By late 2016, Libbs Farmacêutica will inaugurate a new plant to produce biologic medicines and biosimilars – state-of-the-art drugs designed to treat complex illnesses such as cancer, rheumatoid arthritis and other autoimmune diseases. The unit, christened Biotec, was designed as a platform for the development, production and export of biomedicines. It will have the capacity to produce 400 kilograms of biosimilars per year once all lines are in operation. The plant has received R$227 million in funding from the Brazilian Development Bank (BNDES) to build the facility, and another R$250 million from the Brazilian Innovation Agency (FINEP), associated with the Ministry of Science, Technology, Innovation and Communications (MCTIC) to perform clinical studies on the first medicines to be produced at the unit. Construction of the plant took 18 months, and three additional months were needed to install and certify equipment.
Biopharmaceutical is the name given to medicines produced by means of a biological process. Included among these are medicines obtained using biotechnology pathways, in which the active ingredient is extracted from microorganisms or genetically modified animal cells. The active ingredient in these cases is a therapeutic recombinant protein. An example of these are recombinant monoclonal antibodies that have a high degree of specificity for their targets inside the body – in this case, receptors found in cells affected by the disease – with less involvement of the structure and function of healthy cells. The global market for biomedicines, products that began being developed in the 1980s, is estimated at US$160 billion a year.
|São Paulo, SP|
|Nº of employees|
|Medicines for cardiovascular, oncological and dermatological diseases in addition to drugs used in transplants|
Libbs’ initial focus will be on producing biosimilars, which are medicines similar to innovative biologics, but that have subtle differences in their chemical, physical, structural and biological properties. “The difference between biosimilars and innovative biologics is in the strategy used for their development. Biologics are generally created for an unmet medical need, a new target, involving a different mechanism of action. Biosimilars, however, are copies of these innovative products and they follow a regulatory path that involves comparison with the original product in order to prove the physical-chemical, structural and biological biosimilarity. They also need to undergo comparisons in animal and clinical studies to prove that they present the same safety and efficacy as the original biologic,” explains pharmacist Fernanda Monteiro Kapritchkoff, a specialist in external research and development (R&D) at Libbs, and leader of the company’s technology transfer project involving recombinant monoclonal antibodies. “Biosimilars can only be marketed when the patent on the innovative biologic expires, and after approval of the registration dossier—for biosimilars, that includes, in addition to modules that are common to biological products, a comparative study of the molecules in vitro, along with preclinical and clinical studies—by regulatory agencies, in Brazil’s case, the Brazilian Health Surveillance Agency (ANVISA),” she adds.
Biosimilar for lymphoma
The first medication to be manufactured at Biotec will be the biosimilar rituximab. The original drug, sold in Brazil as MabThera, was developed by the U.S. company Genentech and distributed by Swiss pharmaceutical Roche in 1998. It is a monoclonal antibody indicated for the treatment of non-Hodgkin’s lymphoma – a cancer of the lymphatic system –, rheumatoid arthritis and other autoimmune diseases. Antibodies are molecules produced by the immune system that bind to a specific target in the body of the patient. Recombinant monoclonal antibodies are derived from a clone of a mammalian cell that after genetic modification in which it receives the gene that encodes the antibody, becomes capable of synthesizing such molecules, which will serve as a specific target of interest in the human body.
“For now, we’re producing engineering batches of the medicine. The ANVISA registration process will take place after we complete the clinical studies that are currently underway,” says Giuliano Barissa, Libbs’ manager of external R&D, the unit responsible for managing R&D activities involving partnerships with companies, research centers and universities. He explains that the project to produce the drug was made possible by a technology transfer from the Spanish pharmaceutical company mAbxience, responsible for developing the biosimilar molecule. Under the agreement, Libbs became accountable for some of the clinical tests and acquired the rights to sell the drug in Brazil.
At Biotec, Libbs plans to produce five other biosimilars, indicated for the treatment of cancer and autoimmune diseases: adalimumab, bevacizumab, etanercept, palivizumab and trastuzumab. All of them are the focus of Productive Development Partnerships (PDPs), a Ministry of Health incentive program to promote domestic production of drugs and medicines. To do this, the Ministry provides for the transfer of knowledge – in this case, the biopharmaceutical manufacturing process – to public laboratories such as the Butantan Institute of São Paulo and the Oswaldo Cruz Foundation (Fiocruz) of Rio de Janeiro. In the case of Libbs, the partnership is with the Butantan Institute for a period of five years in which the Institute can produce the medicine along with the company. “Biomedicines produced in Brazil using PDPs will reduce the country’s dependence on high-cost imports,” Kapritchkoff points out. Today, 51% of what the Ministry of Health spends on medicines – an estimated total sum of R$15 billion for 2016 – is allocated to biological products.
When it begins operations, Biotec will be one of South America’s largest and most modern biopharmaceutical companies. It will employ an innovative technology known as single-use (disposable). In the conventional process, medicines are manufactured in stainless steel bioreactors that are required to undergo a cleaning process at the end of each production lot. In the Libbs single-use system, the stainless steel of the bioreactor is simply a wrapper that serves as support for the plastic disposable bags in which the cultivation of cell cultures and the production of monoclonal antibodies takes place, and it never comes into contact with the medium or the product. “The technology offers greater flexibility in the manufacturing process,” says chemist Patrícia Tambarussi Baraldi, manager of chemical development at Libbs. “This eliminates the waste of large volumes of water for cleaning as required in conventional systems. It also avoids the need for validation steps in the sanitation process, so we end up gaining in terms of time and cost,” Baraldi explains.
The new plant is being installed at the Libbs industrial complex in the city of Embu das Artes, in Greater São Paulo, on a site measuring 150,000 square meters, already home to pharmaceutical and pharmochemical plants responsible for the production of medicines and pharmaceutical inputs, respectively – assets that supply the plant –, as well as the Integrated Development Center (CDI), which is the company’s R&D unit. Voted best pharmaceutical company in Brazil in 2015 and 2016 by Anuário Época Negócios 360o, Libbs sells 87 medicines designed to treat cardiovascular, gynecological, oncological, respiratory and dermatological diseases.
In addition to Libbs, other pharmaceutical companies based in Brazil are in the process of developing biopharmaceutical drugs, especially biosimilars. These include BioNovis, a joint venture by the laboratories Aché, EMS, Hypermarcas and União Química, Orygen Biotecnologia, which comprises Eurofarma and Biolab, as well as the companies Cristália and Recepta. Last year, Eurofarma obtained ANVISA approval to produce Fiprima, whose active ingredient is filgrastim. The first biosimilar medicine developed completely in Brazil, Fiprima – a version of medication originally developed by Roche – is indicated for patients with immune system problems that arise from chemotherapy treatment.
Founded in 1958, Libbs ranks ninth in value among laboratories in Brazil’s retail pharmaceutical market, according to the consulting firm IMS Health, based on data from the first seven months of 2016. The 100% domestic company has 2,500 employees and generated earnings of R$1.33 billion in 2015. In the first six months of 2016, it registered 16.6% growth in gross income compared to the same period in 2015. The company invests 17% of its annual earnings in research, development and innovation. The R&D unit is divided into four departments: pharmaceutical, chemical and analytical development along with external development in new business, and it works with nearly 120 collaborators, including biologists, pharmacists, biotechnologists and chemists. Ten percent of the company’s researchers hold PhDs and 6% hold master’s degrees in various fields such as pharmacy, biotechnology and chemistry.