INDEFAR: a pilot plant for the production of national drugs
CONICET/DICYT The Research and Development Platform for the Development of Pharmochemical and Pharmaceutical Processes (INDEFAR in Spanish) – constituted by the CONICET, the National Institute for Industrial Technology (INTI) and the Universidad de Quilmes– was designed to promote the national production of medicine, develop new drugs and train human resources. It also provides Research and Development (R+D) services to meet the requirements of different private and public companies.
INDEFAR emerged as a result of a call issued by the Ministry of Science, Technology and Productive Innovation in which scientists were invited to present projects of services related to organic chemistry and pharmaceutics, in order to have a pilot plant in the public sector.
One of them was created by Julieta Comin of INTI QUÍMICA, director of the project and associate researcher at the CONICET, linked to the Laboratorio de Biocatálisis y Biotransformaciones of the Universidad de Quilmes (UNQ) [Biocatalysis and Biotransformations Laboratory of the Universidad de Quilmes (UNQ), where Adolfo Iribarren, CONICET principal researcher, and Elisabeth Lewkowicz, independent researcher of the Council-, and the Unidad de Microanálisis y Métodos Físicos Aplicados a la Química Orgánica (UMYMFOR, CONICET-FCEN-UBA), with the participation of Javier Ramirez and Pau Arroyo Mañez.
The main objective is to increase work capabilities to rise up the laboratory scale-up and make the plant run with good practices so as to have the results transferred to companies. “It is possible to synthesize a drug or molecule in different scales, for instance, in the laboratory we use small flasks up to 2,5 or 10 litres but to produce larger quantities, it is necessary to change the scale-up. This involves the development of processes to adapt them to variables that begin to be different. There are things that become visible when they are in a larger scale so we have to optimize the process to make it scalable, that is to say, make it profitable and possible to be reproduced”, Lucía Gandolfi Donadio, CONICET assistant researcher at the INTI, explains.
They are currently working to improve the capecitabine (see box) synthesis, a chemotherapy drug against breast and colon cancer. Besides, the scientists aim to enhance benznidazole, a compound used to treat Chagas disease, which was not produced any more by the international laboratory that used to do it, and began to be produced in national laboratories that took the information from the first one. “We study some alternatives to make this process more efficient”, Comin explains.
As an example of the studies conducted after some consultations that come from research and development of companies that aim to improve the production of drugs or active principles, the researcher explains: “We are currently making a scaling of a compound to treat ocular herpes. We also have some lines of work to synthesize molecules that serve to study biological processes or to be possible drug candidates for cancer treatments”, the researcher describes.
For his part, Gandolfi Donadio comments that he conducts a study about the carbohydrate synthesis that would serve to test vaccines against leishmaniasis disease in rodents, canines and humans, so there is great therapeutic interest. “Carbohydrates are part of the cover of the parasite and it is known that this oligosaccharide mother, where the part I am synthesizing is, generates antibodies. This oliglosaccharide is called LPG and there are experimental vaccines based on LPG extracted from the parasite. The idea is to synthesize and test if there is reaction and study what part of that macromolecule produces immune response. First, it is necessary to try if it is useful or not. If it is, it is possible to think about a therapy based on oligosaccharides”, the scientist affirms.
It is also worth mentioning the coordination of INDEFAR. After some meetings with the Agencia Nacional de Laboratorios Públicos (ANLAP) [National Agency of Public Laboratories], the aim is to reach the national development of high cost active principles such as sofosbuvir and tenofovir – new generation drugs used to treat hepatitis C and HIV respectively.
Furthermore, through the recent signature of a cooperation agreement between the INTI and ANMAT, INDEFAR participates in the Programa de Desarrollo de Sustancias de Referencia – directed by the INAME- providing its synthesis capabilities and analytic chemistry for the national development of impurity patterns of necessary process for quality control of raw materials and drugs in the pharmaceutical industry.
Comin’s team has recently received an honourable mention in the TECNO INTI 2015 conferences for the capecitabine synthesis, an Active Pharmaceutical Ingredient (API) used for the treatment of patients with colorectal and breast cancer. The studies managed to simplify and scale a method to obtain the drug through the research and optimization of a new synthesis route, which was first developed by the UMYMFOR (CONICET-UBA) as part of a project that emerged after the need of a company that produced the drug. The study aimed to enhance each of its steps, simplify and eliminate operations and make them scalable. The capecitabine is imported mainly from China and India. The objective is to substitute its import with these developments in the future.