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CORPORATE RESEARCH

Innovation is the cure

Cristália paves the way to developing new drugs and manufacturing processes

Company directors and researchers in Itapira, from left: Edson Lima, Eduardo Gottardo, Danielle Cavalcante, Kesley de Oliveira, Marcos Alegria, Ney Leite and German Wassermann

Léo Ramos Company directors and researchers in Itapira, from left: Edson Lima, Eduardo Gottardo, Danielle Cavalcante, Kesley de Oliveira, Marcos Alegria, Ney Leite and German WassermannLéo Ramos

An ointment containing collagen, used in treating wounds and burns, was presented at the 2016 BIO International Convention, an important global trade fair and conference held in the U.S. city of San Francisco in June 2016.  Formulated by the pharmaceutical company Cristália, headquartered in Itapira (SP), the drug does not exactly offer anything new in terms of chemical substance or treatment, but it does feature novelty with regard to how it is manufactured.  The drug’s active ingredient, an enzyme once produced only in a culture medium that contained animal protein of the Clostridium histolyticum bacteria is now being produced at Cristália in a plant medium.  “This ensures that it contains no animal protein contaminants,” explains physician Ogari Pacheco, Chairman of the Board of Directors and founding partner of the company.  Another advantage is that its active ingredient that was once imported is now being produced domestically.  “Collagenase provides painless treatment and our biotechnology center has managed to develop the active ingredient in the purest, safest form for patients, which opens the door to international markets.”

“This was the first biotechnological product made from microorganisms from Brazilian biodiversity. It was approved by the Brazilian Health Surveillance Agency (ANVISA) in April 2016.  We received a warm welcome at the BIO Convention and are now planning to market the collagen domestically as well as internationally,” announced chemist Marcos Alegria, biotechnology director for the company, and a former researcher at Alellyx, a biotech firm in the area of sugarcane and oranges, spun off from  the Xyllela fastidiosa Genome Project completed in 2000.  “While pursuing my PhD at USP from 1999-2004, I also took part in sequencing the genome of the Xanthomonas citri bacteria, which causes citrus canker.”

Company
Cristália
R&D center
Itapira, SP
Nº Of employees
3.186 across the business
Principal products
Anesthetics, antipsychotic and erectile dysfunction medications as well as medicinal healing products and burn treatments

Cristália is hoping its bold move with regard to collagenase will turn it into a representative of the Brazilian pharmaceutical industry that not only makes generic and herbal medicines, but also innovates by marketing process technologies and unique active ingredients.  The path to innovation began in 2007 when after seven years of research, the company developed the first Brazilian drug formulated from a novel active ingredient that had passed through all levels of clinical trials and production to arrive at the drug Helleva, then one of only four medications in the world used to treat erectile dysfunction.

Pacheco, a surgeon, says that the company has always embraced innovation. In 1972, as a partner in a psychiatric clinic known as Cristália, in Itapira, Pacheco saw the potential in a city that had several clinics of this type.  He built up Cristália to produce medications for the clinics and went on to produce products that were basically for hospital use such as anesthetics.  According to company information, Cristália is present in 95% of Brazilian hospitals and exports to 30 countries in Latin America, Africa and the Middle East.  Revenue for 2015 was R$1.7 billion with 7% invested in research, development and innovation.  “Eighteen percent of this revenue comes from medications developed here in Brazil,” Pacheco says.  The company has 3,186 employees, including 31 who hold PhDs and 18 who hold master’s degrees and are engaged in research.

Chemical synthesis to produce pharmaceutical inputs at the R&D laboratory

Léo RamosChemical synthesis to produce pharmaceutical inputs at the R&D laboratoryLéo Ramos

“We look for products that are more difficult to produce.  It’s not just about making copies,” says the company founder.  To follow this path, Cristália began to look outwards; seeking ideas from universities and research institutes that it could build upon.  In 2004, the company established a scientific council in collaboration with a former medical school colleague of Pacheco, Dr. Regina Scivoletto, a retired professor at the Institute of Biomedical Sciences (ICB) at USP who serves as council chair.  “Today there are dozens of universities and institutes presenting the council with results of their research or that of their development partners,” Scivoletto says.  The council looks to academia to find ideas for producing medicines. Within the council, researchers from both inside and outside the company introduce projects, which undergo thorough analysis in terms of patents, regulatory requirements and chemical synthesis.  The council is multidisciplinary in nature and includes researchers from USP and from the University of Campinas, (Unicamp), the Federal Universities of Rio de Janeiro (UFRJ), Amazonas (UFAM) and São Paulo (Unifesp).  Sometimes, at universities, the chemical formulation is very good in terms of satisfying therapeutic requirements and wins council approval, but during laboratory tests at Cristália, it exhibits toxicity.

Since 2004, the company has developed 89 patents ­­– on molecules, new uses of drugs and processes ­­– many international in scope.  Cristália’s Center for Research, Development and Innovation, opened in 2009, consists of the New Products Department (DNP) and Research and Innovation Department (P&I) that make use of the same laboratory infrastructure.  One of the products under development in the P&I area is nanostructured mesoporous silica, an adjuvant that can be used as a means for delivering oral vaccines.  Vaccines such as that for hepatitis, now injectable, may in years to come have a version that can be administered through drops, thus reducing application costs.  This type of silica began to take shape in studies conducted by physicist Márcia Carvalho de Abreu Fantini, at the Crystallography Laboratory of the USP Physics Institute, and Osvaldo Augusto Sant’Anna, researcher at the Immunochemistry Laboratory of the Butantan Institute, who devised the substance for the vaccine to fight Hepatitis B.  In 2005, the company and Butantan signed a partnership agreement to develop the vaccine adjuvant.

Analysis of bacterial cultures in the study of new drugs

Léo RamosAnalysis of bacterial cultures in the study of new drugsLéo Ramos

Mesoporous silica also proved to be capable of expanding the population protected by vaccines. Many vaccines do not immunize everyone; sometimes only 90% of people.  “This has been shown to be the case in animals,” says biomedical scientist Danielle Cavalcante, coordinator of Cristália’s Research and Innovation Department.  “Our studies are showing that this type of silica is a platform that can be used in other products.  Particles adhere not only to the surface of the vaccine antigen, but also to the molecules of other drugs,” says Cavalcante.  The product is currently undergoing clinical testing.  She expects mesoporous silica to enter the market in two years.

No toxic effects
Another drug developed at Cristália and already available on the market is Novabupi (bupivacain hydrochloride), a local anesthetic.  “We modified the chemical structure of this substance to eliminate the part that causes toxicity, making the injectable medicine more acceptable, with fewer side effects,” explains pharmacologist Edson Lima, director of Cristália’s Pharmochemical Division, which produces 53% of the active ingredients used by the company.  Lima is a former professor at the Chemical Institute of the Federal University of Rio de Janeiro (IQ-UFRJ) as well as a former researcher at the Institute of Drug Technology (Farmanguinhos), also in Rio de Janeiro.  Molecular modification and rearrangement comprise a product line on which Cristália is increasingly focusing its investment, together with the formulation of new active ingredients.  One of the professionals working in this area is physicist Kesley Moraes de Oliveira, in charge of triage and computer simulation of new molecules.  She worked on the Helleva project and says that the team has already studied more than 180 molecules, and many more are still under analysis.

Reaction calorimeter in the scale-up laboratory

Léo RamosReaction calorimeter in the scale-up laboratoryLéo Ramos

In order to better position itself for the domestic market, the company also focused on the infrastructure involved in manufacturing inputs.  In 2013, it opened a biotechnology center in the same industrial complex situated along the highway that connects Itapira to Lindóia.  There the company is producing three medicines that are currently undergoing clinical trials: the generic monoclonal antibody trastuzumab for treating breast cancer; the protein etanercept, also generic, for treating arthritis and psoriasis; and somatropin, the human growth hormone produced using recombinant DNA technology based on hormone encoder gene cloning.

Collagenase is produced in another plant, which works in anaerobic biotechnology.  All of these initiatives have benefited from the consulting services of Spartaco Astolfi Filho, now a professor at UFAM, and Josef Ernst Thiemann, two former researchers at Biobras, a Minas Gerais company that developed technology to produce human insulin in the late 1970s. That company was bought out by the Danish firm Novo Nordisk in 2001.  The two have also encouraged researchers at Cristália to look to Brazil’s biodiversity for new molecules, including those that could be used to produce new antibiotics.

Cristália Institutions_245

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