate expected revenues under its existing license agreements and may experience significant costs as the result of potential delays under its supply agreements; Ligand and its Captisol partners may experience delays in the commencement, enrollment, completion or analysis of clinical testing for product candidates, or significant issues regarding the adequacy of clinical trial designs or the execution of clinical trials, which could result in increased costs and delays, or limit the ability to obtain regulatory approval; unexpected adverse side effects or inadequate therapeutic efficacy of Ligand's or its Captisol partners’ product(s) could delay or prevent regulatory approval or commercialization; and ongoing or future litigation could expose Ligand to significant liabilities and have a material adverse effect on the company. The failure to meet expectations with respect to any of the foregoing matters may reduce Ligand's stock price. Additional information concerning these and other risk factors affecting Ligand can be found in prior press releases available at www.ligand.com as well as in Ligand's public periodic filings with the Securities and Exchange Commission available at www.sec.gov. Ligand disclaims any intent or obligation to update these forward-looking statements beyond the date of this release. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. a Monahan, et al. Biology of Blood and Marrow Transplantation, September 2020 Read the article on Business Wire website  

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Ligand Announces its Captisol Business is Positioned for Major Growth and Forecasts 2021 Captisol Material Sales of $200 Million

Sep 23, 2020

Lisbon, Portugal, 23rd September, 2020 - Hovione today announced the signing of a partnership agreement with Ligand to significantly ramp up the production output of Captisol®. Captisol®, a Ligand product, is a chemically modified cyclodextrin proven to improve the solubility and stability of drugs. It is used in the formulation of Gilead’s Covid-19 treatment Veklury® (remdesivir). Hovione is the sole producer of this key enabling excipient. The Covid-19 pandemic has to date killed one million people; studies show that in the next 3 months cumulative deaths may more than double. “To meet Captisol® demand associated with Veklury®, Hovione will soon be producing per month the quantity it usually produces in one year. This sudden spike in demand has required unique mobilization efforts across the Hovione network to secure additional raw material supply, execute major capital expenditure projects at our sites, maximize operational efficiency, hire additional talent and identify external partners to expand our overall capacity, The pharmaceutical supply chain is working together in an unprecedented fashion to treat patients and save lives.  Hovione is privileged to be part of this truly global response.” said Jean-Luc Herbeaux, Chief Operating Officer. “Ligand values its longstanding partnership with Hovione,” said Matt Foehr, President and Chief Operating Officer of Ligand. “Their excellent customer service, global commitment to quality and high pharmaceutical standards make them an ideal partner for Captisol®, a critical component for a number of life-saving medicines. We commend them for responsibly and efficiently partnering with Ligand to manage the scale up and expansion of their operations to contribute to global health during the pandemic.”   About Captisol® Ligand’s Captisol® technology is a patent protected, uniquely modified cyclodextrin, with a chemical structure that was rationally designed to enable the creation of new products by significantly improving solubility, stability, bioavailability and dosing of active pharmaceutical ingredients (APIs). It uses a green manufacturing process that uses water as process solvent.   About Veklury® (remdesivir) Gilead Sciences’ Veklury® is an investigational nucleotide analog with broad-spectrum antiviral activity both in vitro and in vivo in animal models against multiple emerging viral pathogens. Multiple ongoing international Phase 3 clinical trials are evaluating the safety and efficacy of Veklury® for the treatment of SARS-CoV-2 infection, the virus that causes COVID-19, in different patient populations, formulations, and in combination with other therapies. The U.S. Food and Drug Administration (FDA) expanded the Emergency Use Authorization (EUA) enabling use of the investigational antiviral Veklury®  to treat all hospitalized patients with COVID-19, in addition to the previous authorization for patients hospitalized with severe COVID-19.   About Hovione Hovione is an international company with over 60 years of experience as a Contract Development and Manufacturing Organization (CDMO) and is currently a fully integrated supplier offering services for drug substance, drug product intermediate and drug product. With four FDA inspected sites in the USA, China, Ireland and Portugal and development laboratories in Lisbon, Portugal and New Jersey, USA, the company provides branded pharmaceutical customers services for the development and compliant manufacture of innovative drugs including highly potent compounds. For generic pharmaceutical customers the company offers niche API products. Hovione also provides proprietary product development and licensing opportunities for drug products. In the inhalation area, Hovione is the only independent company offering a complete range of services.   Contact Isabel Pina | Director External Communications Tel.: 0035121 982 9362

Press Release

Hovione Announces Partnership to Support Manufacturing of Antiviral Veklury® for COVID-19

Sep 23, 2020

Hovione recently announced the signing of a partnership agreement with Ligand to significantly ramp up the production output of Captisol, a Ligand product, which is a chemically modified cyclodextrin proven to improve the solubility and stability of drugs.  It is used in the formulation of Gilead’s Covid-19 treatment Veklury (remdesivir). Hovione is the sole producer of this key enabling excipient. The Covid-19 pandemic has to date killed 1 million people; studies show that in the next 3 months cumulative deaths may more than double. “To meet Captisol demand associated with Veklury, Hovione will soon be producing per month the quantity it usually produces in 1 year. This sudden spike in demand has required unique mobilization efforts across the Hovione network to secure additional raw material supply, execute major capital expenditure projects at our sites, maximize operational efficiency, hire additional talent, and identify external partners to expand our overall capacity. The pharmaceutical supply chain is working together in an unprecedented fashion to treat patients and save lives.  Hovione is privileged to be part of this truly global response,” said Jean-Luc Herbeaux, Chief Operating Officer. “Ligand values its long-standing partnership with Hovione,” added Matt Foehr, President and Chief Operating Officer of Ligand. “Their excellent customer service, global commitment to quality, and high pharmaceutical standards make them an ideal partner for Captisol, a critical component for a number of life-saving medicines. We commend them for responsibly and efficiently partnering with Ligand to manage the scale up and expansion of their operations to contribute to global health during the pandemic.” Ligand’s Captisol technology is a patent-protected, uniquely modified cyclodextrin, with a chemical structure that was rationally designed to enable the creation of new products by significantly improving solubility, stability, bioavailability, and dosing of active pharmaceutical ingredients (APIs). It uses a green manufacturing process that uses water as process solvent. Gilead Sciences’ Veklury is an investigational nucleotide analog with broad-spectrum antiviral activity both in vitro and in vivo in animal models against multiple emerging viral pathogens. Multiple ongoing international Phase 3 clinical trials are evaluating the safety and efficacy of Veklury for the treatment of SARS-CoV-2 infection, the virus that causes COVID-19, in different patient populations, formulations, and in combination with other therapies. The US FDA expanded the Emergency Use Authorization (EUA) enabling use of the investigational antiviral Veklury to treat all hospitalized patients with COVID-19, in addition to the previous authorization for patients hospitalized with severe COVID-19. Hovione is an international company with over 60 years of experience as a Contract Development and Manufacturing Organization (CDMO) and is currently a fully integrated supplier offering services for drug substance, drug product intermediate, and drug product. With four FDA inspected sites in the US, China, Ireland, and Portugal and development laboratories in Lisbon, Portugal, and New Jersey, US, the company provides branded pharmaceutical customers services for the development and compliant manufacture of innovative drugs, including highly potent compounds. For generic pharmaceutical customers, the company offers niche API products. Hovione also provides proprietary product development and licensing opportunities for drug products. In the inhalation area, Hovione is the only independent company offering a complete range of services.   Read the article on Drug Development & Delivery website    

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Hovione Announces Partnership to Produce Ligand’s Captisol; Used in Gilead’s Covid-19 Treatment

Sep 23, 2020

Hovione has signed a partnership agreement with Ligand to significantly ramp up the production output of Captisol Captisol, a Ligand product, is a chemically modified cyclodextrin proven to improve the solubility and stability of drugs. It is used in the formulation of Gilead’s Covid-19 treatment Veklury (remdesivir). Hovione is the sole producer of this key enabling excipient. The COVID-19 pandemic has, to date, killed one million people; studies show that in the next 3 months cumulative deaths may more than double. “To meet Captisol demand associated with Veklury, Hovione will soon be producing per month the quantity it usually produces in one year. This sudden spike in demand has required unique mobilisation efforts across the Hovione network to secure additional raw material supply, execute major capital expenditure projects at our sites, maximise operational efficiency, hire additional talent and identify external partners to expand our overall capacity." "The pharmaceutical supply chain is working together in an unprecedented fashion to treat patients and save lives. Hovione is privileged to be part of this truly global response,” said Jean-Luc Herbeaux, Chief Operating Officer. “Ligand values its longstanding partnership with Hovione,” said Matt Foehr, President and Chief Operating Officer of Ligand. “Their excellent customer service, global commitment to quality and high pharmaceutical standards make them an ideal partner for Captisol, a critical component for a number of life-saving medicines." "We commend them for responsibly and efficiently partnering with Ligand to manage the scale up and expansion of their operations to contribute to global health during the pandemic.”   Read the article on Manufacturing Chemist website  

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Hovione to support production of antiviral Veklury for COVID-19

Sep 23, 2020

1st September 2020 – Bilim Pharmaceuticals, a Turkish company manufacturing and marketing pharmaceutical drugs, H&T Presspart, a global provider of respiratory drug-delivery devices and components to the pharmaceutical sector, and Hovione Technology, a pharmaceutical specialist in the development of innovative pulmonary device technology, today unveiled a collaboration supporting Bilim Pharmaceutical’s launch into the Turkish market of Ventofor Combi Fix, a formulation of Budesonide Formoterol for Asthma and COPD management, delivered by the PowdAir Plus Dry Powder Inhaler (DPI). Worldwide over 500 million people suffer from Asthma and COPD. In Turkey, there is growing patient demand for effective, readily accessible and affordable respiratory treatments. Aiming at fulfilling these patient needs, the three companies have been collaborating in Bilim Pharmaceuticals’ development program to bring into the Turkish market Ventofor Combi Fix delivered by the PowdAir Plus DPI, an innovative capsule DPI providing maximum simplicity, ease of use and affordability. The PowdAir Plus DPI is exclusively manufactured and commercialized by H&T Presspart under patent license from Hovione Technology.  “It’s a great pleasure for us to launch our new product Ventofor Combi Fix with a close collaboration with esteemed companies H&T Presspart and Hovione Technology. As being one of the strong drivers of Asthma and COPD treatment area, Ventofor Combi Fix is and will be an important part of our portfolio for this treatment area. We are confident that Ventofor Combi Fix will be a remarkable product in its market and crown all the outstanding efforts of the collaborators”, said Okan Oncel, Bilim Pharmaceuticals’s General Manager. “We are very happy to see that Bilim Pharmaceuticals has selected the PowdAir Plus DPI for their launch of Ventofor Combi Fix. Due to the strong collaboration of Bilim Pharmaceuticals with Hovione Technology and H&T Presspart this milestone could be reached. The individual expertise in each of their fields has allowed us to develop a strong partnership in the design, development and manufacture of PowdAir Plus. We look forward to seeing Bilim Pharmaceuticals launch the product to the market and will continue to strongly support them with their inhalation strategy.” said Christian Kraetzig, H&T Presspart’s President. “We are delighted to have started an inhalation collaboration with Bilim Pharmaceuticals, one of Turkey’s largest pharmaceutical companies, and that they selected our PowdAir Plus DPI to bring Ventofor Combi Fix to patients’ hands. We are also happy to continue our partnership with H&T Presspart, a master of large-scale industrialization and distribution, to turn our patented inhaler technology into a commercial ready product that is now globally available to pharmaceutical companies”, said Peter Villax, Hovione Technology’s CEO.  About Bilim Pharmaceuticals Founded in 1953, Bilim Pharmaceuticals is a 100% Turkish capital owned company that manufactures and markets drugs, a strategically important commodity. Ranked as the second largest Turkish Pharma Company in the Turkish pharmaceutical industry, Bilim Pharmaceuticals consistently continues to grow at a higher rate than the market with a marketing and sales team of app. 1000. Bilim Pharmaceuticals carries out its production activities at two separate plants. Approved by EU GMP, Bilim Çerkezköy is one of Turkey’s most significant penicillin manufacturing facilities. Approved by EU GMP, Bilim Gebze is Turkey’s largest, most innovative and most environment-friendly drug manufacturing plant. Bilim Pharmaceuticals owns the largest R&D center of the Turkish pharmaceutical industry with a laboratory area of 4,500 square meters, where it develops new products, contributing significantly to the Turkish economy. Exporting to over 60 countries, Bilim Pharmaceuticals has representative offices in Moldova and Albania. In a sensitive sector which is directly related to human health, Bilim Pharmaceuticals prioritizes quality and adopts respect towards future generations as a corporate value.  www.bilimilac.com.tr  About H&T Presspart H&T Presspart offers pharmaceutical customer’s high-precision injection moulded plastic components and deep-drawn metal cans for respiratory drug delivery systems, with 50 years' experience and a worldwide reputation for competence, quality and innovation in the pharmaceutical market.  H&T Presspart’s New Product Development Center (NPDC) & Inhalation Product Technology Centre (IPTC) support new product developments and strategic initiatives with our customers. Founded in 1970 and acquired by the Heitkamp and Thumann group in 2002, H&T Presspart has 3 European manufacturing sites with additional sales offices in China, India, the U.S.A. and Uruguay. For more information, please visit www.presspart.com. About Hovione Technology Hovione Technology offers access to a complete portfolio of innovative, cost-effective dry powder inhalation devices – disposable, capsule-based, blister-based and large dose DPIs. With over 20 years of expertise developing innovative inhaler technology, Hovione Technology’s team has been behind the first market approved disposable dry powder inhaler for influenza treatment, the TwinCaps DPI, and the new market approved capsule DPI for Asthma and COPD management, the PowdAir Plus DPI. Millions of patients are being treated every year with Hovione Technology’s innovative inhaler technology. For more information, please visit www.hovionetechnology.com  and contact info@hovionetechnology.com

Press Release

Bilim Pharmaceuticals, H&T Presspart and Hovione Technology unveil collaboration for new asthma product: Ventofor Combi Fix delivered by PowdAir Plus

Sep 01, 2020

With the help of outsourcing partners, the small biotech firm Nabriva brought lefamulin to patients by itself. Now it needs to make a profit in the tough-to-crack antibiotic business.   In November 2006, Rosemarie Riedl synthesized an antibacterial molecule that she logged into Nabriva Therapeutics' database as BC-3781. It was not just another entry in a compound collection. In 2019, after almost 13 years of development and testing, the US Food and Drug Administration approved that same molecule, lefamulin, for the treatment of community-acquired bacterial pneumonia. Marketed as Xenleta, lefamulin was the first antibiotic with a novel mechanism of action to win FDA approval for pneumonia in nearly two decades. With the help of contract manufacturing firms from across Europe and China, Nabriva took the drug to market without a big pharma partner. Inventing a drug in its own labs and getting it approved solo is something few biotech firms have done. And yet it won't be enough for the small company. Nabriva must now turn a profit on lefamulin, a goal that has eluded many independent antibiotic developers. Judging from Nabriva's stock price, investors have their doubts that the firm will be in the black anytime soon.   DISCOVERY Although Nabriva's corporate offices are in the US, and its global headquarters are in Ireland, its research efforts are based in Vienna, where the culture is decidedly more European than American. Riedl, Nabriva's senior director of medicinal chemistry, has been with the company and its predecessor, Sandoz, since earning her PhD in pharmaceutical chemistry. And she's not the only long-tenured employee. "The core team has been together for a long, long time," says Werner Heilmayer, Nabriva's vice president for intellectual property and chemistry, manufacturing, and controls. Like Riedl, Heilmayer has been there from the start. He joined Sandoz in 1995 after graduate school and went with Nabriva when it became an independent company in 2006. That was the year that Novartis, Sandoz's parent company, decided it was done researching and developing new antibiotics, a field that has long been a money pit for big pharma. With about $50 million in financing from venture capital firms and its own venture arm, Novartis set the antibiotic operation off on its own. As an independent company, Nabriva continued Sandoz's quest for useful derivatives of pleuromutilin, an antibiotic molecule that occurs naturally in an edible mushroom sometimes called Pleurotus mutilus. Pleuromutilin was discovered in the 1950s, and Sandoz launched two semisynthetic derivatives, tiamulin and valnemulin, as veterinary antibiotics in 1979 and 1999, respectively. GlaxoSmithKline (GSK) later succeeded in creating a topical human drug, but systemic human pleuromutilins with a wider potential market eluded drug hunters for decades. One reason for the lack of success was that, for many years, researchers were focused on finding new beta-lactam antibiotics like amoxicillin and cephalosporin, still the most widely used antibiotic class. Drug company interest in pleuromutilins finally perked up around the turn of the century as bacterial resistance to beta lactams increased, according to a review paper that Riedl and a colleague, Susanne Paukner, published in 2017 in Cold Spring Harbor Perspectives in Medicine. According to the paper, pleuromutilins work by binding to the peptidyl transferase center on the bacterial ribosome, interfering with protein production and impeding growth. It's a unique mode of action for an antibiotic, even among those that work by blocking bacterial growth. Both mechanistic studies and in vitro experiments show a low potential for resistance to develop. While pleuromutilin can kill bacteria in the lab, it doesn't have what it takes to make a good drug. Chemists needed to tweak the molecule to improve properties like how long it lingers in the bloodstream. A year after Novartis spun off Nabriva, the FDA approved the first human pleuromutilin derivative, GSK's retapamulin. But the skin infection treatment, created by modifying the hydroxyacetyl side chain of pleuromutilin with a bicyclic N-methylpiperidine group, only works as an ointment; GSK was unable to put it into a pill or IV bag. XENLETA AT A GLANCE Discovered: 2006 Approved: Aug. 19, 2019 Active ingredient: Lefamulin Indication: Community-acquired bacterial pneumonia Mode of action: Binds to the peptidyl transferase center on the bacterial ribosome, interfering with protein production and impeding growth Although Nabriva wasn't first to the market, the company was determined to come up with a systemic drug. When it became independent, the firm didn't have a viable drug candidate of its own. What it did have was a deep knowledge of pleuromutilin chemistry and well-honed skills for making derivatives. The Nabriva researchers drew on those insights when they, like the chemists at GSK, sought to modify the hydroxyacetyl side chain. Their goal was a modification that would give the natural product the elusive balance of antimicrobial activity, solubility, and metabolic stability needed to turn a molecule into a systemic drug. Unlike their counterparts at GSK, Riedl and her colleagues didn't have huge compound libraries and combinatorial chemistry machinery at their disposal. Instead, they relied on old-fashioned medicinal chemistry savvy. "We always did dedicated chemistry and synthetic derivatives, compound by compound," Heilmayer says. In 2006, Riedl tried yet another modification of the side chain: adding an aminohydroxycyclohexyl group. The result was BC-3781, later renamed lefamulin. Riedl's choice of that side chain involved a bit of luck, of course, but mostly it was the culmination of years of carefully directed effort. She describes the moment modestly: "I always had a good feeling about that idea and that it could solve many of the problems we had at the time."   DEVELOPMENT What Riedl actually got was a mixture of diastereomers that had to be separated on a chiral high-performance liquid chromatography column. And even after separation, BC-3781 did not instill a lot of confidence. It was a difficult-to-handle amorphous salt. And the laboratory synthesis required two classical chromatographic purifications. "You cannot have these things on scale," Heilmayer points out. The Vienna team needed to develop a chirally selective synthesis that avoided chromatography, and a crystalline late-stage intermediate that could be isolated and purified. The team also had to come up with an acceptable salt form. "These were some of the problems we had to solve after discovering lefamulin," Heilmayer says. The team solved them, and by 2014, lefamulin had successfully completed Phase I and II clinical trials showing it was safe as well as effective in a small group of bacterial pneumonia patients. Because the Vienna facility didn't operate under the good manufacturing practice standards required by the FDA, Heilmayer had hired the chemistry outsourcing firms Aptuit and Almac to produce the small quantities of active pharmaceutical ingredient (API) needed for those trials. But Phase III clinical trials and, ultimately, commercialization would be a whole new ball game. New people, new outsourcing partners, and new money would be needed. The company hired a drug industry veteran as CEO and established a US subsidiary in Philadelphia where its clinical development team would be based. The following year Nabriva made an initial public offering of stock on the Nasdaq exchange. One of the new executives was Steven Gelone, who is now Nabriva's president and chief operating officer, responsible for business development and technical operations. Gelone was a good fit. Earlier in his career as an infectious disease clinician at GSK, he and his colleagues were stymied by Sandoz's robust intellectual property (IP) around pleuromutilin derivatives. "We kept hitting roadblocks," he recalls. "We just could not solve the problem, in large part because the Sandoz/Novartis team, which ultimately became Nabriva, had an IP portfolio that blocked us from doing some interesting chemistry on one of the key side chains." When Nabriva later offered Gelone a job, he couldn't say no. Working with the Nabriva executives in the US, Heilmayer looked to secure firms that could manufacture the quantities needed under quality systems that would satisfy inspectors with the FDA and the European Medicines Agency. "Our desire was, as best we could as a small biopharma company, to create a gold standard supply chain for this product," Gelone says. The critical synthetic step in lefamulin production is combining pleuromutilin with the aminohydroxycyclohexyl side chain. Heilmayer and his team needed to find large-scale suppliers of pleuromutilin and a chiral building block for the side chain, and a company to join the two pieces into the API. It also needed firms to produce the tablet and intravenous forms of the drug. For pleuromutilin, Nabriva executives thought they had it easy. Sandoz had pioneered the fermentation of pleuromutilin to produce the two animal antibiotics, and the firm was Nabriva's supplier during clinical development of lefamulin. But in 2014, Eli Lilly and Company acquired the Sandoz/Novartis animal health business. Suddenly, Nabriva was told to look elsewhere for pleuromutilin supply. Heilmayer had to scramble to find a new company that could supply pleuromutilin at the required purity and with quality systems that would satisfy regulators. He soon settled on the Chinese firm SEL Biochem Xinjiang. SEL is the world's largest producer of pleuromutilin, using it mainly for its own production of the animal antibiotic tiamulin, according to Grace Xu, a vice president at Zhejiang University Sunny Technology, which owns SEL. For Nabriva, SEL developed a special high-purity version using higher quality standards, Xu says. For the side chain building block, a cyclohexene carboxylic acid, Nabriva first contracted with an Indian pharmaceutical chemical company, which made it for Nabriva's clinical trials. But because the intermediate is a liquid acid, it had to be shipped from India via sea, rather than air, creating an unacceptably weak link in the supply chain, Heilmayer says. So, with approval and commercialization of lefamulin looking more and more likely, Nabriva sought an intermediate supplier closer to home. It ended up choosing the Irish firm Arran Chemical, which Almac acquired in 2015. Arran had the right capabilities and equipment, and Heilmayer was impressed that it was able to quote a price for the intermediate lower than what Nabriva paid the Indian firm. Companies in Ireland have higher labor costs than do those in India, acknowledges Tom Moody, Almac's vice president of technology development and commercialization. To offset them, Arran drew on other strengths. "In Ireland we have to do things efficiently," he says. Almac, which is based over the border in Northern Ireland, acquired Arran during this period, mainly for its biocatalysis and API building block scale-up skills. Almac had worked with the Irish firm for more than a decade and wanted to bring those capabilities in-house, Moody says. The chiral building block contract with Nabriva was an intriguing sweetener, he adds, because Almac had produced the API in the early days of lefamulin development and formulated it into tablets for administering to patients during clinical trials. To put the intermediates together into the final lefamulin molecule, Heilmayer and his team settled on the pharmaceutical services firm Hovione at its site in Cork, Ireland, just a 3 hour drive from the site in Athlone, Ireland, where Arran makes the side chain. In choosing Hovione, Nabriva weighed the usual factors of quality, technical fit, timing, and price. But underlying the individual considerations was the knowledge that, unlike a big drug company, Nabriva couldn't afford to hire a second supplier in case things went wrong. "Whoever we chose," Gelone says, "we had to be highly confident in, because we knew we weren't going to have a second supplier when we launched lefamulin." Hovione, a Portuguese firm, had acquired the Cork facility from Pfizer in 2009. At the time, the plant made only one API-atorvastatin, the active ingredient in Pfizer's cholesterol-lowering drug Lipitor. But by 2014, when Hovione and Nabriva started discussions, Hovione had succeeded in bringing new products to Cork, including several APIs, recalls Paul Downing, general manager of the site. Staffing at the facility had doubled since the acquisition to about 100. By the time Nabriva and Hovione signed a contract in 2016, it was clear that lefamulin, now in Phase III studies, would need to be made on an accelerated schedule. Hovione typically developed synthetic methods for pharmaceutical chemicals at its pilot plant in Portugal and then produced initial quantities there before transferring the process to the commercial-scale reactors in Cork. "The timeline Nabriva required meant we had to skip the middle piece," Downing says. Both parties knew that Hovione's job was more than just connecting two molecules. The cyclohexene carboxylic acid from Arran had to be taken through further chemical steps to form the aminohydroxycyclohexyl side chain that Riedl had conceived in 2006. And the hydroxyacetyl group on pleuromutilin has to be activated through an exchange of sulfur for oxygen to form a sulfanylacetyl linker that couples with the side chain. "It seems simple, but it's actually a very long process that requires care and attention," says Rui Loureiro, Hovione's director of process chemistry development and the lead chemist on the development project. From start to finish, a production campaign takes about two months. One area that called for special attention was phase separation. In lab tests of the reaction in Portugal, process chemists were surprised to find that three phases resulted, rather than the usual two. "We had to understand how you make sure in the plant that you take out the right phase of three phases," Loureiro says. Another challenge was crystallizing and recrystallizing a molecule with multiple chiral centers. "That's how to ensure that you get the right isomers out of your reaction," Loureiro says. The API that Hovione manufactures in Cork is the heart of Xenleta, but for people to take it, the white powder has to be turned into tablet and IV forms. For the tablet, Heilmayer turned to Almac again. Nabriva had first hired Almac in the early 2010s to produce the lefamulin API for Phase I and II clinical trials. At the time, says Tommy Burns, an Almac project services manager, Nabriva took the logical next step in a good relationship and asked Almac's finished drug division to formulate the API into tablets. Some years later, with clinical successes under its belt, Nabriva came back to Almac looking for tablet manufacturing and packaging for Phase III trials and commercial launch. "Nabriva needed a firm that could help overcome some of the development challenges they faced with the tablet," Burns says. To be effective, lefamulin needs to be administered in high doses, and 600 mg is tough to squeeze into even a large tablet. Moreover, because the API is sticky, Almac was not able to create a traditional pill with the necessary on-dose product identifier embossed on the surface. Instead, Burns says, Nabriva and Almac worked together to develop a nonstandard pill for which the name is applied with an inkjet printer. For vials of the drug for intravenous delivery, Nabriva contracted with Patheon's sterile liquid production facility in Monza, Italy. It also tapped Fresenius Kabi's sterile liquid contract manufacturing facility in Halden, Norway, to produce special companion IV bags to which the sterile drug is added. As Gelone explains, Nabriva scientists realized early in the development of lefamulin that its pH in solution is important and should be maintained. They worked with Fresenius on a bespoke IV bag which they created by adding a citrate buffer to the conventional saline bags made in Halden. When a health-care professional pours a vial of Xenleta into the bag, the resulting solution is close to physiologic pH, Gelone says. In the end, producing and distributing Xenleta requires a supply chain that stretches from China to multiple sites in Europe and, ultimately, the US. Nabriva took the risk of assembling it without knowing if regulators would actually clear the drug, but the bet paid off. The FDA approved Xenleta on Aug. 19, 2019. "We had the product in the channel and ready for patients 16 days after approval," Gelone says.   MARKETING Nabriva's manufacturing partners continue to refine their processes. At Hovione, for example, Loureiro is eager to develop continuous solvent extraction to decrease the amount of solvent required to recover the API. By his calculation, lefamulin generates 3% less waste than the typical API, but he says Hovione can cut waste further. "We believe there is space to improve the process." And Burns says Almac is in the process of moving the granulation process for Xenleta tablets from pilot to commercial scale. Once the switch is complete, Almac's capacity to manufacture the pills will be markedly higher. But even as Nabriva's partners streamline production, healthy demand for Xenleta is far from a sure thing. In the past few years several biotech firms have won FDA approval of new antibiotics that are effective against resistant bacteria, only to find physicians and hospitals reluctant to prescribe them. In 2019 alone, three small antibiotic firms-Melinta Therapeutics, Aradigm, and Achaogen-all declared bankruptcy. Public health experts say doctors and hospitals need new medicines to fight antibiotic-resistant infections, yet the companies that invent them too often find few customers. "One of the conundrums that's very unique for anti-infectives is the strong desire to have innovation available but not wanting to use that innovation for fear you're going to ruin it by creating resistance," Gelone says. The health-care community thus thoroughly reviews the differentiating characteristics of a new antibiotic to understand the patients for which it is best suited. "I've run the committees that do it, and the process takes time," he says. Nabriva contends that Xenleta falls in the right place. Pleuromutilin antibiotics, the firm says, have a lower propensity for resistance than most established antibiotics because they bind to bacterial ribosomes in a unique way and via multiple interactions. And lefamulin has the advantage of being approved in both IV and oral forms, meaning it has the potential to be administered first in a hospital and later at home. New antibiotics aren't going to be billion-dollar-a-year drugs, Gelone acknowledges. "There has to be a perceived unmet medical need that the physician community believes this product will address," he says. "That's where lefamulin fits in." Nabriva is finding the process of fitting in to be slow. In April, the company announced that it is laying off its hospital-oriented salesforce of 66 people, more than a third of its overall staff. Nabriva described the decision as part of a new strategy of focusing on community health-care professionals. Restrictions on interacting with hospital personnel during the coronavirus pandemic also played a role in the layoffs. On May 11, Nabriva reported that it had product sales in the first quarter of 2020 of only $156,000. The firm also disclosed that it was in danger of being delisted from the Nasdaq stock market because its shares were trading for less than $1.00. In early 2017 they were changing hands for more than $12.50. Still, Gelone is optimistic. European regulators just handed down a positive opinion, and Nabriva is working with its partner in China, Sinovant, on approval there. He notes that Xenleta could play a role in treating people infected with the novel coronavirus who also have contracted pneumonia. In Vienna, Heilmayer and Riedl remain proud of what Nabriva has accomplished. Heilmayer wonders if a larger company would have stuck with the compound through the tougher moments. "They establish certain thresholds, and if you don't achieve these thresholds, the compound is gone," Heilmayer says of big drug firms. "In the biotech world, if you have a challenge you will always look for ways to overcome it." Today, Heilmayer and Riedl are tackling new challenges. Heilmayer continues to work with Nabriva's outsourcing partners to support and troubleshoot Xenleta manufacturing. In one recent program, they elucidated and synthesized a new impurity encountered during large-scale API manufacturing. As for Riedl, she and her colleagues are working on next-generation pleuromutilin antibiotics as well as other projects that she is keeping close to the vest. "Stay tuned for the next molecules from Nabriva," she says.   Read the article at C&EN  

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One molecule’s journey from discovery to market

Jun 22, 2020

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