Statistical process control of manufacturing tablets for antiretroviral therapy

Abstract In this study, the manufacturing process of lamivudine (3TC) and zidovudine (AZT) tablets (150+300 mg respectively) was evaluated using statistical process control (SPC) tools. These medicines are manufactured by the Fundação para o Remédio Popular "Chopin Tavares de Lima" (FURP) laboratory, and are distributed free of charge to patients infected with HIV by the Ministry of Health DST/AIDS national program. Data of 529 batches manufactured from 2012 to 2015 were collected. The critical quality attributes of weight variation, uniformity of dosage units, and dissolution were evaluated. Process stability was assessed using control charts, and the capability indices Cp, Cpk, Pp, and Ppk (process capability; process capability adjusted for non-centered distribution; potential or global capability of the process; and potential process capability adjusted for non-centered distribution, respectively) were evaluated. 3TC dissolution data from 2013 revealed a non-centered process and lack of consistency compared to the other years, showing Cpk and Ppk lower than 1.0 and the chance of failure of 2,483 in 1,000,000 tablets. Dissolution data from 2015 showed process improvement, revealed by Cpk and Ppk equal to 2.19 and 1.99, respectively. Overall, the control charts and capability indices showed the variability of the process and special causes. Additionally, it was possible to point out the opportunities for process changes, which are fundamental for understanding and supporting a continuous improvement environment.

Global human-made mass exceeds all living biomass.

Humanity has become a dominant force in shaping the face of Earth1-9. An emerging question is how the overall material output of human activities compares to the overall natural biomass. Here we quantify the human-made mass, referred to as 'anthropogenic mass', and compare it to the overall living biomass on Earth, which currently equals approximately 1.1 teratonnes10,11. We find that Earth is exactly at the crossover point; in the year 2020 (± 6), the anthropogenic mass, which has recently doubled roughly every 20 years, will surpass all global living biomass. On average, for each person on the globe, anthropogenic mass equal to more than his or her bodyweight is produced every week. This quantification of the human enterprise gives a mass-based quantitative and symbolic characterization of the human-induced epoch of the Anthropocene.

Towards a common framework for defining ancillary material quality across the development spectrum.

Ancillary materials (AMs) play a critical role in the manufacture of cell and gene therapies, and best practices for their quality management are the subject of ongoing discussion. Given that the final product cannot be sterilized, AM quality becomes increasingly critical to the clinical advancement of cell and gene therapies. Despite a lack of direct legislative direction regarding AM quality, internationally harmonized guidance is available from several industry-standard bodies that describe the principles and application of a risk-based approach to AM qualification and related supply-chain risk management. According to a best-practice risk-based approach, AMs must be adequately qualified to a degree that reflects the level of risk the material presents to patient safety and the drug product's specification. This general approach can be implemented in different ways, and balancing quality with cost of goods is critical to the cost-effective manufacture of advanced therapy medicinal products. In some cases, it may be preferable or necessary to use AMs that are produced in compliance with current Good Manufacturing Practice. However, developers may be able to suppress manufacturing costs without undermining safety or regulatory compliance in the case that a material presents a lower risk profile. Despite a great deal of attention and interest in the quality of AMs in the cell and gene therapy space, there is still a need for greater harmonization to create a shared understanding of what constitutes a risk-based approach to AM production and sourcing. In this article, we propose a staged approach to AM quality that achieves a balance between the competing demands of risk mitigation and cost of goods containment at the various stages of AM quality development. Our novel, heuristic framework for communication among AM suppliers, users and regulators aims to bring down development and manufacturing costs and lessen the workload around regulatory compliance.

A multiscale simulation framework for the manufacturing facility and supply chain of autologous cell therapies.

BACKGROUND AIMS: Autologous cell therapy (AuCT) is an emerging therapeutic treatment that is undergoing transformation from laboratory- to industry-scale manufacturing with recent regulatory approvals. Various challenges facing the complex AuCT manufacturing and supply chain process hinder the scale out and broader application of this highly potent treatment. METHODS: We present a multiscale logistics simulation framework, AuCT-Sim, that integrates novel supply chain system modeling algorithms, methods, and tools. AuCT-Sim includes a single facility model and a system-wide network model. Unique challenges of the AuCT industry are analyzed and addressed in AuCT-Sim. Decision-supporting tools can be developed based on this framework to explore "what-if" manufacturing and supply chain scenarios of importance to various cell therapy stakeholder groups. RESULTS: Two case studies demonstrate the decision-supporting capability of AuCT-Sim where one investigates the optimal reagent base stocking level, and the other one simulates a reagent supply disruption event. These case studies serve as guidelines for designing computational experiments with AuCT-Sim to solve specific problems in AuCT manufacturing and supply chain. DISCUSSION: This simulation framework will be useful in understanding the impact of possible manufacturing and supply chain strategies, policies, regulations, and standards informing strategies to increase patient access to AuCT.

[Biomanufacturing of monoclonal antibodies]. / La bioproduction des anticorps monoclonaux.

Antibody-based drugs are an increasingly important part of the therapeutic arsenal against a wide variety of medical conditions. As the number of commercial products and pipeline candidates grows, a crucial issue facing the industry is the current and future state of biomanufacturing. The productivity of the protein expression platforms, along with the performance of the technologies impacting upstream and downstream bioprocessing, are critical factors affecting the cost and time of therapeutic antibody development and commercialization. Cell engineering strategies are being used to improve the production of antibodies and to better control their quality in terms of posttranslational modifications, in particular with regards to their glycosylation state, as this can influence their therapeutic activity. Additionally, the advance of "omics" technologies have recently given rise to new possibilities in improving these expression platforms. We review here the various advances in biomanufacturing essential to the continued growth of the therapeutic antibody market.

TITLE: La bioproduction des anticorps monoclonaux. ABSTRACT: Les anticorps monoclonaux font désormais partie intégrante de l'arsenal thérapeutique pour une multitude de maladies. Étant donné le nombre croissant de produits commerciaux et de candidats en développement, l'état actuel des systèmes de bioproduction est une préoccupation majeure de l'industrie. La productivité des plateformes d'expression, ainsi que la performance des technologies utilisées dans les procédés en amont et en aval, sont des facteurs critiques qui ont un impact sur le coût et la durée du développement des anticorps thérapeutiques. De multiples stratégies de génie cellulaire peuvent être utilisées pour l'amélioration de la production des anticorps et pour un contrôle accru des modifications post-traductionnelles, comme la glycosylation, particulièrement importante, car elle peut avoir un effet prononcé sur l'activité thérapeutique des anticorps. Les avancées des techniques « omiques ¼ rendent maintenant possibles de nouvelles approches pour l'amélioration de ces plateformes. Nous passons ici en revue les progrès en bioproduction essentiels à la croissance continue du marché des anticorps thérapeutiques.

Young consumers' considerations of healthy working conditions in purchasing decisions: a qualitative examination.

Research has suggested that products manufactured under healthy work conditions (HWC) may provide a marketing advantage to companies. This paper explores young consumers' considerations of HWC in purchasing decisions using data from qualitative interviews with a sample of 21 university students. The results suggest that interviewees frequently considered the working conditions of those who produced the products they purchased. Participants reported a willingness to pay 17.5% more on a $100 product if it were produced under HWC compared to not. Their ability and willingness to act on this issue was, however, hampered by  a lack of credible information about working conditions in production, the limited availability of HWC goods and a presumed higher price of HWC goods. While caution should be applied when generalising from this targetable market segment to a general population, these results provide actionable direction for companies interested in using a HWC brand image to gain a strategic sales advantage. Practitioner Summary: This interview study shows that young consumers are interested in, and willing to pay a premium for, goods made under healthy working conditions (HWC). Reported barriers to acting on this impulse include a lack of credible information on working conditions. Ergonomics can help provide a strategic marketing advantage for companies.

Emergency material allocation and scheduling for the application to chemical contingency spills under multiple scenarios.

In the emergency management relevant to chemical contingency spills, efficiency emergency rescue can be deeply influenced by a reasonable assignment of the available emergency materials to the related risk sources. In this study, an emergency material scheduling model (EMSM) with time-effective and cost-effective objectives is developed to coordinate both allocation and scheduling of the emergency materials. Meanwhile, an improved genetic algorithm (IGA) which includes a revision operation for EMSM is proposed to identify the emergency material scheduling schemes. Then, scenario analysis is used to evaluate optimal emergency rescue scheme under different emergency pollution conditions associated with different threat degrees based on analytic hierarchy process (AHP) method. The whole framework is then applied to a computational experiment based on south-to-north water transfer project in China. The results demonstrate that the developed method not only could guarantee the implementation of the emergency rescue to satisfy the requirements of chemical contingency spills but also help decision makers identify appropriate emergency material scheduling schemes in a balance between time-effective and cost-effective objectives.

Emerging approaches, challenges and opportunities in life cycle assessment.

In the modern economy, international value chains--production, use, and disposal of goods--have global environmental impacts. Life Cycle Assessment (LCA) aims to track these impacts and assess them from a systems perspective, identifying strategies for improvement without burden shifting. We review recent developments in LCA, including existing and emerging applications aimed at supporting environmentally informed decisions in policy-making, product development and procurement, and consumer choices. LCA constitutes a viable screening tool that can pinpoint environmental hotspots in complex value chains, but we also caution that completeness in scope comes at the price of simplifications and uncertainties. Future advances of LCA in enhancing regional detail and accuracy as well as broadening the assessment to economic and social aspects will make it more relevant for producers and consumers alike.

The science of sustainable supply chains.

Recent advances in the science and technology of global supply chain management offer near-real-time demand-response systems for decision-makers across production networks. Technology is helping propel "fast fashion" and "lean manufacturing," so that companies are better able to deliver products consumers want most. Yet companies know much less about the environmental and social impacts of their production networks. The failure to measure and manage these impacts can be explained in part by limitations in the science of sustainability measurement, as well as by weaknesses in systems to translate data into information that can be used by decision-makers inside corporations and government agencies. There also remain continued disincentives for firms to measure and pay the full costs of their supply chain impacts. I discuss the current state of monitoring, measuring, and analyzing information related to supply chain sustainability, as well as progress that has been made in translating this information into systems to advance more sustainable practices by corporations and consumers. Better data, decision-support tools, and incentives will be needed to move from simply managing supply chains for costs, compliance, and risk reduction to predicting and preventing unsustainable practices.

Regenerative medicine, resource and regulation: lessons learned from the remedi project.

The successful commercialization of regenerative medicine products provides a unique challenge to the manufacturer owing to a lack of suitable investment/business models and a constantly evolving regulatory framework. The resultant slow translation of scientific discovery into safe and clinically efficacious therapies is preventing many potential products from reaching the market. This is despite of the need for new therapies that may reduce the burden on the world's healthcare systems and address the desperate need for replacement tissues and organs. The collaborative Engineering and Physical Sciences Research Council (EPSRC)-funded remedi project was devised to take a holistic but manufacturing-led approach to the challenge of translational regenerative medicine in the UK. Through strategic collaborations and discussions with industry and other academic partners, many of the positive and negative issues surrounding business and regulatory success have been documented to provide a remedi-led perspective on the management of risk in business and the elucidation of the regulatory pathways, and how the two are inherently linked. This article represents the findings from these discussions with key stakeholders and the research into best business and regulatory practices.

Rapid medical advances challenge the tooling industry.

The requirement for greater performance in smaller spaces has increased demands for product and process innovation in tubing and other medical products. In turn, these developments have placed greater demands on the producers of the advanced tooling for these products. Tooling manufacturers must now continuously design equipment with much tighter tolerances for more sophisticated coextrusions and for newer generations of multilumen and multilayer tubing.

Six Sigma pricing.

Many companies are now good at managing costs and wringing out manufacturing efficiencies. The TQM movement and the disciplines of Six Sigma have seen to that. But the discipline so often brought to the cost side of the business equation is found far less commonly on the revenue side. The authors describe how a global manufacturer of industrial equipment, which they call Acme Incorporated, recently applied Six Sigma to one major revenue related activity--the price-setting process. It seemed to Acme's executives that pricing closely resembled many manufacturing processes. So, with the help of a Six Sigma black belt from manufacturing, a manager from Acme's pricing division recruited a team to carry out the five Six Sigma steps: Define what constitutes a defect. At Acme, a defect was an item sold at an unauthorized price. Gather data and prepare it for analysis. That involved mapping out the existing pricing-agreement process. Analyze the data. The team identified the ways in which people failed to carry out or assert effective control at each stage. Recommend modifications to the existing process. The team sought to decrease the number of unapproved prices without creating an onerous approval apparatus. Create controls. This step enabled Acme to sustain and extend the improvements in its pricing procedures. As a result of the changes, Acme earned dollar 6 million in additional revenue on one product line alone in the six months following implementation--money that went straight to the bottom line. At the same time, the company removed much of the organizational friction that had long bedeviled its pricing process. Other companies can benefit from Acme's experience as they look for ways to exercise price control without alienating customers.

Documentation of a heroin manufacturing process in Afghanistan.

The present article documents an authentic process of heroin manufacturing in Afghanistan: white heroin hydrochloride produced using simple equipment and a small quantity of chemicals. The quantities of chemicals actually used corresponded to the minimum needed for manufacturing heroin. The only organic solvent used was acetone, and only a very small quantity of it was used. Because the chemicals used in the demonstration were from actual seizures in Afghanistan, some of the chemicals had been disguised or repackaged by smugglers. Others had been put into labelled containers that proved to be counterfeit, and some glass containers used were not the original containers of the manufacturer displayed on the label. The brown heroin base prepared as an intermediate step in the process shares some of the characteristics of the South-West Asia type of heroin preparations often seized in Germany. The final product of the documented heroin manufacturing process was white heroin hydrochloride, which shares the key characteristics of the white heroin occasionally seized in Germany and other countries in Western Europe since 2000. The present article demonstrates that this kind of heroin can be produced in Afghanistan.

Intravenous immunoglobulin: regulatory perspectives on use and supply.

Technological advancements in the fractionation of plasma in the early 1970s led to the production of immunoglobulin preparations which could be administered intravenously. The ability to deliver larger doses than was possible with intramuscular products was accompanied by clinical studies demonstrating the efficacy of immunoglobulin treatment in a number of autoimmune and inflammatory conditions. This has led to a continuing increase in the usage of this product such that, currently, it is considered to be the driving force for plasma procurement. In recent years, difficulties have been experienced in the supply of this product in various markets. While intravenous immunoglobulins (IVIG) have undoubted clinical superiority over intramuscular products for the majority of indications, their use should be tempered with caution. Early clinical studies revealed that the risk of viral transmission from these products was higher than that of the traditional intramuscular presentation. This has had a profound impact on blood transfusion science as it has provided a major impetus for nucleic acid testing (NAT) for viral agents in blood donations. Perhaps less widely appreciated are the pressures which may be felt in blood services as the traditional drivers for plasma procurement - factor VIII and albumin - become secondary to IVIG. This review discusses the factors affecting the supply and safety of IVIG and the implications of recent global regulatory decisions on the delivery of this product and other therapeutic products derived from human plasma.

Informe del Ministerio de Salud sobre la epidemia del cólera a la comunidad internacional / Report of Ministry of Health to international community about cholera epidemy

Informe presentado en una reunión con los organismos internacionales y embajadas en el Perú. Contiene cuadros estadísticos y gráficos sobre los casos reportados al 20 de febrero de 1991 y lineamientos básicos sobre la canalización de la cooperación externa mediante el MINSA. Finalmente hace un listado presupuestado por rubros, con lo que se necesita para combatir la epidemia