Production of vaccines, issue of national sovereignty

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By RAQUEL DE LIMA CAMARGO GIORDANO, RENATO MANCINI ASTRAY, ROBERTO DE CAMPOS GIORDANO, TERESA CRISTINA ZANGIROLAMI & VIVIANE MAIMONI GONÇALVES*

Why are we not self-sufficient in the production of vaccines – and biopharmaceuticals more broadly?

In June 2021, we continue to witness, with regret, the biggest health crisis in our history. It is common knowledge that Brazil has a structure for vaccination that is unique worldwide, already tested on other occasions, the National Immunization Program (PNI)[I], inserted in the Unified Health System, SUS. However, an indispensable requirement to set this machine in motion is the availability of vaccines.

We have large parks set up for the industrial production of immunobiologicals in Bio-Manguinhos/Fundação Oswaldo Cruz and at Instituto Butantan, two public institutions that are a source of pride for the Brazilian people – along with other smaller institutions across the country. However, in the midst of this pandemic, we find ourselves dependent on the import of active pharmaceutical ingredients (APIs)[ii] or even the product already formulated, only to be bottled in Brazil. This is despite the fact that we also have centers of excellence in basic research at various universities and public institutes, with the capacity to develop different solutions for this vaccine.

The work of these groups continues today, but turning these proposals into an available product to fight COVID-19 will take longer than most vaccines already available and the more than 100 candidates currently in clinical trials around the world. At the time we write this text, no vaccine developed mainly in Brazil or with national technology is in phase III clinical trials. Thus, we are at the mercy of erratic and therefore inefficient policies and the productive capacity of other countries to obtain vaccines abroad.

Why are we not self-sufficient in the production of vaccines – and biopharmaceuticals more broadly? How can this national security issue be resolved? We interviewed several actors involved in the development and production of biological medicines in Brazil to understand this situation, as can be seen in the acknowledgments at the end of this text. Their contributions were invaluable to this reflection. The ideas that follow, however, are solely the responsibility of the authors, who sought to take a transversal look at the problem, integrating its multiple facets also from the perspective of engineering and industrial production processes. We thought, with this, to contribute to the debate already carried out by ABC's GT-Vaccines.[iii]

Establishing a State Policy for the production of vaccines with national technology will undoubtedly depend on complex political decisions that address the various dimensions of the problem. Here, we raise some topics that we understand as structuring: the conception of a vertical productive chain; the regulatory issue; the issue of funding, including the proactive use of government purchasing power (Ministry of Health, MS/SUS); technology transfer in biopharmaceuticals, as proposed by the Partnerships for Productive Development (PDPs) program[iv]; the problem of having a critical mass of highly qualified personnel. These ideas are summarized below.

Consolidation of a productive chain as a State policy

There have been, in the past, attempts to build self-sufficiency in vaccines in Brazil, such as the National Self-sufficiency Program in Immunobiologicals (PASNI)[v]. However, until today, we have not been able to implement an integrated system, based on national technologies, with the capacity to dominate the entire arc that goes from basic science to industrial technology. On the contrary, in recent decades the technology transfer approach has become increasingly dominant (as is now the case with Butantan's and FioCruz's anti-SARS-COV-2 vaccines). There are, therefore, several bottlenecks to face, but we believe that the best way to overcome them is to think about the problem in a systemic way: it is necessary to consolidate a system of science, technology, innovation and industrial production, based on State Policies (and not just of government) consistent, and integrated with the sectors of the economy that can contribute to this task.

Vaccine production demands a complex structure, ranging from basic science groups that develop new proposals for immunizers, to large-scale industrial units. This chain needs to be present in the country, although contracting services abroad and importing inputs will probably continue to occur in the long term.

The first link in this chain is the highly qualified research groups in biotechnology in silico molecular biology, and test planning and analysis in vivo. In this respect, universities and public research institutes in Brazil already have important competence, established in decades of hard work. The issue here is funding, for maintaining these groups and expanding their numbers.

Unfortunately today we have a very bad situation in the country[vi], whose rapid overcoming will be essential for us not to lose this intellectual heritage.

These groups, however, need to be linked to the sequence of the chain. There must be a connection between basic research and the development and improvement of the industrial process, which will allow for an increase in production scale. In other words, we believe that there is a lack of articulation between antigen discovery and bioprocess engineering. It is necessary to design a large-scale production process, going from upstream (preparation of inputs, maintenance of cell banks, among many other operations), going through bioreactors (from embryonated eggs to animal cell cultures), to the downstream (active ingredient separation and purification, stabilizing formulation, choice of adjuvants, vaccine filling). Simultaneously, an analysis of technoeconomic viability (and environmental impacts too, why not?) must be carried out from the first conception of the process. This articulation, now sparse or non-existent, will make it possible to go back to the initial stages of development when necessary, in an interactive process to increase production, stability, quality and cost-effectiveness. This includes feedback between process and molecular biology people, eventually even “going back to the drawing board” to remake a clone to meet traits that will be important for industrial API processing. These elements are part of the daily life of companies producing medicines and vaccines in the world. It is no coincidence that several vaccines against SARS-CoV-2 currently in use, or that will be approved in a short time, originated in large pharmaceutical companies allied with biotechnology companies, whose integrated view of these stages allows rapid progress in development of technology.

In addition, before reaching the industrial process, it is necessary to produce batches for clinical trials under conditions of good manufacturing practices, an essential intermediate step that requires the bioprocess to be already defined, so that it can then be implemented in laboratories specially built and operating at high cost, using a solid quality environment, and demanding investment in process validations and analytical tests[vii].

International experience indicates that there is a need to articulate several of these stages with multiple agents. It is not normally the final producer who performs them alone. Contracting manufacturing services (CMOs, for manufacturing contracting organizations) and research services (CROs, research contracting organizations) is a common practice in this field. Thus, a State Policy must necessarily include the stimulus to the nucleation of national companies of this type.

On the other hand, production itself demands inputs and services that can, to a large extent, be provided by small-medium-sized companies, including start-ups e spin-offs. Services and products can be contracted from these companies, with encouragement from the government through national participation clauses in government contracts, for example. Analytical tests, highly specialized inputs (such as resins, membranes, reagents), not to mention equipment (both for production units and for analyses) are today essentially imported, and this picture needs to be gradually changed. We believe that a major obstacle here may be having qualified personnel. It is necessary to organize an attractive environment for the staff we train in our public universities – and who, many times, find it difficult to be placed in the market. We need to attract brains, from Brazilian men and women who sought opportunities abroad, and also from qualified foreign professionals.

A government program that stimulates and finances groups and companies to carry out engineering, perhaps in a conception that is inspired by the experience of the PDPs – but with a guarantee of continuity (without judicial interruptions), we reiterate, as a State Policy – ​​can be a solution to help to fill this gap. There are already consolidated experiences in this area, such as, for example, the PIPE-FAPESP program for financing small high-tech companies, which can be incorporated. Mainly in this environment are the best opportunities for Brazil to develop innovative technological platforms, opening the possibility for the proposition and perhaps the rapid development of national solutions to our challenges. What would the Zika outbreak have been like years ago, if the country had even had a rapidly developing technological platform for proposing a vaccine? Clearly, the dimension of the global problem of the COVID-19 pandemic provided us with an opportunity to face the situation with vaccines produced abroad, which did not happen with the Zika outbreak, which was restricted to Latin American countries, offering little risk to countries of the global North. The difference that a State Policy makes in this context is clearly exemplified by the Oxford vaccine. It was the UK government that injected research funds for years into that University for the development of a platform. The result was seen in practice, when the United Kingdom became one of the first countries to have high vaccination coverage rates against COVID-19.

The final link in the production chain is the industrial units. We believe that a consistent policy should be based on the production structure that we already have in public institutions. Evidently, alternatives in the private sector could also be encouraged, as important support. Likewise, technology transfer, which will certainly continue, cannot be stigmatized as an alternative solution, although it should not be an obstacle to national development.[viii]. But we defend that the support of our autonomy will have public institutes such as Butantan and FioCruz as its backbone. However, the governance of these institutions must be modified. Certainly, its research labs need to be supported and expanded (as part of the first link in the chain, already mentioned). But production has another scope, requiring administrative agility and flexibility. Just to give an example, Bio-Manguinhos is now one of the sixteen technical-scientific units of the Oswaldo Cruz Foundation. This implies the need to comply with the bidding law 8666/93, which governs public sector purchases. The Butantan Foundation has a similar profile. These bonds have to be untied. Operating a plant serving 8666 becomes an arduous exercise in skill and adaptation. A huge effort, which could be focused on improving processes and products, needs to be invested in purchases and bids for works, for example. And often with very bad results. Part of the tragic anecdote in the sector is the purchase of gloves at the lowest price, which, due to their constant defects, force technicians to use two of them overlapping. Or the contracting of works requiring high specialization, also at the lowest price, done against the will of the contractors, future users, resulting in a bid won by a company that had “informal links” with builders already prosecuted for not having delivered a similar work within the specifications. Dantesque situations that need to be overcome with a reformulation of legislation. Just as it makes no sense to use law 8666 for research activities at universities and public institutes, it makes no sense to use it for industrial purchases. The same can be said of processes for importing material for research. An urgent overhaul of the legal framework is needed. It is lethal for projects and for competitiveness to have to wait, sometimes for months, for an essential research reagent.

On the other hand, the administrative structure of public institutes, at least with regard to the production sectors, needs to be changed. There are already proposals matured by the industry community, such as the transformation of Bio-Manguinhos into a public company[ix], fully controlled by the State. This discussion urgently needs to be deepened.

The regulatory issue

This is a very sensitive issue. Anvisa undoubtedly plays an essential role in guaranteeing the quality of the products offered to the population, and nobody can defend a relaxation of criteria that could be harmful to this mission. On the other hand, we believe that, respecting these criteria, the action of this agency should also be part of the state policy pro-national vaccines. This policy needs to be seen in a systemic way, with each part of it interconnected to the others. There are several points here that can be analyzed and improved. An example is the accreditation process for laboratories and production units that already work with similar products, which could have a fast track.

On the other hand, the qualification of the staff of this agency is notorious. However, there are models abroad in which the agencies themselves have research laboratories. When laboratories of excellence are not available, including the development of methodologies, the natural tendency is to adopt conservative criteria. And it cannot be denied that the policy of “raising the bar” on these criteria by agencies in central countries, headquarters of large pharmaceutical corporations, can be a surreptitious control strategy on the part of oligopolies[X]. Thus, a technical staff from Anvisa that conducts cutting-edge research can be fundamental to ensure our sovereign industrial policy, critically considering the requirements of agencies in other countries. This proposal would certainly take decades to consolidate. Initially, cooperation agreements with laboratories in centers of excellence at universities/institutes in Brazil and internships abroad would be indispensable, but in the medium term, this change in Anvisa's role, moving from an essentially supervisory agency to formulating analysis and evaluation criteria, may be a very important differentiator for the country.

This whole issue involves an apparent opposition between “wanting the best for the people” and the development of a national industry. This type of challenge was faced by countries that today are the largest suppliers of inputs worldwide, India and China for example. And they are faced on a daily basis by countries with a tradition in biotechnology, but outside the axis of the Western pharmaceutical industry (the big pharma), such as Cuba and Russia. Cooperation agreements with these countries, also in this area, can be of great value. One possibility in Brazil would be the constitution of some kind of scientific council for the consolidation of regulatory policies, with the participation of the national scientific community.

The issue of funding

Funding for a national park for the production of vaccines – or, more generally, for biopharmaceuticals – is obviously a crucial point, and will be the responsibility of the State. BNDES already has a rich history in the construction of PDPs, a program that articulates national private companies in technology transfer agreements with foreign companies, with the public sector through Bio-Manguinhos, Butantan, Tecpar and with the Ministry of Health, for production of biopharmaceuticals. This experience of articulation between sectors can be very important in the construction and financing of a program such as the one outlined here. However, a great difficulty has been felt with regard to the continuity of the PDPs when governments change – hence the importance of having a State Program, not a government one.

A crucial point in this framework is the role of government procurement. The SUS is the major buyer of drugs and immunobiologicals. The government's purchasing power is, therefore, a central element for the economic support of all this construction. A conception that has the lowest price as its sole objective may, apparently, be preferable from the point of view of public accounts, in a liberal economistic view. However, it is necessary to understand that it is up to the Union to give sustainability to the system. The guarantee of purchase of national products, at a fair price, regardless of attempts to dumping made by foreign producers, is the element that will give stability to a proposal of self-sufficiency[xi]. There have already been situations in which the absence of this policy by the Ministry of Health led to the failure of indigenous enterprises – a notorious example was the national recombinant insulin. Today the same insecurity may be hanging in the air for PDP companies. This mistake cannot be repeated; there is a need for government funding to consolidate a complex area such as vaccines. And one of the forms of financing is the purchase guarantee at a fair price. How to build a transparent and efficient pricing system? Once again, the opening of such decisions in committee with the participation of the technical and scientific community, of the institutional representation of the executive and legislative powers, of organized civil society, can be an interesting way to deal with this crucial problem.

Financing of clinical trials, whose planning and execution are already dominated nationally, is another important point. Tests in an initial phase, perhaps even phase I, could also be supported by research funding agencies such as FINEP/CNPq and FAPs, while phases II and III could have state funding sources in BNDES, and eventually in FINEP.

Qualified people

It would be redundant to insist on the importance of having a critical mass of scientists, technicians, researchers from the most diverse areas who interact in this transversal industry. From the medical field to the pharmaceutical field, from engineering to statistics, from biochemistry to bioinformatics. We have a considerable number of training centers in Brazil, at the undergraduate and graduate levels, but we observe that many of these people do not work in industrial biotechnology companies focused on human health.

In addition to seeking to consolidate these training centers, it is necessary to expand them, deepen exchange programs, repatriate brains and attract talent from abroad. The path of stones is known, but there is a lack of a consistent policy that, for decades, promotes the development of these frameworks. The very implementation of a State Program for the consolidation of the national immunobiological industry will be a stimulus in this direction, including the nucleation of new high technology companies, whose presence may be a requirement in proposals submitted to this program.

Finally, we believe that great crises can generate great opportunities. The reindustrialization of Brazil, after a tragic period in our history, full of setbacks, can and should encompass high technology areas, with socio-environmentally correct production systems. Our expectation is that awareness spread nationwide of the importance of having included in this reindustrialization process a biopharmaceutical production park, a sector that can adhere to sustainable production concepts, generating vaccines not only for Brazil, but also for export, notably for neighbors in Latin America, for countries in the global South and in the future for the entire planet. A dream dreamed together, who knows one day becoming reality.

PS The author(s) are immensely grateful for the attention that highly respected specialists have given us in lengthy interviews. Obviously, the ideas presented here are the sole responsibility of the authors, but the contribution of these colleagues greatly enriched our view of the subject. We are therefore grateful to Dr. Antonio Barbosa, Bio-Manguinhos; Prof. Jorge Kalil, FM-USP; Prof. Leda Castilho, Coppe-UFRJ; doctor Luciano Vilela, Biomm; doctor Pedro Palmeira, consultant for pharmaceutical and biotechnology companies; doctor Thiago Mares Guia, Bionovis.

*Raquel de Lima Camargo Giordano is a senior professor at the Department of Chemical Engineering at UFSCar.

*Renato Mancini Astray is a scientific researcher at the Butantan Institute.

*Roberto de Campos Giordano is a senior professor at the Department of Chemical Engineering at UFSCar.

*Teresa Cristina Zangirolami is a senior professor at the Department of Chemical Engineering at UFSCar.

*Viviane Maimoni Goncalves is a scientific researcher at the Butantan Institute.

Notes


[I] The PNI was created in 1973, therefore even before the creation of the SUS by the 1988 Constitution, to which it was promptly incorporated. This program achieved great achievements over the years, such as the 1975 National Vaccination Campaign against Meningococcal Meningitis, when it managed to vaccinate 9 million people in just four days in the metropolitan region of São Paulo, and the elimination of poliomyelitis in Brazil, whose The last case was registered in 1989.

[ii] The active pharmaceutical ingredient is the fundamental substance of the pharmaceutical product; in the case of viral vaccines, it is a molecule, inactive virus, attenuated virus or viral vector, after its production and purification on an industrial scale.

[iii] Vaccines for Brazil. Working Group of the Brazilian Academy of Sciences. April 2021. Available at: http://www.abc.org.br/

[iv] The Partnerships for Productive Development, PDPs, are part of an industrial policy mechanism to expand access to strategic and/or high-cost medicines for the SUS, fostering national development to reduce import costs. The Ministry of Health signs agreements with private laboratories to transfer production technology to public laboratories. During the transfer period, the government guarantees private laboratories exclusivity in the purchase. At the end of the period, the public laboratory becomes the holder of the technology and becomes the producer and supplier of the SUS.

[v] PASNI was created in 1986 to face a huge crisis in the production of immunobiological products in Brazil. The program allowed the recovery of public institutes with the aim of making the country independent in the production of serums and vaccines by 1990, investing in the acquisition of equipment, adaptation of facilities and modernization of production processes (Ibañez, Wen, Fernandes. Self-sufficiency in production of immunobiologicals and the creation of the Biotechnology Center of the Butantan Institute. php?script=sci_arttext&pid=S2007-3&lng=en).

[vi] After a significant increase in R&D expenditures by CAPES, CNPq and FNDCT from 2004, reaching just over R$ 13 billion in 2015, the estimate of federal budgetary execution to support scientific and technological research in Brazil plummeted to just over of R$ 2 billion in 2020, going back to values ​​below those of the year 2000 (Koller, P. Federal investments in research and development: estimates for the period 2000-2020, Technical Note 56, Diset-Ipea. Available at: http:/ /repositorio.ipea.gov.br/bitstream/11058/9656/1/NT_56_Diset_Investimentos%20federais%20em%20pesquisa%20e%20desenvolvimento.pdf)

[vii] Much has been said in the sense that the problem would be the lack of production sites in conditions of good manufacturing practices, without considering that before that it is necessary for the production process to be developed (in addition to the aforementioned ABC, note 4, see also https://www12.senado.leg.br/noticias/infomaterias/2021/02/vacinas-brasileiras-lutam-para-ir-alem-da-pesquisa-basica)

[viii] If, on the one hand, technology transfer is an option to meet the PNI more quickly, since the product, first bottled and then in bulk, is imported during the process, on the other hand, the time to complete the transfer and the Invested resources must be carefully evaluated against the possibility of applying the same resources to local technology development. Furthermore, the time to complete the transfer cannot be so long that the technology or product is obsolete by the end.

[ix] This proposal is detailed in Silva, Soares, De La Veja, Lacerda. Innovation in public management: the construction of the company Bio-Manguinhos, Porto Alegre: Bookman, 2017.

[X] Methods or equipment with greater sensitivity are constantly adopted by large companies, often with high investments, without necessarily having a correlation with the quality of the product, since the detection of 0,1% more or less of an impurity, for example, can have no impact on the effectiveness of the product. Thus, large companies end up pressuring regulatory bodies to adopt increasingly strict criteria that only they can follow.

[xi] In 1995, the imported hepatitis B vaccine cost US$ 8,00 a dose. That year, the Brazilian vaccine for hepatitis B, the first recombinant vaccine produced in Latin America, began to be tested at a health center at USP and, after about five years, the price of the imported vaccine dropped to US$ 0,50, while the estimated cost of producing the national vaccine was US$0,35 (Cerqueira Leite RC, Tendências/Debates, Folha de São Paulo, November 11, 2001)

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