Press Room

Integration of new modeling and analytical tools with flow chemistry are notable trends A key focus of the pharmaceutical industry today is increasing efficiency and productivity to reduce cost and time to market. These issues are being addressed across the entire development lifecycle, including in API development labs. From improvement of existing technologies to the introduction of more advanced analytical instruments and modeling software, development labs are focused on increasing speed of optimization and reducing issues during scale up. Need for speed Innovation in API development labs is taking place at all pharmaceutical companies. Adam Kujath, senior director of global manufacturing sciences and technology at Alcami, points out how this innovation is being driven largely by smaller pharma and biotech companies. “Speed is the most important thing for these organizations as they work to get into and through the clinic as quickly as possible. Therefore, most investments are not necessarily for exotic new technologies, but rather expansion and improvement of those that drive more efficient throughput,” he comments. Examples include robotic screening equipment, parallel reactors, and more advanced in-line analytics to support process characterization. Flow chemistry for the synthesis of APIs is an important trend in the industry, according to Rui Loureiro, director of R&D process chemistry development for Hovione. “Flow chemistry enables the implementation of chemistries that previously were not possible due to a lack of technology. As a result, chemists are gaining access to new methods for producing new and more complex molecules,” he says. It can also dramatically reduce scale-up times because the same equipment can be used in the lab and for production, just for longer periods of time and/or in multiple copies. A side benefit of the interest in flow chemistry is improvements in process analytical technology (PAT)—including nuclear magnetic resonance (NMR) spectroscopy and high-performance liquid chromatography (HPLC)—are being developed to allow their use for continuous manufacturing, according to Loureiro. Equipment integration and miniaturization Not only advances in equipment technology, but the ability to integrate different aspects of API development laboratory initiatives is helping to speed up activities. Access to a growing selection of miniaturized probes with high resolutions allows researchers to more quickly gain a better understanding of how crystals are formed and how polymorphic forms can be controlled, according to Jerod Robertson, a senior process chemist at Hovione. He points to smaller probes for focused- beam reflectance measurements and particle vision and measurement from Mettler Toledo as examples that allow performance of crystallization studies in smaller reactors using smaller quantities of expensive API. “Using less material is important since at the beginning of development there normally aren’t significant amounts of product available, but the shape and size of the obtained crystals should be understood as in-depth as possible because these parameters can significantly impact process development down the road to reaching the commercial phase,” Robertson explains. Most notable for Alcami when it comes to equipment advances has been the integration of multiple systems, according to Kujath. “When a piece of equipment capable of performing automated, high-throughput synthesis or crystallization experiments is directly integrated with direct sampling for multiple forms of analysis on the same system, it drives efficiency, such as the Bruker D8 Discover HTS2. Better, more robust data sets can be obtained, making tools such as design of experiments more accessible for earlier development activities and thereby allowing Alcami to create stronger early clinical processes,” he observes. More intuitive software Advances in software are equally important as improved equipment and technology. “Software packages are becoming more intuitive, which is important as the databases behind them grow,” Kujath notes. “Scientists today build on the developments of those who came before them, and the software packages that exist today are making that information more accessible for application on a daily basis,” he adds. At Hovione, using the simple but effective Dynochem (Scale-Up Systems) and Visimix (VisiMix Ltd.) software packages for optimizing scale up and mixing processes and equipment have been great tools for chemists responsible for the scale-up of API syntheses. “The use of Dynochem has enabled Hovione to achieve faster development of unit operations such as solvent swapping, and it has also been a great tool for understanding reaction mechanisms, including those that lead to impurity formation,” Loureiro says. Such understanding helps the development chemists implement effective control strategies that ensure product quality. The use of tools such as Visimix provides chemists with a greater understanding of effects like mass transfer and mixing and how they can impact product quality, according to Robertson. This information can be used to gain insight into how reactions will run at scale or when they are changed from one piece of equipment to another. Hovione is also leveraging software designed for ab initio calculations, such as Gaussian calculations. “These types of software are very important because they provide chemists with a better understanding of the possible transition states that can be formed during the different steps in an API synthesis route. This information is helpful for identification of pathways that lead to impurity formation,” says Loureiro. Better modeling for greater control The software packages used at Hovione mainly help with modeling. The information that is obtained on process kinetics and impurity formation is used to determine the optimum control strategies, according to Robertson. The company also uses software such as SuperPro Designer (Intelligen) for batch process simulations and computational fluid dynamics software for modeling the scale up of processes when moving from the lab to large-scale production. The algorithms used in modeling tools are becoming more accurate and predictive in part because the data behind them continue to grow, according to Kujath. Alcami has seen that they are as a result useful for further refining processes. Better modeling for greater control The software packages used at Hovione mainly help with modeling. The information that is obtained on process kinetics and impurity formation is used to determine the optimum control strategies, according to Robertson. The company also uses software such as SuperPro Designer (Intelligen) for batch process simulations and computational fluid dynamics software for modeling the scale up of processes when moving from the lab to large-scale production. The algorithms used in modeling tools are becoming more accurate and predictive in part because the data behind them continue to grow, according to Kujath. Alcami has seen that they are as a result useful for further refining processes.   C. Challener, “Efficiency Demands Drive Advances in API Labs,” Pharmaceutical Technology 42 (10) 2018.   Read the article on Pharmaceutical Technology website


Efficiency Demands Drive Advances in API Labs

Oct 02, 2018

In general, how has the efficiency and productivity of pharmaceuticals increased/evolved over the last 20 years and how much of this evolution is due the knowledge and experience contract development and manufacturing companies bring to the industry? The technological evolution in manufacturing of pharmaceuticals has not evolved as rapidly as in other industries. Therefore, gains in efficiency and productivity have improved less than in those industries which needed to change. Contract and development and manufacturing companies have brought a higher productivity and more efficiency to the pharmaceutical industry through higher and better utilization of assets and leveraging the knowledge and experience gathered by working in many different products. These companies contributed significantly to the industry during the last 20 years as their business model focused intensely on increasing productivity and efficiency. Over this same time period what has been Hovione’s mission? How has the company helped the pharmaceutical industry bring safe and effective treatments to market over the last 20 years? Hovione’s mission was the contract development and manufacturing company that not only provides the benefits of an organization focused on development and manufacturing mentioned above but mostly an organization that brings innovation to the industry helping solve most complicated issues in development and manufacturing of medicines. For example, Hovione started many years ago devoting a significant effort in the understanding of particle engineering, how this could solve formulation challenges and what technologies could enable those engineered particles. Focusing on the inhalation and oral formulation of poorly soluble drugs through amorphous solid dispersions Hovione developed a wealth of knowledge and capabilities that have helped numerous companies developing new medicines that today help millions of patients worldwide that otherwise would not have been possible. Hovione today leads the development and manufacturing of amorphous solid dispersions by spray drying and has developed a wide range of new technologies like spray congealing and a combination of technologies that control particle size distribution, morphology, provide taste masking and controlled release properties that are of paramount importance for today’s pharmaceutical development and manufacturing. Specifically, what services and expertise does Hovione currently offer to assist pharmaceutical clients to bring new drugs to market? Can you talk about your Integrated Science offering, capacity expansion, and your continuous manufacturing technologies? Hovione constantly seeks new technologies, develops scientific knowledge and sees how we evolve our organization to solve issues for the pharmaceutical industry. Hovione today offers a comprehensive range of services from API to final drug product that include process development, clinical batch and commercial manufacturing involving experts in chemistry, process engineering, analytical sciences, particle engineering and formulation scientists. The development of a new medicine involves a wide range of expertise and technologies that Hovione has brought together ultimately (spray drying, microfluidization, spray congealing, co-precipitation) to provide better drugs and faster development so patients in need can have access to life changing medicines quicker. Hovione offers an integrated approach from API to drug product as mentioned above. This integration not only speeds up product development but also allows our organization, scientists and engineers to share product/process knowledge. Our strategy has been also to develop this integrated approach at the same location to facilitate all the complex process associated with developing a drug and outsourcing.  Therefore, Hovione started an investment program to add capacity at multiple locations (Europe and US) in API, spray drying and drug product formulation namely in tableting. Hovione believes that continuous manufacturing (in chemistry and drug product) brings a new way of developing and manufacturing medicines adding more quality and flexibility into the manufacture of medicines while allowing a faster development path by reducing the effort necessary in scaling up processes. Hovione has embraced these technologies and has invested in continuous tableting because we believe that this will be a transformational technology to the industry. Looking ahead, are there any drug development and manufacturing technologies being developed now that will help pharma companies bring innovative products to the market? How will Hovione meet this challenge for its current and future clients? Continuous processing is still a relatively new technology in the pharmaceutical industry. Its adoption will certainly help pharma companies to bring innovative products to the market faster. Hovione is very much interested in providing this option to pharma companies and having a contract manufacturing organization capable of providing this solution is of paramount importance for biotech companies and for the overall drug development industry. There are other technologies being developed to address the challenge of poorly soluble drugs and other particle engineering manipulation solutions that Hovione is evaluating with the goal to bring these technologies to market to provide companies with options and better results. Being an innovative company with a strong pool of scientists Hovione is very well prepared to take some of these technologies into an industrial reality and providing a real solution to develop innovative products.   Read the article at APR's website.    


An Interview with Marco Gil, PhD

Sep 01, 2018

What is happening to the CMO industry (particularly the pharmaceutical fine chemical industry) looks pretty similar to what it did almost 20 years ago. The attached 13 articles written between 1998 and 2005 -half of which were written by me- recount a well-known story: exuberance and over-investment results in write-offs and losses. What happened then was crystal clear to me when in 1998 someone came with a large cheque book convinced that a $500m API business could be built in 3-5 years. Shortly thereafter a well-known Deutsche Bank analyst’s report made sure the herd mentality took over. By 2005 most of the $15bn or so spent in M&A deals were mostly written off and a number of wonderful brands and several major companies had vanished. It is interesting to note that at the time that some entered the CMO business Honeywell was exiting and said: “...pharmaceutical chemical manufacture is a highly capital intensive business plagued by over-capacity, clinical trial failures, limited new drug approvals, new drug marketing disappointments, and price wars…”  Maybe there is an opportunity to learn from history. The challenge today is to check whether what looks the same is indeed the same, and whether what is really different can contribute to a different outcome. What remains to be seen is whether outsiders understand what they are getting into, and one thing is certain: when the dust settles you will have the usual suspects picking up the pieces. If anything we should be concerned because as of today over $33bn have already been spent in CMO related M&A activity in the last 4 years – in exactly the same pattern as in 1995-7, 1998-2000. Yours, Guy # Title  Type Author Date 1 The API Solution Provider article Guy Villax 1998 2 Aggressive goals - $500m in 3-5 years ppt Solutia 1998 3 Deutsche Bank analyst's report on CMO article DB 1999 4 Hovione in the CPHI show daily 2001 article Guy Villax 2001 5 Pharma Fine Chemicals - Nothing has changed! article Guy Villax 2002 6 Outsourcing: The dust has now settled  article Guy Villax 2002 7 European producers face unique issues article Maureen Rouhi 2005 8 Why Fine Chemical Business Development has failed  ppt Peter Pollak 2005 9 GMP fraud - largest ever penalties in criminal pharma  web 2005 10 Clients, competitors and Consultants  ppt Guy Villax 2005 11 Fine Chemicals Revisited  article Guy Villax 2005 12 5 years after its buying spree…  article Clay Boswell 2005 13 The Gold Sheet  article  Bill Paulson  2006 View the full set of documents (PDF, 8MB)   Guy Villax Hovione +351 917 888 899


Learning From History: For CMOs the Cycle is Back

Nov 10, 2017

Hovione, an established Portuguese pharmaceutical company, has opened a representative office in Osaka in June 2016 and now established Hovione K.K. in February 2017. The company has been engaged in R&D and manufacturing of drug ingredients and compounds for more than 50 years since its foundation in 1959. Its strength lies in its expertise and advanced technology in areas such as inhalation development. It has expanded manufacturing sites in the US, Macau and Ireland. In Japan, Hovione distributes their Active Pharmaceutical Ingredients (API) for generic drugs to major pharmaceutical companies via sales agents, and it is also engaged in contracted development and manufacturing development as well as the particle engineering. Hovione plans to apply for a license of Marketing Authorization Holder (MAH) and to obtain additional sales approval of its API. For the establishment of Hovione’s base in Japan, the JETRO Invest Japan Business Support Center (IBSC) provided support such as consultation (corporate registration, labor affairs and tax matters) and invitation to Japan to assist the establishment of the base. JETRO   ポルトガルの製薬会社Hovioneが大阪に進出 ポルトガルに本社を置く、老舗製薬会社であるHovione が2016年6月、大阪に日本駐在員事務所を開設し、 2017年2月にホビオン株式会社を設立した。 同社は、1959年の創業以来50年以上にわたり、原薬や化合物の研究開発と製造を行っており、特に吸入剤などの分野で高い技術を持っている。海外では、米国、マカオ、アイルランドにも製造工場を保有。日本では、代理店経由で大手製薬会社を対象に主にジェネリック医薬品(後発薬)向け原薬販売を行っているほか、受託開発製造、粒度設計などにも従事している。 今後は日本法人の医薬品製造販売認可や日本で販売する原薬の追加承認申請等を進めていく。 日本拠点設立に際し、ジェトロ対日投資・ビジネスサポートセンター(IBSC)は、拠点設立にかかるコンサルテーション(登記・労務・税務)、個別招へい等支援を行った。 JETRO / ジェトロ


Hovione establishes presence in Osaka

Mar 17, 2017

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