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IntroductionThere has been a dramatic global surge in dengue fever (DF) in recent years, with a projected 100-400 million cases annually and large outbreaks expected every 3-4 years. This concerning scenario is in sharp contrast to the very low availability of dengue vaccines to meet this spiraling demand, particularly affecting developing countries in Latin America and Africa. In our study, we aim to identify current vaccine development constraints, from a technological perspective, based on clinical trials and patent landscape data.MethodsThis study was conducted in a two-step methodology. First, candidates and launched products and methods used in the development or as part of DF vaccines were identified from the Cortellis Drug Discovery Intelligence (CDDI) platform. Second, the Derwent Innovation database was used to retrieve patent documents related to dengue vaccines. Data were collected in the period 2014-2024 (to identify the candidate and or launched vaccines) and 2018-2022 (to identify patent documents) with claims involving applications for dengue vaccine development. We presented these descriptive data in the following format: quantitative and qualitative assessments describing the vaccine development scenario and the claimed vaccine technologies.ResultsOur study indicated that 65% of dengue vaccines are still in phase 1 of development. The few current dengue vaccines that have reached phase 3 (1) and launched (2) have shown limited levels of individual protection for one or more dengue serotypes and there is an anemic pipeline of the next generation of more effective tetravalent dengue vaccines. Although the intelligent use of multiple dengue vaccine formulations in immunization campaigns can result in effective protection against all serotypes at the population level, the implementation of this is complex and challenging. The results of our study thus provide evidence of a worrisome global situation regarding the development of new dengue vaccine candidates.ConclusionTo reverse this scenario, there is an urgent need to implement new knowledge governance approaches and business models to stimulate an exponential increase in global vaccine development funding for dengue and several other vaccines.

O declínio global das coberturas vacinais levou a Organização Mundial da Saúde (OMS), em 2019, a definir a hesitação vacinal como uma das dez maiores ameaças mundiais à saúde pública. No Brasil, a queda da cobertura vacinal teve início em 2012, acentuando-se a partir de 2016, e sendo agravada pela pandemia de COVID-19. O alerta da baixa cobertura vacinal vem acompanhado pela reintrodução de doenças imunopreveníveis como o sarampo. O retorno de doenças até então eliminadas, como a poliomielite, pode agravar a crise sanitária ainda em curso. Mesmo sendo reconhecido como um dos mais efetivos programas de imunizações do mundo e dos esforços permanentes, o Programa Nacional de Imunizações enfrenta um cenário extremamente adverso no que tange às coberturas vacinais. Este artigo descreve o Projeto pela Reconquista das Altas Coberturas Vacinais (PRCV) e a estratégia de trabalhar na ponta do sistema, executada nos territórios, que vem sendo implementada desde 2021 e já começa a apresentar resultados promissores. O PRCV foi organizado em três eixos temáticos com atuação compartilhada e ações específicas, a saber: vacinação; sistemas de informação; comunicação e educação. Os resultados já alcançados permitem afirmar que é possível conseguir a reversão das baixas coberturas vacinais, a partir da articulação de ações estruturais e interinstitucionais, com o fortalecimento das políticas públicas e desenvolvimento de medidas de curto, médio e longo prazos. Os fatores mais potentes do PRCV são sua abordagem junto aos profissionais da ponta, o pacto social pela vacinação, e a estruturação de redes locais de apoio às imunizações.

We evaluated the duration of neutralizing antibodies and the status of 17DD vaccine–specific T- and B-cell memory following primary and revaccination regimens for yellow fever (YF) in Brazil. We observed progressive decline of plaque-reduction neutralization test (PRNT) seropositivity and of the levels of effector memory CD4+ and CD8+ T cells, as well as interferon-γ+CD8+ T cells, 10 years after primary vaccination. Revaccination restored PRNT seropositivity as well as the levels of effector memory CD4+, CD8+, and interferon-γ+CD8+ T cells. Moreover, secondary or multiple vaccinations guarantee long-term persistence of PRNT positivity and cell-mediated memory 10 years after booster vaccination. These findings support the relevance of booster doses to heighten the 17DD-YF–specific immune response to guarantee the long-term persistence of memory components. Secondary or multiple vaccinations improved the correlates of protection triggered by 17DD-YF primary vaccination, indicating that booster regimens are needed to achieve efficient immunity in areas with high risk for virus transmission.

The Yellow Fever (YF) vaccination is recommended for people living in endemic areas and represents the most effective strategy to reduce the risk of infection. Previous studies have warned that booster regimens should be considered to guarantee the long-term persistence of 17DD-YF-specific memory components in adults living in areas with YF-virus circulation. Considering the lower seroconversion rates observed in children (9–12 months of age) as compared to adults, this study was designed in order to access the duration of immunity in single-dose vaccinated children in a 10-years cross-sectional time-span. The levels of neutralizing antibodies (PRNT) and the phenotypic/functional memory status of T and B-cells were measured at a baseline, 30–45 days, 1, 2, 4, 7, and 10 years following primary vaccination. The results revealed that a single dose induced 85% of seropositivity at 30–45 days and a progressive time-dependent decrease was observed as early as 2 years and declines toward critical values (below 60%) at time-spans of ≥4-years. Moreover, short-lived YF-specific cellular immunity, mediated by memory T and B-cells was also observed after 4-years. Predicted probability and resultant memory analysis emphasize that correlates of protection (PRNT; effector memory CD8+ T-cells; non-classical memory B-cells) wane to critical values within ≥4-years after primary vaccination. Together, these results clearly demonstrate the decline of 17DD-YF-specific memory response along time in children primarily vaccinated at 9–12 months of age and support the need of booster regimen to guarantee the long-term persistence of memory components for children living in areas with high risk of YF transmission.

The present study aims to determine whether 17DD-YF-specific humoral and cellular immunological memory is maintained 8-years after primary vaccination with subdoses (10,447IU;3,013IU;587IU;158IU;31IU). For this purpose, this follow-up study was carried out in a subset of volunteers (n = 98) originally enrolled in the dose-response study in 2009 and 46 non-vaccinated controls. Our results demonstrated that vaccinees, who had seroconverted following primary vaccination and had not been revaccinated, present similar neutralizing antibodies levels and YF-specific cellular memory, particularly CMCD4 and EMCD8 as compared to the reference full dose (27,476IU). Although, PRNT seropositivity rates were similar across subgroups (94, 82, 83, 94, 80, and 91%, correspondingly), only doses above 587IU elicited similar iterative proportion of seropositivity rates, calculated as a progressive decrease on seropositivity rates along time (89, 80, 80, and 91%, respectively) as compared to 158IU and 31IU (68 and 46%, respectively). Noteworthy were the strong positive correlations (“EMCD4,EMCD8” and “TNFCD8,IFNCD8”) observed in most subdoses, except for 31IU. Major similarities underscored the preserved antibody titers and the outstanding levels of EMCD8, relevant correlates of protection for YF-specific immunity. These findings provide evidences to support the regular use of dose sparing strategy for YF vaccine in adults.

The need for improved dengue vaccines remains since the only licensed vaccine, Dengvaxia, shows variable efficacy depending on the infecting dengue virus (DENV) type, and increases the risk of hospitalization for severe dengue in children not exposed to DENV before vaccination. Here, we developed a tetravalent dengue purified and inactivated vaccine (DPIV) candidate and characterized, in rhesus macaques, its immunogenicity and efficacy to control DENV infection by analyzing, after challenge, both viral replication and changes in biological markers associated with dengue in humans. Although DPIV elicited cross-type and long-lasting DENV-neutralizing antibody responses, it failed to control DENV infection. Increased levels of viremia/RNAemia (correlating with serum capacity at enhancing DENV infection in vitro), AST, IL-10, IL-18 and IFN-γ, and decreased levels of IL-12 were detected in some vaccinated compared to non-vaccinated monkeys, indicating the vaccination may have triggered antibody-dependent enhancement of DENV infection. The dengue macaque model has been considered imperfect due to the lack of DENV-associated clinical signs. However, here we show that post-vaccination enhanced DENV infection can be detected in this model when integrating several parameters, including characterization of DENV-enhancing antibodies, viremia/RNAemia, and biomarkers relevant to dengue in humans. This improved dengue macaque model may be crucial for early assessment of efficacy and safety of future dengue vaccines.

We discuss the complex eco-social factors involved in the puzzle of the unexpected rapid viral spread in the ongoing Brazilian yellow fever (YF) outbreak, which has increased the reurbanisation risk of a disease without urban cases in Brazil since 1942. Indeed, this rapid spatial viral dissemination to the Southeast and South regions, now circulating in the Atlantic Forest fragments close to peri-urban areas of the main Brazilian megalopolises (São Paulo and Rio de Janeiro) has led to an exponential increase in the number of yellow fever cases. In less than 18 months, 1,833 confirmed cases and 578 deaths were recorded most of them reported in the Southeast region (99,9%). Large epizooties in monkeys and other non-human primates (NHPs) were communicated in the country with 732 YF virus (YFV) laboratory confirmed events only in the 2017/2018 monitoring period. We also discuss the peculiarities and similarities of the current outbreak when compared with previous great epidemics, examining several hypotheses to explain the recent unexpected acceleration of epizootic waves in the sylvatic cycle of the YFV together with the role of human, NHPs and mosquito mobility with respect to viral spread. We conclude that the most feasible hypothesis to explain this rapidity would be related to human behavior combined with ecological changes that promoted a significant increase in mosquito and NHP densities and their contacts with humans. We emphasize the urgent need for an adequate response to this outbreak such as extending immunisation coverage to the whole Brazilian population and developing novel strategies for immunisation of NHPs confined in selected reserve areas and zoos. Finally, we stress the urgent need to improve the quality of response in order to prevent future outbreaks and a catastrophic reurbanisation of the disease in Brazil and other South American countries. Continuous monitoring of YFV receptivity and vulnerability conditions with effective control of the urban vector Aedes aegypti and significant investments in YF vaccine production capacity and research and development for reduction of adverse effects are of the highest priority.

In this investigation, machine-enhanced techniques were applied to bring about scientific insights to identify a minimum set of phenotypic/functional memory-related biomarkers for post-vaccination follow-up upon yellow fever (YF) vaccination. For this purpose, memory status of circulating T-cells (Naïve/early-effector/Central-Memory/Effector-Memory) and B-cells (Naïve/non-Classical-Memory/Classical-Memory) along with the cytokine profile (IFN/TNF/IL-5/IL-10) were monitored before-NV(day0) and at distinct time-points after 17DD-YF primary vaccination-PV(day30-45); PV(year1-9) and PV(year10-11). A set of biomarkers (eEfCD4; EMCD4; CMCD19; EMCD8; IFNCD4; IL-5CD8; TNFCD4; IFNCD8; TNFCD8; IL-5CD19; IL-5CD4) were observed in PV(day30-45), but not in NV(day0), with most of them still observed in PV(year1-9). Deficiencies of phenotypic/functional biomarkers were observed in NV(day0), while total lack of memory-related attributes was observed in PV(year10-11), regardless of the age at primary vaccination. Venn-diagram analysis pre-selected 10 attributes (eEfCD4, EMCD4, CMCD19, EMCD8, IFNCD4, IL-5CD8, TNFCD4, IFNCD8, TNFCD8 and IL-5CD4), of which the overall mean presented moderate accuracy to discriminate PV(day30-45)&PV(year1-9) from NV(day0)&PV(year10-11). Multi-parameter approaches and decision-tree algorithms defined the EMCD8 and IL-5CD4 attributes as the top-two predictors with moderated performance. Together with the PRNT titers, the top-two biomarkers led to a resultant memory status observed in 80% and 51% of volunteers in PV(day30-45) and PV(year1-9), contrasting with 0% and 29% found in NV(day0) and PV(year10-11), respectively. The deficiency of memory-related attributes observed at PV(year10-11) underscores the conspicuous time-dependent decrease of resultant memory following17DD-YF primary vaccination that could be useful to monitor potential correlates of protection in areas under risk of YF transmission.

The macaque is widely accepted as a suitable model for preclinical characterization of dengue vaccine candidates. However, the only vaccine for which both preclinical and clinical efficacy results were reported so far showed efficacy levels that were substantially different between macaques and humans. We hypothesized that this model's predictive capacity may be improved using recent and minimally passaged dengue virus isolates, and by assessing vaccine efficacy by characterizing not only the post-dengue virus challenge viremia/RNAemia but also the associated-cytokine profile. Ten recent and minimally passaged Brazilian clinical isolates from the four dengue virus serotypes were tested for their infectivity in rhesus macaques. For the strains showing robust replication capacity, the associated-changes in soluble mediator levels, and the elicited dengue virus-neutralizing antibody responses, were also characterized. Three isolates from dengue virus serotypes 1, 2 and 4 induced viremia of high magnitude and longer duration relative to previously reported viremia kinetics in this model, and robust dengue virus-neutralizing antibody responses. Consistent with observations in humans, increased MCP-1, IFN-γ and VEGF-A levels, and transiently decreased IL-8 levels were detected after infection with the selected isolates. These results may contribute to establishing a dengue macaque model showing a higher predictability for vaccine efficacy in humans.

Aim: To investigate whether 1-step titration of the rivastigmine patch (initiated at 5 cm2 and titrated to 10 cm2 after 4 weeks) is well tolerated in Japanese patients with Alzheimer's disease (AD) as compared to 3-step titration (initiated at 2.5 cm2 and titrated by 2.5 cm2 every 4 weeks to 10 cm2). Methods: A 24-week, multicenter, randomized, double-blind study was conducted in Japan between July 2012 and May 2014. Patients with mild to moderate AD aged 50-85 years were randomized 1:1 to 1-step or 3-step titration of the rivastigmine once-daily patch. The primary endpoint was the proportion of patients with adverse events leading to discontinuation. Results: Of 216 patients randomized, 215 (1-step, n = 107; 3-step, n = 108) were included in the safety analysis. The primary endpoint outcome was 15.0% in the 1-step group and 18.5% in the 3-step group. The observed treatment difference was −3.6% (95% confidence interval: −17.0, 9.6), falling within the prespecified acceptance range. Conclusion: The tolerability of two different titration schemes was similar in Japanese patients with AD.

This paper presents, from the perspective of technological development and production, the results of an investigation examining 61 clinical studies with vaccines conducted in Brazil between 1938-2013, with the participation of the Oswaldo Cruz Institute (IOC) and the Oswaldo Cruz Foundation (Fiocruz). These studies have been identified and reviewed according to criteria, such as the kind of vaccine (viral, bacterial, parasitic), their rationale, design and methodological strategies. The results indicate that IOC and Fiocruz have accumulated along this time significant knowledge and experience for the performance of studies in all clinical phases and are prepared for the development of new vaccines products and processes. We recommend national policy strategies to overcome existing regulatory and financing constraints.

Background/Aims: CIBIC plus-J is the Japanese language version equivalent to CIBIC plus. Variability of CIBIC plus-J arises among raters in accordance with their experience and their memories of patients’ conditions at baseline. Therefore, in a multicenter trial of Alzheimer’s disease, CIBIC plus-J interviews with Alzheimer’s disease patients were videotaped, and the tapes were assessed by central raters as a means to improve the reliability of CIBIC plus-J assessment. Methods: Two of eight central raters were randomly selected and independently assessed the CIBIC plus-J of each patient. Results: CIBIC plus-J of 41 patients was assessed. The agreement rate between the two raters was 46.3% (19/41), when two raters assessed the CIBIC plus-J of the same patient. However, when considering disagreement between adjacent points as ‘agree’, the agreement rate was 97.6% (40/41). Although the kappa coefficients contained coincidence, simple and quadratic weighted kappa coefficients [95% confidential interval (CI)] were 0.226 (0.066–0.386) and 0.633 (0.507–0.759), respectively, and when considering disagreement between adjacent points as ‘agree’, the agreement kappa was 0.896 (0.752–1.041). The interclass coefficient from the two-way layout model was 0.639. Conclusion: The reliability of the CIBIC plus-J assessment with the videotaped method was acceptable.

Walking aids are vehicles that need to carry a major part of the user's weight and to run on roads. Therefore, automotive engineering was applied in this study to improve the walking aid design. The walking aid developed can turn in a small space such as in an elevator, ride over gaps such as curbs, and keep straight trajectories on rough and slanted surfaces with minimum user effort. The core part of this design lies in the adoption of a multi-functional swing-arm suspension for the front caster wheels and direct yaw-moment control by the rear-wheel motor drives.

Background: The rate of use of nursing-care services has been increasing dramatically in recent years with the upgrading of the public long-term care insurance system in Japan. We addressed how the increased use of the nursing-care services might affect the information on the patients provided by their caregivers. Methods: A questionnaire survey of 531 family caregivers caring for dementia patients at home was carried out to investigate how the use of these services might affect the information about the patients provided by the caregivers. The survey revealed that the use of the nursing-care services reduced the burden (quality, quantity, time of nursing care, and feeling) on the caregivers. Results: According to the observation provided by the caregivers, the patients’ behaviors and activities at home tended to decrease. These results indicated that the use of the nursing-care services resulted in a reduction in the opportunity for and the time spent on observation of the patients by the caregivers, making it more difficult for the caregiver to provide an appropriate assessment of the patient’s condition. Conclusions: We discussed the impact of the use of the nursing-care services on the Clinician’s Interview-Based Impression of Change plus (CIBIC-plus) rating. Due to the reduction in the time spent on nursing care and in the opportunity for observation of the patient’s activities of daily living by the caregiver resulting from the use of the nursing-care services, it is difficult to obtain an accurate picture of the patient’s clinical condition using the CIBIC-plus, probably leading to an inappropriate CIBIC-plus rating.

Background: As of 2010, the rivastigmine patch was licensed for the treatment of Alzheimer’s disease (AD) in 64 countries. Methods: This 24-week, multicenter, randomized, double-blind, placebo-controlled study evaluated the efficacy, safety and tolerability of the 5-cm2 (9-mg loading dose; 4.6 mg/24 h delivery rate) and 10-cm2 (18-mg loading dose; 9.5 mg/24 h delivery rate) rivastigmine patch in Japanese patients with AD. Results: In the primary analysis population (intent-to-treat last observation carried forward) at week 24, delayed deterioration was seen with the 10-cm2 patch versus placebo on the Japanese version of the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-J cog; p = 0.005) and the Japanese version of the Clinician’s Interview-Based Impression of Change plus Caregiver Input (CIBIC plus-J; p = 0.067). Participants receiving the rivastigmine patch showed numerically less decline versus placebo at week 24 on the CIBIC plus-J, although this did not reach statistical significance. Statistical significance for the CIBIC plus-J was met following adjustment for body weight and baseline Mini-Mental State Examination score as dynamic allocation factors (p = 0.042) and on the Disability Assessment for Dementia (DAD; p = 0.024) and Mental Function Impairment (MENFIS; p = 0.016) subscales. Serious adverse events were rare and were consistent with the known safety profile of the rivastigmine patch. Conclusion: The rivastigmine patch has a favorable efficacy and tolerability profile in Japanese patients with AD.

A randomized, double-blinded study evaluating the immunogenicity, safety and consistency of production of a combined diphtheria-tetanus-pertussis-Haemophilus influenzae type b vaccine entirely produced in Brazil by Bio-Manguinhos and Instituto Butantan (DTP/Hib-BM) was undertaken. The reference vaccine had the same DTP vaccine but the Hib component was produced using purified materials supplied by GlaxoSmithKline (DTP/Hib-GSK), which is registered and has supplied the Brazilian National Immunization Program for over more than five years. One thousand infants were recruited for the study and received vaccinations at two, four and six months of age. With respect to immunogenicity, the vaccination protocol was followed in 95.6% and 98.4% of infants in the DTP/Hib-BM and DTP/Hib-GSK groups, respectively. For the Hib component of the study, there was 100% seroprotection (>0.15 µg/mL) with all three lots of DTP/Hib-BM and DTP/Hib-GSK. The geometric mean titer (GMT) was 9.3 µg/mL, 10.3 µg/mL and 10.3 µg/mL for lots 1, 2 and 3 of DTP/Hib-BM, respectively, and the GMT was 11.3 g/mL for DTP/Hib-GSK. For diphtheria, tetanus and pertussis, seroprotection was 99.7%, 100% and 99.9%, respectively, for DTP/Hib-BM, three lots altogether and 99.2%, 100% and 100% for DTP/Hib-GSK. GMTs were similar across all lots and vaccines. Adverse events rates were comparable among the vaccine groups. The Brazilian DTP/Hib vaccine demonstrated an immunogenicity and reactogenicity profile similar to that of the reference vaccine.

OBJETIVO: Avaliar a segurança da vacina combinada de difteria-tétano-coqueluche de células inteiras e Haemophilus influenzae tipo b usada no Programa Nacional de Imunizações, e em especial a incidência de episódios hipotônicos-hiporresponsivos. MÉTODO: Acompanhamento de uma coorte de 21.064 lactentes (20.925 ou 99,7% aderiram ao protocolo de estudo), nas 48 horas após a aplicação da vacina de difteria, tétano, coqueluche de células inteiras e Haemophilus influenzae tipo b em centros de saúde na cidade do Rio de Janeiro, para determinar e investigar eventos adversos graves, espontâneos e solicitados. Cada criança foi monitorada durante somente uma dose. RESULTADOS: A incidência de episódios hipotônicos-hiporresponsivos foi de 1:1.744 doses (casos confirmados) e de 1:1.495 doses (casos confirmados mais casos suspeitos). A taxa de incidência de convulsões foi de 1:5.231 doses. Não foram detectados casos de apnéia. Esses resultados são comparáveis àqueles relatados na literatura para a vacina contra difteria-tétano-coqueluche de células inteiras. CONCLUSÃO: A vacina contra difteria, tétano, coqueluche de células inteiras e Haemophilus influenzae tipo b em estudo pode ser usada com segurança no Programa Nacional de Imunizações, de acordo com as precauções e contra-indicações correntes.OBJECTIVE:To evaluate the safety of a combined diphtheria-tetanus-whole cell pertussis-Haemophilus influenzae type b vaccine used on the Brazilian National Immunizations Program, chiefly the incidence of hypotonic-hyporesponsive episodes. METHOD: Follow-up of a cohort of 21,064 infants (20,925 or 99.7% adhered to the study protocol), within 48 hours of vaccination with diphtheria-tetanus-whole cell pertussis-Haemophilus influenzae type b vaccine in health care units in the City of Rio de Janeiro, to ascertain and investigate spontaneous and solicited severe adverse events. Each child was followed-up for one dose only. RESULTS: The rate of hypotonic-hyporesponsive episodes was 1/1,744 doses (confirmed cases) and 1/1,495 doses (confirmed plus suspect cases). The rate of convulsions was 1/5,231 doses. No cases of apnea were detected. These results are comparable to those found in the literature with diphtheria-tetanus-whole cell pertussis vaccine. CONCLUSION: The diphtheria-tetanus-whole cell pertussis-Haemophilus influenzae type b vaccine under study can be safely used in the National Immunizations Program, according to the current precautions and contraindications.

Vaccination of infants with conjugated Haemophilus influenzae type b (Hib) vaccines has been proven to reduce Hib meningitis by 95% and pneumoniae by 20%. The routine use of Hib vaccine is facilitated by the introduction of combination vaccines into the EPI (Expanded Plan of Immunization). The objective of this study was to compare the immunogenicity and reactogenicity of an extemporaneously mixed DTPw/Hib (diphtheria-tetanus-whole cell pertussis) combination, using the technology of two Brazilian manufacturers, against a licensed DTPw/Hib European combination in 108 infants vaccinated at 2, 4 and 6 months according to the local national schedule. The Brazilian combination was highly immunogenic with Hib seroprotection rates (anti-PRP > 0.15 mg /ml of 98% after 2 doses and 100% after 3). Also for tetanus and pertussis the new Brazilian combination was as immunogenic as the European counterpart, except the diphtheria seroprotection rates and titers were lower. There was also no clinically relevant difference in reactogenicity. If these feasibility results are confirmed, the Brazilian DTPw/Hib combination should help to boost the uptake of Hib vaccination in Brazil.

O governo federal, nos anos mais recentes, vem desenvolvendo importantes iniciativas no sentido de fortalecer o sistema de ciência, tecnologia e inovação (CT&I) e, conseqüentemente, de aumentar os resultados da inovação tecnológica em várias áreas importantes da economia do país. Essas iniciativas, no entanto, ainda são insuficientes para diminuir a enorme dependência de insumos e tecnologias vindas de países mais desenvolvidos. Apresenta-se neste trabalho a situação da vacinação, produção e desenvolvimento tecnológico de vacinas no mundo e no Brasil; também são feitas algumas reflexões sobre a complexidade da inovação tecnológica de vacinas e as diversas etapas do processo de desenvolvimento tecnológico requeridas para esse completo desenvolvimento. Descrevem-se as várias etapas envolvidas, com análise dos parâmetros e fatores integrantes em cada etapa, os requisitos técnicos de instalações e equipamentos, as normas de boas práticas de fabricação (BPF), a necessidade organizacional, de infra-estrutura e de gestão, o longo período e o alto custo demandados para essa atividade.