[On the issue of logistic support of export of medicinal preparations of national production].

The current geopolitical situation raised pointed question of developing new supply chains and looking for rolling stock to develop newly formed cargo flows, including medicinal preparations transportation. Considering necessity in timely and safe supply of medicines, it is necessary to develop set of measures permitting to implement export of this production of national industry to ensure ultimate independence from unfriendly states. The article considers main indicators of import and export operations of medicinal preparations and measures taken by the state to support industry in current conditions, requirements for international transportation of this category of goods. The measures increasing exports within the framework of the Pharmaceutical Industry Development Strategy until 2030, such as expansion of fleet of autonomous refrigerated containers, use of consolidation warehouses in Turkey and Kazakhstan to ensure decreasing of cost of multi-modal transportation of medicinal preparations, as well as validation of rolling stock in accordance with GDP requirements.

Reasons for implementation success despite health system constraints: qualitative insights on 'what worked' for cotrimoxazole preventive therapy.

BACKGROUND: Although Cotrimoxazole preventive therapy (CPT) has shown to be highly efficacious in reducing morbidity and mortality among people living with Human immunodeficiency virus (HIV) under 'ideal world' study conditions, operational challenges are limiting its effectiveness when implementing in countries most affected by the HIV epidemic. The fact that Mozambican authorities reported high coverage of CPT among patients with HIV, has led to this qualitative case study aimed at exploring possible factors responsible for the successful implementation of CPT in the Province of Maputo. METHODS: Between February and April 2019, we individually interviewed nine governmental stakeholders, including the person responsible for the HIV Program, the person responsible for the TB Program and the person responsible for Pharmaceutical management at three administrative levels (central, provincial and district level). Interviews were recorded, transcribed, and analysed thematically using MAXQDA Analytics Pro. Findings were translated from Portuguese into English. RESULTS: Five themes iteratively emerged: (a) Role of governance & leadership, (b) Pharmaceutical strategies, (c) Service delivery modifications, (d) Health care provider factors, and (e) Patients' perspectives. Interviews revealed that continuous supply of cotrimoxazole (CTZ) had been facilitated through multiple-source procurement and a push-pull strategy. One part of CTZ arrived in kits that were imported from overseas and distributed to public health facilities based on their number of outpatient consultations (push strategy). Another part of CTZ was locally produced and distributed as per health facility demand (pull strategy). Strong district level accountability also contributed to the public availability of CTZ. Interviewees praised models of differentiated care, the integrated HIV service delivery and drug delivery strategies for reducing long queues at the health facility, better accommodating patients' needs and reducing their financial and organisational burden. CONCLUSIONS: This study presents aspects that governmental experts believed to be key for the implementation of CPT in the Province of Maputo, Mozambique. Enhancing the implementation outcomes - drug availability and feasibility of the health facility-based service delivery - seemed crucial for the implementation progress. Reasons for the remarkable patient acceptability of CPT in our study setting should be further investigated.

[Overwiew of compounding oncology pharmacy in France in 2021]. / États des lieux de la pharmacotechnie oncologique en France en 2021.

The pharmacotechnical expert group of the French Society of Oncological Pharmacy presents the results of its national survey carried out in 2021 in the form of an inventory of pharmaceutical compounding units dedicated to oncology. Premises, equipment, controls, production flows and trends are described in this article, providing an overview of the sector at a time when the new Good Manufacturing Practices (GMP) are applicable. This overview will allow us to better address the needs and expectations of production pharmacists regarding the application of GMP and the development of their units.

Localizing pharmaceuticals manufacturing and its impact on drug security in Saudi Arabia.

Local production of pharmaceuticals plays a vital role in maintaining resilience of national healthcare systems, especially when it comes to facilitating access to needed medicines and decreasing exposure to imports and international supply chains. Pharma is a research-intensive industry and the systemic lack of governance and support to R&D activities in this sector, among other host of related issues such as unsupportive regulatory regimes and human resources capacity limitations, is one of the major impediments to the diversifying of locally produced pharmaceuticals portfolio. In this review, an overview of the current pharmaceutical production system in Saudi Arabia, its major challenges, and proposed remedies to address them will be highlighted.

An Overview of Pharmaceutical Production in Thai Hospitals.

Purpose: The purpose of this research was to provide an overview of pharmaceutical production in Thai hospitals. Methods: A cross-sectional survey was developed to study pharmaceutical production in the 1347 Thai hospitals. A representative sample was chosen using multistep selection arriving at a final total of 750 hospitals. Five experts in hospital pharmacy production were recruited to evaluate the content validity. The questionnaire consisted of 2 parts: (1) general details of the hospitals and (2) the type of pharmaceutical products. The latter classification were further divided into 6 types: (1) nonsterile products, (2) extemporaneous preparations, (3) total parenteral nutrition, (4) intravenous admixtures, (5) cytotoxic preparations, and (6) herbal medicine products. All data were analyzed via descriptive statistics. Results: From the 750 questionnaires sent out, 395 hospitals (52.67%) responded to the questionnaires. Regarding the 395 respondent sample group, approximately 60% of the hospitals were involved in pharmaceutical production. The top 3 pharmaceutical products were as follows: (1) cytotoxic preparations (315 items); (2) liquid nonsterile preparations (60 items), and (3) liquid extemporaneous preparations (52 items). The most frequently mentioned reasons for the production of each dosage form were as follows: (1) no commercially available product in appropriate dosage form or strength needed and (2) product was prepared following the hospital's policy. The support needs in hospital pharmacy production were revealed as follows: (1) master formula, (2) quality assurance and quality control processes, (3) equipment, (4) standard references, (5) buildings, (6) personnel, (7) budget, (8) raw material suppliers, and (9) the coordination between the faculties of pharmaceutical sciences and hospitals. Conclusions: Approximately 60% of the respondents had pharmaceutical production in their hospitals. The greatest need for support was for a master formula to inform hospital-based pharmaceutical production. These findings provide essential information, especially for stakeholders, to understand the professional challenges and likely pharmaceutically related health service changes in the future.

The politics of COVID-19 vaccination in middle-income countries: Lessons from Brazil.

As the world struggles to meet the challenges of vaccination against COVID-19, more attention needs to be paid to issues faced by countries at different income levels. Middle-income countries (MICs) typically lack the resources and regulatory capacities to pursue strategies that wealthier countries do, but they also face different sets of challenges and opportunities than low-income countries (LICs). We focus on three dimensions of vaccination: procurement and production; regulation of marketing registration; and distribution and uptake. For each dimension we show the distinct challenges and opportunities faced by MICs. We illustrate these challenges and opportunities with the case of Brazil, showing how each dimension has been affected by intense political conflicts. Brazil's procurement and production strategy, which builds on a long trajectory of local production and technology transfer, has been riddled by conflicts between the national government and state governments. The regulatory approval process, based around one of Latin America's most highly-regarded regulatory authorities, has also been subject to acute inter- and intra-governmental conflicts. And with regard to distribution and uptake, in the face of high uncertainty, even with a solid health infrastructure, Brazil encounters difficulties in promoting vaccine delivery. The research also reveals the importance of coordination among these dimensions, in Brazil and beyond. Pandemic preparedness and response must include sharing knowledge of how to produce vaccines and recognition of the crucial linkages between procurement, regulation, delivery, and uptake that are necessary for ensuring access to these products.

Developing Multisensory Approach to the Optical Spectral Analysis.

This article presents an overview of research aimed at developing a scientific approach to creating multisensor optical systems for chemical analysis. The review is mainly based on the author's works accomplished over the recent 10 years at Samara State Technical University with broad international cooperation. It consists of an introduction and five sections that describe state of the art in the field of optical sensing, suggested development methodology of optical multisensor systems, related aspects of experimental design and process analytical technology followed by a collection of practical examples in different application fields: food and pharmaceutical production, medical diagnostics, and ecological monitoring. The conclusion summarizes trends and prospects of the multisensory approach to optical spectral analysis.

Antibiotic Resistance, Biofilm Formation, and Presence of Genes Encoding Virulence Factors in Strains Isolated from the Pharmaceutical Production Environment.

The spread of bacterial resistance to antibiotics affects various areas of life. The aim of this study was to assess the occurrence of Pseudomonas aeruginosa, and other bacteria mainly from orders Enterobacterales and Staphylococcus in the pharmaceutical production sites, and to characterize isolated strains in the aspects of antibiotic resistance, biofilm formation, and presence of genes encoding virulence factors. Genes encoding selected virulence factors were detected using PCR techniques. Antimicrobial susceptibility testing was applied in accordance with the EUCAST recommendations. A total of 46 P. aeruginosa strains were isolated and 85% strains showed a strong biofilm-forming ability. The qualitative identification of genes taking part in Quorum Sensing system demonstrated that over 89% of strains contained lasR and rhlI genes. An antimicrobial susceptibility testing revealed nine strains resistant to at least one antibiotic, and two isolates were the metallo-ß-lactamase producers. Moreover, the majority of P. aeruginosa strains contained genes encoding various virulence factors. Presence of even low level of pathogenic microorganisms or higher level of opportunistic pathogens and their toxic metabolites might result in the production inefficiency. Therefore, the prevention of microbial contamination, effectiveness of sanitary and hygienic applied protocols, and constant microbiological monitoring of the environment are of great importance.

Industrial wastewater treatment plant enriches antibiotic resistance genes and alters the structure of microbial communities.

Antibiotic resistance is an emerging global health crisis, driven largely by overuse and misuse of antibiotics. However, there are examples in which the production of these antimicrobial agents has polluted the environment with active antibiotic residues, selecting for antibiotic resistant bacteria and the genes they carry. In this work, we have used shotgun metagenomics to investigate the taxonomic structure and resistance gene composition of sludge communities in a treatment plant in Croatia receiving wastewater from production of the macrolide antibiotic azithromycin. We found that the total abundance of antibiotic resistance genes was three times higher in sludge from the treatment plant receiving wastewater from pharmaceutical production than in municipal sludge from a sewage treatment plant in Zagreb. Surprisingly, macrolide resistance genes did not have higher abundances in the industrial sludge, but genes associated with mobile genetic elements such as integrons had. We conclude that at high concentrations of antibiotics, selection may favor taxonomic shifts towards intrinsically resistant species or strains harboring chromosomal resistance mutations rather than acquisition of mobile resistance determinants. Our results underscore the need for regulatory action also within Europe to avoid release of antibiotics into the environment.

Institutional barriers and enablers to implementing and complying with internationally accepted quality standards in the local pharmaceutical industry of Pakistan: a qualitative study.

Complying with good manufacturing practices (GMP) and ensuring a quality system is integral to production and supply of quality medicines and achieving universal health coverage. This study focus on the local production of medicines in Pakistan, a lower middle-income country that has observed considerable growth in the number of pharmaceutical companies over the past two decades. Against this background, we investigated: (1) How is quality assurance (QA) and GMP compliance understood and acted upon by local pharmaceutical manufacturers?; (2) What are the institutional barriers and enablers for QA and GMP compliance in the local pharmaceutical sector from the perspective of key stakeholders?; and (3) What are the institutional barriers and enablers for strengthening local regulatory capacity to improve QA in the industry in the long term? We used a qualitative study design involving 22 interviews of the drug regulatory bodies (n = 9), academia (n = 3) and local manufacturers (n = 10), identifying key themes in data by thematic analysis. Document analysis was used to collect additional information and supplement the interview data. We identified that manufacturing facilities operated under different GMP standards and interpretations, pointing towards an absence of harmonization in quality standards across the industry. Views diverged about the status of GMP compliance, with interviewees from academia presenting a more critical view compared with regulators who promoted a more positive story. Among the barriers explaining why companies struggled with quality standards, the lack of a mindset promoting quality and safety among profit-oriented manufacturers was prominent. At the federal level, DRAP's establishment represented an institutional improvement aiming to promote QA through inspections and guidance. While some positive measures to promote quality have been observed, the need for DRAP to strengthen its technical and regulatory capacity, enhance its engagement in international collaboration and learning, and improve transparency and accountability were highlighted. Overall, since the challenges in Pakistan are shared with other low- and middle-income countries with local production, there is a need to commit to international collaborative mechanisms, such as those lead by WHO, on this issue.

Evaluation of an in-line NIR spectroscopic method for the determination of the residence time in a tablet press.

In the current study, the ability to use in-line NIR inside the feed frame of a tablet press to monitor the residence time distribution inside the tablet press was investigated. Pulse-response experiments were performed. In-line measurements inside the feed frame were compared to measurements on the actual produced tablets and the influence of different tableting parameters on the concentration profiles were studied. Turret speed had a major influence on the concentration profiles and RTD parameters. The in-line and off-line concentration profiles did not align with each other as spiking material was still detected in the tablets when no spiking material was observed in the powder blend by the in-line measuring method. The cause of this mismatch between the in-line and off-line curves was the in-line measuring position. By adjusting the position of the NIR probe to the bottom of the feed frame instead of at the top of the feed frame, a perfect alignment between in-line and off-line concentration curves was acquired. In-line measurements at the bottom of the feed frame could, if optimisation to avoid probe fouling is possible, be ideal for real-time measurement and control of the blend concentration during tableting. When probe fouling cannot be avoided, the correlation between the in-line measured concentration at the top of the feed frame and the concentration of the produced tablets should be investigated and modelled to enable real-time measurement and control based on in-line measurements.

How can a policy foster local pharmaceutical production and still protect public health? Lessons from the health-industry complex in Brazil.

The global health community is increasingly advocating for the local production of pharmaceuticals in developing countries as a way to promote technology transfer, capacity building and improve access to medicines. However, efforts to advance drug manufacturing in these countries revive an old dilemma of fostering technological development versus granting access to social services, such as healthcare. This paper explores the case of Brazil, a country that has developed large-scale health-inspired industrial policies, but is, yet, little understood. Brazil's experience suggests that progressive healthcare bureaucrats can create innovative practices for technology and knowledge transfers. It also demonstrates that highly competitive pharmaceutical firms can collaborate with each other, if a government provides them the right incentives. Reforming regulatory policies is crucial for guaranteeing high-quality products in developing countries, but governments must play a crucial role in supporting local firms to adapt to these regulations. These findings send a strong message to global health policymakers and practitioners on the conditions to create a suitable environment for local production of medical products.

Evaluating enzymatic synthesis of small molecule drugs.

There have been many achievements in applying biochemical synthetic routes to the synthesis of commodity chemicals. However, most of these endeavors have focused on optimizing and increasing the yields of naturally existing pathways. We sought to evaluate the potential for biosynthesis beyond the limits of known biochemistry towards the production of small molecule drugs that do not exist in nature. Because of the potential for improved yields compared to total synthesis, and therefore lower manufacturing costs, we focused on drugs for diseases endemic to many resource poor regions, like tuberculosis and HIV. Using generalized biochemical reaction rules, we were able to design biochemical pathways for the production of eight small molecule drugs or drug precursors and identify potential enzyme-substrate pairs for nearly every predicted reaction. All pathways begin from native metabolites, abrogating the need for specialized precursors. The simulated pathways showed several trends with the sequential ordering of reactions as well as the types of chemistries used. For some compounds, the main obstacles to finding feasible biochemical pathways were the lack of appropriate, natural starting compounds and a low diversity of biochemical coupling reactions necessary to synthesize molecules with larger molecular size.

Dynamic cross-flow filtration: enhanced continuous small-scale solid-liquid separation.

In a previous study, a small-scale dynamic filtration device (SFD) was analyzed and the basic mechanisms governing the filtration process were characterized. The present work aims at improving the device's performance in terms of actual production. Various operation modes were tested in order to increase permeate flow and concentration factors (CF), while maintaining a fully continuous production mode. Both, a vacuum-enhanced and a pulsating operation mode, proved to be superior to the currently implemented open-operation mode. For example, for lactose, an increase of the CF could be achieved from 1.7 in open mode to 7.6 in pulsating operation mode. The investigated operation strategy enables process control systems to rapidly react to fluctuating feeds that may occur due to changes in upstream manufacturing steps. As a result, not only filtration performance in terms of permeate rate but also process flexibility can be significantly increased. Overall, vacuum-enhanced operation was shown to be most promising for integration into an industrial environment. The option to elevate achievable concentration factors, ease of flow monitoring as well as the ability to react to changes in the feed conditions allow for effective and efficient continuous small-scale filtration.

Experimental investigation of granule size and shape dynamics in twin-screw granulation.

A twin-screw granulator (TSG), a promising equipment for continuous high shear wet granulation (HSWG), achieves the desired level of mixing by a combination of the appropriate screw configuration and a suitable set of process settings (e.g. feed rate, screw speed, etc.), thus producing a certain granule size and shape distribution (GSSD). However, the primary sizing and shaping mechanism behind the resulting distribution is not well understood due to the opacity of the multiphase system in the granulator. This study experimentally characterised the GSSD dynamics along the TSG barrel length in order to understand the function of individual screw modules and process settings, as well as their interaction. Particle size analysis of granules collected at the outlet of the TSG suggested significant interaction between the process and screw configuration parameters influencing the heterogeneity in the GSSD. By characterising the samples collected along the screw length, a variable influence of the screw modules at different process conditions was observed. At low liquid-to-solid ratio (L/S), the first kneading module seemed to play a significant role in mixing, whereas the second kneading module was found to be more involved in reshaping the granules. At high L/S and high throughput, aggregation mainly took place in the second kneading module changing the GSSD. The results obtained from this study will be further used for the calibration and validation of a mechanistic model and, hence, support future development of a more detailed understanding of the HSWG process in a TSG.

Cancer risk of immunosuppressants in manufacturing.

During the chemical and pharmaceutical production of active pharmaceutical substances which are intended for immunosuppressive therapy, the employees may be exposed to these substances via inhalation. Immunosuppressants are linked to development of certain types of cancers e.g., lymphoma or skin cancer in transplant patients. The development of these cancers in patients is linked to the level of immunosuppression needed for transplantation in order to avoid organ rejection. Below these levels, with the immune system functioning uninhibited, cancer is unlikely to develop. An internal workshop was conducted to compare several pharmaceutical substances with the intrinsic property to cause immunosuppression, with the attempt to define the risk of healthy employees to develop cancer due to exposure to immunosuppressive substance at work and to determine the appropriate hazard classification for regulatory purposes. Data are discussed with emphasis on cyclosporine to reason the dose-response relationship and the safe level for occupational exposure. Our review indicates that if the exposure to cyclosporine at the workplace is below the threshold necessary to induce immunosuppression, the risk to develop cancer is negligible. Non-mutagenic immunosuppressants do not contribute to malignancies in occupational setting if their air concentrations do not exceed the immunosuppressive threshold limited with occupational exposure limits (OELs), which is for cyclosporine 17.5µg/m(3).