Press Room

Hovione is pleased to announce that it has installed a new state-of-the-art Spray Drying facility to address the latest technology in particle design. The unit, installed at Hovione's API manufacturing plant in Portugal, operates under the most stringent cGMP conditions both as a conventional spray dryer for very fine particles (< 5 - 10µ) and as a fluidized spray dryer for agglomerated, free-flowing dustless materials (100 - 400µ). Supplied and designed by Niro A/S to the most advanced specifications, this multipurpose unit is capable of evaporating 35 to 90 Kg of water per hour and is equipped with two atomizer systems (a pressure nozzle and co-current two-fluid nozzle). The spray dryer is fit to deliver injectable grade APIs and is configured to be "cleaned-in-place", discharging into a classified clean-room. The facility allows Hovione to produce dry solids in either powder, granulate or agglomerate form from liquid feedstocks such as solutions, emulsions and pumpable suspensions. This technology enables continuous production, at low-cost and with a high degree of precision over particle design; it allows control of particle size over a wide range of sizes (< 5 to 400µ), as well as control over bulk density and degree of crystallinity. When operating as a fluidized spray dryer, the unit produces free-flowing dustless materials, which are uniform and can be used directly in tableting. The system meets the most stringent explosion-proof requirements and can therefore spray-dry out of most organic solvents in a safe and compliant environment. It uses nitrogen in a closed cycle as the drying gas thus enhancing its safety and economical production aspects. The spray drying facility is the result of a close collaboration between Hovione and Niro; the supplier of the equipment has described the unit as one of the most flexible and versatile GMP compliant spray-dryers that they have ever built. Hovione will be presenting its new technology and facility at Biofine in Berlin, on May 5th and 6th, stand nr. E3. In its programme to expand scientific know-how in advanced technologies, Hovione is actively developing expertise in other particle design techniques: Supercritical Crystallization - this technology offers a trouble-free separation of the product from the solvent and the capability to control the size and form of the crystals. The principle is based on replacing a conventional solvent with a supercritical fluid, which may act as a solvent or as an anti-solvent. This technique may be used to produce very small particles with narrow size distribution.   Ultra Sound Assisted Crystallization- this technology uses ultrasound to influence crystallization behavior by promoting cavitations within the liquid media, which serve as nuclei for new crystals to form. Benefits can include improved crystal habit, purity and the ability to manipulate crystal-size distribution and powder flow characteristics. It also offers a useful and more controllable alternative to seeding. Hovione is an international group dedicated to the process development and synthesis of APIs (active pharmaceutical ingredients) serving exclusively the pharmaceutical industry. With FDA inspected plants in Europe and the Far East and a Technology Transfer Centre in New Jersey, USA, Hovione is committed to the highest levels of service and quality. Hovione's capabilities include process chemistry, worldwide regulatory affairs, kilo to multi-ton manufacture of complex multi-step chemistry of APIs under FDA and ICH cGMP quality standards. Note: please be informed that we have photos of the spray dryer available, contact us.

Press Release

Hovione launches new Particle Design technology and state-of-the-art Spray Drying facilities

Apr 12, 2004

Carla Vozone, business development manager for generics, and Manuel Lourenço marketing & sales director, of Hovione look at Simvastatin as a case study in the supply of off-patent APIs The supply chain of off-patent APIs has been through a number of changes in the past few years. Originally, independent API suppliers developed, manufactured and sold APIs to supply local generics houses in essentially national markets. Today, there are billion dollar multinational generic houses, vertically integrated into API manufacture and carrying out synthesis and/or fermentation. Sandoz, for example, has owned Biochemie, a world leader in fermentation, for some years. It recently acquired Lek, probably in part to access its fermentation capabilities and so strengthen its position in the generic Augmentin market. Teva recently bought Sicor, as well as some plants from Honeywell. These large groups have multinational distribution and manufacture APIs. Nevertheless, they also source active ingredients from independent producers in the product-by-product collaborations traditional in the generics industry. The selection criteria that the vertically integrated generic firms use for their API product development is unclear. What is certain is that an integrated strategy is only likely to succeed if it is implemented with above average capabilities in its execution along the whole value chain. Teva, for instance, is highly regarded for the way its management maximizes marginal returns; it can access the available production capacity that will make extra production possible for that extra tender at that borderline price and thus improve overall profitability. Another noteworthy trend is the growing business of registration dossiers in Europe. The key differentiators of the players in this field, like Synthon and Substipharm, are know-how in regulatory affairs, careful monitoring of patent situations and an early start. Because of the SPC legislation and the absence of Bolar exemption in Europe, registration houses do their validation lots with the help of Far Eastern API sources and/or formulators in patent-free locations (Iceland, Malta and Turkey have all been used) and sell their registration dossiers all over Europe, thereby gaining significant control over the supply chain. Undoubtedly, this type of business brings short-term gains to the generics houses, because it accelerates market access; companies can enter the market with a generic product one day after patent expiry with minimum resources and avoid the patent constraints that Europe-based producers face. However, the long-term gains are less certain, as multiple registrations lead to price erosion and margins are squeezed. There are cases, like simvastatin, glucophage or paroxetine, where formulation prices dropped by over 60% in only a few months. These vicious downward price spirals raise the question of the API supplier’s sustainability in that product. Traditional suppliers whose core business is the manufacture and supply of APIs, like Dipharma, Esteve, Hovione or Cambrex Profarmaco are not involved in the drug product business and focus on long-term relationships with customers, offering added value based on reliable service and technical expertise. These companies look for partnerships with pharmaceutical manufacturers rather than aiming to extend their control over the supply chain or making a quick buck. The original patent on simvastatin, the API of Merck’s Zocor, expired in May 2003 in most European countries. As one of the top cholesterol lowering agents (HMG CoA reductase inhibitors) with worldwide sales of $5.58 billion in 2002, it naturally attracted the interest of several API producers. It is a good example of industry trends. The generic versions of Zocor were launched in Germany and the UK last May. They rapidly achieved sales of about €30 million in Germany in the first month alone, according to IMS Health. Their performance in the first quarter after launch suggest that the impact of the generic entry may not remain confined to this molecule but might affect the overall statins class market.  Indeed recent price pressures have led to growth in generic lovastatin prescriptions. Generic simvastatin may well cannibalise some of the sales of Pfizer’s Lipitor, if not Merck and SP’s Zetia. We are currently two years away from generic simvastatin’s entry in the US, where some 45 tonnes of API were sold in 2002. Traditionally, the volume of scripts more than doubles and the price more than halves after a generic market entry, so simvastatin might well grow into a product of >100 tonnes/year. Capacity is very likely to be an enduring issue, because simvastatin is technically difficult to make and lovastatin supplies are limited.

Press Release

The APIs supply chain: A case study

Mar 02, 2004

Hovione for CPhI 2003 Sticking to your knitting... When the going gets tough, Guy Villax, CEO of Hovione, argues the importance of keeping your business focused Business conditions are tough. The pharmaceutical fine chemicals sector is now heading South, the largest players -even the Rolls-Royces of the industry- have announced lay-offs and issued profit warnings. Two years have not elapsed since CPhI was throbbing with the excitement of billion dollar acquisitions: BTP, Catalytica, Chirex... A time when the exuberant optimism of the stock-markets made anything possible. This was a period of major re-structuring not just for the fine chemical sector but also of the pharma sectors. Relentless focus on their core-business of prescription medicines led Pharma Giants to spin-off a number of big businesses: non-prescription medicines, chemicals, fragrances, etc… and overnight new multi-billion dollar companies appeared. Large pharma concentration was driven by both a desire to grow sales forces and to address R&D pipeline issues (whether for lack of innovation or to address a block-buster patent expiry calendar). During this time the Biotech sector had a tough time getting funding, the IPO markets dried up and the private equity firms, unfairly, looked at drug development with the biased look of someone who just got burnt by a dot.com. Generics were quietly booming. As a result for those making APIs the short term horizon looks grim, except for those that serve the generics industry. Over the past 5 years most fine chemicals company invested in GMP facilities. In addition to billions spent in mergers and acquisitions, there was also a genuine expansion in capacity. If there is now a cycle in this business, then 2003 is clearly in the downward slope. No one talks of growth. Those with empty vessels offer very aggressive, and in my mind unsustainable, prices - this is particularly noticeable of smaller firms that were taken over by chemical giants. In exclusive manufacturing - is the problem structural or cyclical? There is certainly a structural part to the issue: in the past 7 years the number of compounds in Phase I and II have grown at a CAGR of 9 and 6% respectively - whereas Phase III compounds are unchanged at 500, with zero growth. Approved genuine NCEs numbered only 17 last year, but averaged about 30 in the previous years. Sir Michael Rawlins who chairs the UK government body that monitors the cost-effectiveness of medicines recently told a conference that the cost of development of new medicine was becoming “unsustainable”, and that unless regulators backed-off "by the year 2015 we will not have any new NCEs". There is also a cyclical component - capacity has to adjust. In addition to the lay-offs there will be plant closures. At least one European based multinational is looking to close half its primary plants in its home country. On the other hand we can be sure that capital expenditure will be dramatically cut this year and for the next few years, and we all know that without investment a GMP primary plant goes out of compliance in just a few years. Indeed nothing causes obsolescence faster than GMP design. Where does this leave us? I think that those that are totally dedicated and committed to pharmaceutical APIs will plough through. These are usually private companies, well capitalized and well-entrenched in preferred supplier lists. But especially they are not subjected to the pressure of quarterly reports or stock-markets, as such they will weather the storm better than those that have to tack to short term winds. Customers know only too well that cut-throat pricing is not a good indicator of long-term survival, and although they will take advantage of it, they will not burn bridges with the suppliers that were there over time, solved problems and delivered the occasional miracle. The other advantage that the private firms have is that they walk on two legs - they serve both the exclusive manufacturing sector as well as the generic sector, and they benefit from the manufacturing synergies offered by the combination. Generics are up - a significant number of products will come off patent from over the next few years. Now to the companies that discovered that getting into exclusive manufacturing was an expensive mistake, I would say they should be just as careful if they think they will find a quick fix in the generic API business. Hovione's generic development methodology sets as rule Nº1 to start early - this means that from the start of a development program you will have to wait at least 7 years for your first invoice. About the same time as going from Phase I to launch - and in generics there are no development fees! It is all a question of sticking to your knitting; a question of focus. Guy Villax Chief Executive

Article

Sticking to your knitting...

Sep 23, 2003

Hovione for CPhI 2003 Cholesterol lowering agents (HMG CoA reductase inhibitors) recorded sales close to US$19 bil. in 2002 according to IMS Health figures. Atorvastatin from Pfizer and Simvastatin from Merck are the top two drugs of this therapeutic class, indeed they rank in the top two drugs in sales worldwide. They account for 71% of this market followed by Bristol-Myers Squibb’s Pravastatin. In the US alone the statins reached sales of nearly US$12 bil. in 2002 – well over one hundred tons of API. The generic versions of Merck’s Zocor®, the second biggest product in worldwide sales, entered the German and UK markets last May, after Merck’s patent expired, rapidly achieving sales of about Euro 30 mil. in Germany in the first month alone (IMS Health). The performance of the generic versions of simvastatin in the first quarter after launch already suggested that the impact of the generic entry may not stay confined to this molecule, but might affect the overall statins class market. Indeed recent price pressures have seen growth in generic lovastatin prescriptions; which might indicate that generic simvastatin is likely to cannibalise some of the sales of Lipitor, if not even Zetia… We are currently 2 years away from the simvastatin generic entry in the US, where approximately 40 tonnes of API were sold in 2002. Traditionally, after a US generic entry the volume of scripts more than doubles and the price more than halves. It should not come as a surprise that simvastatin might grow into a product of more than 100 tons of API. Capacity is very likely to be an enduring issue because simvastatin is technically difficult to make and the supplies of lovastatin limited. European pharmaceutical generic companies entered the market using registrations developed outside Europe by integrated houses able to make the API and the formulations. This is a normal course of action in Europe and enabled a very fast access to the market. As the quick entry focus looses ground to serving the market and expanding share – reliable supply will become a major concern. The competitive landscape looks to us to be as follows: * : The issue as to whether a supplier is a “partner or a competitor” is a very sensitive one. In the USA this is addressed earlier than Europe as most Generic firms usually develop their dossiers and source bulk. However given the high probability of a scenario of simvastatin API shortage it is very likely that an integrated player -both API producer and seller of formulations- will give preference to its own needs, to the detriment of supplying other generic firms. Choosing the right API supplier has significant long-term impact. Hovione is fully committed to supplying simvastatin bulk, and has no involvement in the dosage form business. This position, allied with a strong partnership with CKD that ensures the control and supply of the Lovastatin starting material, enables Hovione to present to customers a unique differentiation that guarantees a reliable supply of simvastatin API.

Article

Simvastatin - Supply Chain Reliability

Sep 23, 2003

Hovione for CPhI 2003 The service of an API manufacturer not only involves the development of the chemical process and the supply of high quality API, when and where required, but also paying close attention to those physical parameters which make up the necessary requisites for a successful formulation. Chemical skills must be complemented by a pharmaceutical culture. For a successful custom synthesis partnership it is imperative that the API contractor be both cognizant of the importance of having the correct particle size and morphology, and be able to develop a process that delivers consistently the required crystal form and size. This is key in many galenic forms; in the field of inhalation for instance it is absolutely critical; it can also be the source of many last-minute surprises and frustrations until the matter is well controlled. Traditional know-how includes: expertise in controlled crystallisation, micronization and jet milling. These are skills that Hovione has used for decades in its plants to achieve the desired crystal form and consistent particle size. All of this needs to be backed up with analytical techniques, including laser diffractometry and impaction, used in a manufacturing scenario, to assure the necessary QC controls. But technology moves on…. Hovione is pleased to announce it is installing a state of the art Spray Drying facility, capable of evaporating 35 to 90 Kg of water per hour under the most stringent cGMP conditions. The supplier of the Spray Drier, Niro A/S has designed this to the most advanced specifications. It is equipped with two atomizer systems (a rotary and co-current two-fluid nozzle) to deliver injectable grade APIs and is configured to be “cleaned-in-place” it discharges into a classified clean-room. This multipurpose unit was the result of a close collaboration with Niro and allows Hovione to produce dry solids in either powder, granulate or agglomerate form from liquid feedstocks such as solutions, emulsions and pumpable suspensions. This technology will enable continuous production, at low-cost and with a high degree of precision, over a wide range of particle sizes. The system meets explosion-proof requirements and can therefore spray-dry out of most organic solvents in a safe and compliant environment. Niro has described the unit as one of the most flexible and versatile GMP compliant spray-driers that they have ever built. Continuing its programme to expand scientific know-how in advanced technologies, Hovione is actively developing expertise in other particle design techniques: Supercritical Crystallization and Sono-crystallization. Supercritical crystallization offers a trouble-free separation of the product from the solvent and the capability to control the size and form of the crystals. The principle is based on replacing a conventional solvent with a supercritical fluid, which may act as a solvent or as an anti-solvent. This technique may be used to produce very small particles with narrow size distribution. Sono-crystallization uses ultrasound to influence crystallization behaviour by promoting cavitations within the liquid media, which serve as nuclei for new crystals to form. Benefits can include improved crystal habit, purity and the ability to manipulate crystal-size distribution and powder flow characteristics. It also offers a useful and more controllable alternative to seeding.

Article

Particle Design, New Technologies for Better Crystals

Sep 19, 2003

New Generic Drug Developments Mometasone: Hovione’s DMF has been filed worldwide; it had been accessed and all deficiencies satisfactorily and promptly addressed. The relevant pre-approval inspection did not result in a Form 483 being issued. The product is now in routine manufacture   Fluticasone: Hovione filed a DMF for Fluticasone at the FDA in 2002. This product is currently in commercial manufacture addressing the needs of 3rd parties for early intermediates and API for use in clinical supplies and registration. Fluticasone was developed by Glaxo Wellcome and is currently marketed as Flonase®, Flovent® and Cutivate® by GlaxoSmithKline. Its worldwide sales amount to USD3bn.   Simvastatin: Validation for this new generic compound as been successfully completed and a DMF has been filed. Hovione and CKD Bio, a Korean Company with extensive experience in fermentation of APIs, have established a joint collaboration to produce and market Simvastatin. This collaboration guarantees an integrated supply chain for Simvastatin with CKD Bio producing lovastatin that Hovione further transforms into Simvastatin. This collaboration has as primary objective manufacturing capacity and reliability of supply. Availability of API and a challenging specification remain the key issues surrounding this block-buster generic – a matter Hovione has addressed. Simvastatin was developed by Merck and is currently marketed as Zocor®, by Merck & Co. and was the largest selling prescription drug in worldwide sales (USD6.67bn) in 2001. The markets of United States, France, Germany, United Kingdom and Japan account for 58 tons of API annual consumption. Capacity increase for production of Minocycline In order to meet market demands, a project to increase the production capacity of minocycline by 40% is currently underway. This increase in the production line installation represents a significant investment, improving solid handling conditions and increasing the hydrogenation, filtration and drying operations. The additional capacity will go on stream as of Q3 2004 in phases and we expect stepwise increases as from the end of this year. Sales: Hovione has announced sales for the year ended 31st March 2003 amounting to US$70. Generic products for multi-customer remain with the largest share, however custom synthesis business continues to grow at a faster rate. Hovione is committed to serving both segments of the pharmaceutical industry with equal priority. Commercial Products Simvastatin  Sancycline Roxithromycin  Ivermectin Methacycline hydrochloride Minocycline hydrochloride Doxycycline hyclate Doxycycline monohydrate  Beclomethasone dipropionate monohydrate Beclomethasone dipropionate Betamethasone dipropionate Betamethasone valerate Betamethasone acetate Betamethasone disodium phosphate Clobetasol propionate Dexamethasone dipropionate Mometasone furoate  Fluticasone propionate Halobetasol propionate  Hovione is an international group dedicated to the process development and synthesis of APIs (active pharmaceutical ingredients) serving exclusively the pharmaceutical industry. With FDA inspected plants in Europe and the Far East and a Technology Transfer Centre in New Jersey,USA, Hovione is committed to the highest levels of service and quality. Hovione’s capabilities include process chemistry, worldwide regulatory affairs, kilo to multi-ton manufacture of complex multi-step chemistry of APIs under FDA and ICH cGMP quality standards. Note: Hovione does not sell or offer to sell products to countries where they are protected by patents.

Press Release

Hovione generic product portfolio update

Sep 15, 2003

Hovione is pleased to announce that its new and latest facility, the Technology Transfer Centre (TTC) located in East Windsor, NJ, is now open and in full operation. The 30.000 sq.feet / 3000m2. state-of-the-art facility consists of process chemistry R&D labs and scale-up facilities to springboard pharmaceutical pipeline products into full commercialization. Headed by Dave Hoffman, the TTC is ideally located just off exit 8 of the New Jersey Turnpike, in close proximity to nine of the world’s major pharmaceutical companies. A Greenfield project, the site now employs 16 people with the capability of expanding up to 45. The TTC offers Hovione’s US based customers process development and scale up services, along with quality control/assurance and regulatory support. The cGMP kilo-lab and pilot plant, aimed at preparing small quantity NCE’s to support customer’s pre-clinical and early phase clinical development, demonstrate processes locally before transferring them to Hovione’s full scale manufacturing plants, in Europe and Asia. The development labs, staffed with multi-disciplinary project teams, allow fast turn around in producing small quantity pre-clinical APIs and investigate emerging technologies for scale-up for incorporation into Hovione’s core capabilities. Process R&D and scale-up studies, carried out in glassware to 22 lt, aim to identify potential problems arising with the industrialization of the synthetic process.   The kilo lab has a capacity to 200 lt in glass-lined reactors and 100 lt Hastelloy® C-22 cryogenic reactors. The kilo-lab develops the industrialization of the process and produce pre-approval quantities for clinical studies in compliance with strict cGMP procedures.   The Pilot Plant, equipped with a 400 lt Hastelloy® C-22 cryogenic reactor and 800 lt glass-lined vessels, produces kilo quantities of API under cGMP. From the pilot plant, a seamless technology transfer of industrial scale quantities is in place for full-scale commercialization. The Finished Goods storage guarantee local stocking in compliance with cGMP of all Hovione APIs for US customers.   Sales, Marketing and Administrative offices communicating via a global IT connection provide a permanent presence and service to US customers, a market that already represents over 60% of Hovione Group sales. The technical capacity of the TTC mimics that of Hovione’s fully commercial quantities for seamless transition to commercial scale production. The TTC is fully integrated into Hovione’s global quality network offering US customers real time data and regulatory support for ongoing production in the manufacturing plants. Operating under the same procedures, company culture and team management, TTC benefits customers with efficient, seamless and cost-effective technology transfer. “The unique design and equipment of our TTC compliments Hovione’s existing facilities in Europe and Asia and allow us to expand upon our core capabilities,” says Dave Hoffman. “Those of us with Hovione in the US are proud to carry on the tradition of excellence in service to the pharmaceutical industry, first established by Ivan Villax over 40 years ago.” Hovione is an independent, privately held, European-based producer of Active Pharmaceutical Ingredients. Hovione is dedicated to the process development, quality and synthesis of APIs, serving exclusively the Pharma industry, Hovione is a specialist in manufacturing difficult to make APIs and Regulated Intermediates under the most stringent controls of safety, quality and environmental protection. Hovione has more than 40 years of experience in chemical processes and, with 500 m3 of reactor capacity, has produced industrially more than 40 APIs.

Press Release

Hovione opens new Technology Transfer Centre in New Jersey

Sep 03, 2003

Hovione and CKD announce joint collaboration to produce and market Simvastatin1 Hovione and CKD Bio Corporation (CKD Bio) have signed an agreement to produce and market simvastatin on a worldwide basis. The joint collaboration will offer the active pharmaceutical ingredient (API) for simvastatin under cGMP to FDA and ICH requirements as well as the registration dossiers for simvastatin tablets for the European and United States markets. Both companies will be offering the product for sale only in countries where such does not represent an infringement of third party patent rights. The collaboration guarantees an integrated supply chain for simvastatin – CKD Bio produces lovastatin that Hovione further transforms into simvastatin. Hovione has exclusive rights to use CKD Bio´s patented process (WO 01/45484 A2) for simvastatin manufacturing. The process validation batches of simvastatin (API) have been concluded, the filings will be ready in Spring 2003 and are suitable for worldwide registration. The joint collaboration offers the market with probably the most competitive integrated manufacturing platform for the reliable supply of simvastatin API for the generic industry. CKD Bio has dedicated a portion of its fermentation capacity to the production of lovastatin. The new complete automated manufacturing building inaugurated in November 2001 in Macao by Hovione is dedicated to the synthesis of simvastatin. This integrated supply assures the generic industry with a reliable supply of simvastatin as well as a competitive price. The two Companies enjoy a long and fruitful business relationship, having collaborated in several projects involving semi-synthesis active ingredients over the last 30 years. The simvastatin project demonstrates the unique synergies, which the two companies benefit from. One with an unparalleled excellence in fermentation and the other with a long history of success in building synthetically on natural products and scaling the processes to industrial manufacture. This strategic integration puts Hovione and CKD Bio in a unique position to guarantee reliability of supply, competitive terms and complete customer support – for both API supply and/or final formulations including all registration requirements. Simvastatin was developed by Merck and is currently marketed as Zocor®, by Merck & Co. and was the largest selling prescription drug in worldwide sales (USD 6.67bn) in 2001. The markets of United States, France, Germany, United Kingdom and Japan account for 58 tons of API annual consumption.   Hovione is an international Group dedicated to the process development and synthesis of APIs, serving exclusively the Pharma industry. With FDA inspected plants in Europe and Asia and a Technology Transfer Centre in New Jersey, Hovione is committed to the highest levels of service and quality. Hovione is a specialist in manufacturing difficult to make APIs and regulated intermediates under the most stringent controls of safety, quality and environmental protection. Hovione has more than 40 years of experience in chemical processes and, with 500 m3 of reactor capacity, has produced industrially more than 50 APIs. CKD Bio is a Korean company established in 1941, with extensive research and production capabilities in the fermentation of active pharmaceutical ingredients. CKD Bio has a fermentation plant in Korea with a total fermentation capacity of 1.200m3. This plant is FDA inspected for several products. CKD Bio exports 30-40% of its production to the United States and Europe. CKD Bio has a division of Pharmaceutical Technology and New Drug Development of the Research Institute, located in Korea.   1 This announcement is not to be construed as a representation or as an offer to sell in those countries where such would constitute an infringement of third parties’ patent rights

Press Release

Hovione and CKD announce joint collaboration to produce and market Simvastatin

Sep 03, 2003

Hovione announces that sales for the year ended 31st March 2003 amounted to US$70m. This represents a growth of 27% on the previous year, and accounts for the Company´s best sales performance ever. Guy Villax, CEO of Hovione noted that “Hovione has successfully delivered on the business plan approved two years ago. In addition to the good performance of the financial indicators a good management of the product portfolio was successfully managed – Hovione now has two distinct business areas – generics and exclusive manufacturing – accounting, respectively, for 2/3 and 1/3 of sales”. The company forecasts an average annual sales growth of around 15% from 2003 to 2006 through organic growth. Over the past 7 years the company’s sales grew at 13% pa, a growth that was financed by the company’s cash flow and bank loans. During 2002, Hovione pursued on schedule its 3 year US$56m investment programme due for completion in 2003. The investment programme addresses a growth strategy directed at strengthening Hovione’s leading world position in the supply of active pharmaceutical ingredients to Pharma Multinationals, the emerging Biotechs and the Generic houses. - The new Technology Transfer Center in New Jersey, USA was concluded on time and budget in September 2002, suitably qualified to enable it to start taking on customer projects in the last quarter of the year. This greenfield project includes a kilo-lab and a pilot plant and provides a permanent presence in the market that already provides over 60% of Hovione Group sales. - At the Loures plant the construction of a cGMP compliant pilot plant started in 2002. This shall provide Hovione with the necessary facilities to be able to continue expanding its process chemistry R&D resources. A first-phase will enter into service before year-end 2003. - In the Taipa facility in Macau manufacturing equipment and validation is now in place for production of injectable grade APIs. This plant has been regularly inspected by the US FDA since 1987 and Hovione is now well equipped to address the growing outsourcing needs of the NASDAQ quoted Biotechs that operate under the virtual company business model. Hovione is an international group dedicated to the process development and synthesis of APIs (active pharmaceutical ingredients) serving exclusively the pharmaceutical industry. With FDA inspected plants in Europe and the Far East and a Technology Transfer Centre in New Jersey, USA, Hovione is committed to the highest levels of service and quality. Hovione’s capabilities include process chemistry, worldwide regulatory affairs, kilo to multi-ton manufacture of complex multi-step chemistry of APIs under FDA and ICH cGMP quality standards.

Press Release

Hovione Group financial results for the year ended 31st March 2003

Jul 30, 2003

Ivan Villax was fond of saying he had left his country aged 23 with a toothbrush in one pocket, a chemical engineering diploma in the other and the Russians at his heels. Born in 1925 in Magyaóvár, a small town in Hungary just East of Vienna, his mother was of Austro-Hungarian landowner stock and his father a Hungarian scientist. In 1948, while the family was in a displaced persons camp in Salzburg, a letter from Professor Victoria Pires, then Secretary of State for Agriculture in the Portuguese government, invited Ivan's father to come to Portugal. Ödon Villax was to help establish an agronomy research center into plant genetics in Portugal such as those he had run in Hungary. Ivan arrived in Lisbon a little later to join his family after working at the Centre de Recherches Agronomiques de Clermont-Ferrand in France. He knew then that antibiotics were to be his future and while in France he had isolated from soil samples some tetracycline producing strains that he later named Streptomyces lusitanus. He joined the Instituto Pasteur de Lisboa in 1952, then one of the leading pharmaceutical laboratories in the country. His first inventions were in the area of chloramphenicol preparation and tetracycline and penicillin fermentation. During this period he made good use of Prof. Maia Loureiro’s equipment, the inventor of submerged aerobic fermentation. This Portuguese technology had been instrumental in solving the industrial challenges of penicillin fermentation during World War 2. In 1958 he wed Diane Du Boulay; and together with two other Hungarians, Nicholas de Horthy and Andrew Onody, they founded Hovione in 1959. During the first 10 years the company was a research laboratory located in the basement of the family house in Lisbon, not far from the American and British embassies. As Ivan made chemistry in test tubes, Diane typed out invoices and for the next 45 years they made an amazing team. A close collaboration developed with Fermentfarma Spa, Milan - a company also run by Hungarian refugees - Villax became the technical director and a minority shareholder. Technology for the fermentation and isolation of tetracyclines was licensed to Imperial Chemical Industries of the UK, National Fermentation of South Africa, and to International rectifier of El Segundo, California among others. In 1967 Rachelle Laboratories bought out Fermentfarma and the proceeds of Ivan Villax’s share were used to build the first Hovione plant in Loures, just outside Lisbon. Growing tired of the unpredictability of fermentation processes, he directed his research efforts to chemical synthesis. In the Loures plant he developed and industrialized an 18 consecutive step process to produce betamethasone and its derivatives, and throughout the 70s Hovione enjoyed a privileged position in Japan, thanks to Villax's independent process patents. As the business grew, and Portugal went through some troubled times after the 1974 revolution, Ivan sent his children to finish their studies in England and started looking for a location for further expansion. A Hong Kong office was established in 1978, and in the same year Hovione's first purchasing visit to the Canton fair took place. One after the other his four children spent a few years working in the Far East; it was all part of giving them the best possible education. By 1982 the Loures plant had expanded and got organised to supply the US generic market with semi-synthetic antibiotics; the Macau plant went on stream in 1985 to provide additional capacity. This was prior to the Roche-Bolar amendment, and at FDA for several years people remembered how samples of doxycycline were provided at 9am at their Fishers Lane Rockville, Maryland offices, and not a minute too early, or too late, before the innovator’s patent expired. In Europe this product generated extensive patent litigation with Pfizer suing a number of Hovione customers in 8 different countries. True to his beliefs, Villax volunteered as co-defendant in every suit. His tenaciousness in the face of such adversity meant he did not give up and eventually the matter was settled out of court in 1992. This dispute diverted Villax’s efforts from following other creative pursuits much to his disappointment; though throughout this time the industry recognized in Hovione a fighting spirit that was a characteristic of its founder. Today the generic industry worldwide benefits from Hovione's efficient processes in the production of many other active ingredients: minocycline, roxithromycin, are products where Hovione retains a leading role in several countries. Ivan Villax was always grateful to the country that welcomed him and allowed him to make a new life. He was happy that in providing generic contrast media Hovione was somehow celebrating Prof. Egas Moniz, a Portuguese Nobel Laureate, the father of angiography. After the fall of the Berlin wall he made frequent visits to Hungary. The Technical University of Budapest, his Alma Mater, awarded him a PhD in recognition for his 40 years of work in pharmaceutical chemistry and he was made a member of the University's Senate. By then he had authored over 100 patents and scientific articles. In 1995 his health started to weaken and he made arrangements for an organised hand-over of his responsibilities. With the business in the hands of a professional management team led by his son Guy, Ivan Villax still came to the Loures plant on a daily basis, keen on being kept informed on the new chemistries and on the performance of the business, and quick to point out any slack in the rigour, discipline or housekeeping in either the labs or the manufacturing facilities. Every year, together with Diane, he visited the Macau plant keen to encourage the younger generation and to acknowledge the service of long-standing staff. In his last years he saw Hovione becoming an important producer of HIV protease inhibitors, a key medicine in the fight against AIDS, and taking an active role in many drug development projects as the provider of the active ingredient. In 2002 Hovione established a pilot plant in New Jersey, not far from Rahway where in the 50s Villax had turned down an offer for a position at Merck's research laboratories. He and Diane traveled the world, whereby he was able to satisfy one of his other passions, collecting plants from exotic locations, planting and nurturing them in his quinta outside Lisbon. This May, after a severe deterioration of his lung condition, Ivan, ever the fighter, ever determined to control his own fate, realized that hospitals and science could do no more for him and asked to be taken home. At his quinta in Manique surrounded by his flowers and his trees, with his children, grand-children and his wife Diane, his life-long partner, he lived another two happy weeks - he died on Friday June 6th. Church services will be celebrated at the Igreja Matriz of Loures at noon, and at the Basilica da Estrela, in Lisbon, at 7pm on June 12th.

Press Release

Ivan Villax, 1925-2003

Jun 06, 2003

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