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Downstream process (DSP) intensification technologies have the potential to provide faster, more sustainable, and more profitable processes. Nevertheless, the calculation of the possible benefits obtained from the implementation of these technologies is not always evident and usually depends on a particular production scenario. In the present work, we developed a framework for techno-economic feasibility analysis to assess the impact of changes in protein A capture, polishing, and viral filtration on process performance. The simulation used in this analysis is based on fundamental knowledge of the process and incorporates previously developed tools for calculating multi-column chromatography (MCC) and ultrafiltration-diafiltration variables. This framework was used to simulate production scenarios featuring intensified production schedules, increases in feed titers, MCC, integrated batch polishing, and high throughput viral filtration. These process alternatives were compared through key performance indicators that were selected to address specific questions on the suitability of these process intensification strategies in a particular context. Results were presented graphically for decision-makers to easily identify the best process alternatives for a given production scenario. For the conditions proposed in this work, we find that the scheduling practices, and not the unit operation processing times, have the greatest impact on process productivity. For instance, doubling the harvesting frequency resulted in a productivity increase of up to 61 %. Meanwhile, technological intensification strategies like MCC cause the greatest impact on operating costs, reducing cost of goods of the DSP by up to 27 %. Overall, intensification of individual unit operations can yield benefits from a sustainability and cost perspective, but to achieve higher throughputs, it is necessary to have fully intensified DSP and scheduling practices., Competing Interests: Declaration of competing interest Scott Husson has an ongoing financial interest in Purilogics and provides consulting services to the Company. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. The remaining authors declare no known competing interests that could affect the work reported in this article., (Copyright © 2024. Published by Elsevier B.V.)

Technology enabling drug serialisation technology was introduced by regulators to enhance security in pharmaceutical supply chain and protect drugs from infiltration by falsified and substandard medicines. The introduction of systems for serialisation required huge financial outlays manufacturers of pharmaceuticals. This study investigated the impact of serialisation on the operational efficiency and productivity in Irish pharmaceutical sites. A qualitative study was conducted with 11 manufacturing sites in Ireland. The participating companies operated a total of 114 pack-lines, representing approximately 65% of the automated packing lines in the country. The study found that serialisation had a negative effect on packaging production line OEE and line availability and on the individuals cost per unit of packaged pharmaceuticals. The research results estimated that the capital costs of serialisation were four times greater than those estimated by the regulators. There was a 4.1 cents average cost per pack for serialisation with high volume sites reporting an annual cost of serialisation of up to €4.5 m per annum and a 2.7% increase in the average cost of goods sold. A pattern whereby where many pharmaceutical manufacturers are transitioning from smaller batch production and moving toward larger batch production sizes in order to increases efficiencies was identified. The research also proposed the use of a serialisation depreciation factor as a method to determine the impact of serialisation on the cost of goods sold. This is the first study of its kind into the cost of serialisation from a manufacturer's viewpoint and studying the effects of serialisation on productivity, line availability and operational efficiency., (© 2024. The Author(s).)

It is anticipated that effective vaccines will enable the resumption of social and economic normalcy. Current calls for masking, social distancing and other restrictive measures for the public-good are difficult to enforce and are unstainable. As ~2-4% of the 50 million SARS-CoV2-infected have succumbed to Covid-19, the US department of Health and Human Services has organized a public-private partnership called Operation Warp Speed (OWS) to develop, produce and deliver 300 million doses of safe and effective vaccines with a January 2021 target. While a majority of the 300+ Covid-19 vaccine candidates are in various stages of preclinical and early-stage clinical testing, 6 clinical candidates are supported with over 10 billion USD plus integrated resources under the OWS agenda. This unprecedented approach is investing in the manufacture of product candidates ahead of product approval. It is enabled by new gene and recombinant pharmaceutical platform technologies that are accelerating the clinical study timeline from ~10 to less than 1 year. It is anticipated that one or more of the 6 candidates under the OWS initiative will be safe, effective and provide a sustained immune response to prevent infection and disease progression. This way, social and economic activities could return to normalcy., (Copyright © 2020 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Today's biologics manufacturing practices incur high costs to the drug makers, which can contribute to high prices for patients. Timely investment in the development and implementation of continuous biomanufacturing can increase the production of consistent-quality drugs at a lower cost and a faster pace, to meet growing demand. Efficient use of equipment, manufacturing footprint, and labor also offer the potential to improve drug accessibility. Although technological efforts enabling continuous biomanufacturing have commenced, challenges remain in the integration, monitoring, and control of traditionally segmented unit operations. Here, we discuss recent developments supporting the implementation of continuous biomanufacturing, along with their benefits.

Advances in molecular biology and the possibility of differentiating stem cells have opened up new scenarios in therapies that use progenitor or variously differentiated cells. Regardless of the choice of the system, designing a plant for producing advanced therapies requires a clear understanding of the final objective (the product), taking into account all the regulatory, environment, process, risk assessment, asepsis, and validation aspects involved until its implementation. Good Manufacturing Practice (GMP) compliant procedures are a prerequisite for cell production in clinical application, and clean rooms are zones for producing cell therapies. Clean rooms for clinical application require high running and maintenance costs and need trained operators and strict procedures to prepare the rooms and the people involved in the processes. While today production mainly occurs in open systems (clean rooms), there is evidence of processes in closed systems (isolators). The isolator is a Grade A aseptic closed system that requires a controlled environment and at least a Grade D environment in the case of sterile productions (A in D closed system). The use of isolators can ensure a very high level of protection against the risk of product contamination and, at the same time, provide the operators with a very safe working environment. Furthermore, working with closed systems can optimize and facilitate the production of Advanced Therapy Medical Products in GMP environments, by providing an easily reproducible working tool even for large-scale production, with generally lower costs compared to a classical clean room approach. In conclusion, the isolator workstation as a possible alternative to the classic clean room, due to its small size and the simplification of the working and maintenance operational procedures, may represent an interesting solution in the perspective of the increasingly more stringent requests for cost reductions of GMP in clinical application., (© 2020 Wiley Periodicals LLC.)

Financing by patent pledge is an important way for small- and medium-sized pharmaceutical enterprises to address financing problems. In this study, eight indexes are analyzed considering both the pledge patent value and pledger credit value. And a prediction model for the patent pledge financing amount for pharmaceutical enterprises is constructed for the first time using the analytic hierarchy process and the fuzzy comprehensive evaluation method. Three levels of financing amount are concluded through the prediction model and prediction results corresponding with the financing amount are displayed. This model was designed to help small- and medium-sized pharmaceutical enterprises get access to financing through patent pledge to relieve their financial stress. At the same time, it provides guides for pledgees and policymakers to improve the efficiency and quality of patent pledge. This work is reliable and valid in that it constructs this prediction model based on systematical data from official data sources., Competing Interests: The authors have declared that no competing interests exist.

Although probabilistic analysis has become the accepted standard for decision analytic cost-effectiveness models, deterministic one-way sensitivity analysis continues to be used to meet the need of decision makers to understand the impact that changing the value taken by one specific parameter has on the results of the analysis. The value of a probabilistic form of one-way sensitivity analysis has been recognised, but the proposed methods are computationally intensive. Deterministic one-way sensitivity analysis provides decision makers with biased and incomplete information whereas, in contrast, probabilistic one-way sensitivity analysis (POSA) can overcome these limitations, an observation supported in this study by results obtained when these methods were applied to a previously published cost-effectiveness analysis to produce a conditional incremental expected net benefit curve. The application of POSA will provide decision makers with unbiased information on how the expected net benefit is affected by a parameter taking on a specific value and the probability that the specific value will be observed.

This study aims to benchmark and analyze the process development and manufacturing costs across the biopharmaceutical drug development cycle and their contribution to overall research and development (R&D) costs. This was achieved with a biopharmaceutical drug development lifecycle cost model that captured the costs, durations, risks and interdependencies of the clinical, process development and manufacturing activities. The budgets needed for process development and manufacturing at each phase of development to ensure a market success each year were estimated. The impact of different clinical success rate profiles on the process development and manufacturing costs at each stage was investigated, with a particular focus on monoclonal antibodies. To ensure a market success each year with an overall clinical success rate (Phase I to approval) of ~12%, the model predicted that a biopharmaceutical company needs to allocate process development and manufacturing budgets in the order of ~$60 M for pre-clinical to Phase II material preparation and ~$70 M for Phase III to regulatory review material preparation. For lower overall clinical success rates of ~4%, which are more indicative of diseases such as Alzheimer's, these values increase to ~$190 M for early-phase and ~$140 Mfor late-phase material preparation; hence, the costs increase 2.5 fold. The costs for process development and manufacturing per market success were predicted to represent 13-17% of the R&D budget from pre-clinical trials to approval. The results of this quantitative structured cost study can be used to aid decision-making during portfolio management and budget planning procedures in biopharmaceutical development.

Objectives : China has made remarkable achievements in the field of immunization. However, several widespread vaccine safety-related events have recently received worldwide attention and reflect flaws in vaccine management. This study aimed to summarize vaccine safety-related events between 1985 and 2018 in China and analyze the profit motives of these events. Methods . Literature and media reviews were conducted to discover vaccine safety-related events. We developed a conceptual model with profit-related variables, and using information available from each event, we identified which profit-related variable was implicated, and how it related to the pursuit of higher profits. Results : A total of 39 vaccine safety-related events were found in vaccine production, procurement, transportation, and daily management, along with adverse events following immunization (AEFIs). Overall, 90% (35/39) of the events could be classified as profit-driven. The motives of most events could be tied to one or more reasons, including decreasing costs among vaccine producers (67%, 26/39), reducing actual procurement price (67%, 26/39), and reducing costs of transportation and/or cold chain (24/39, 62%). Conclusions : In order to deal with vaccine-related challenges, a more restrictive supervision system on vaccine production and more emergency preparedness, including health and risk communication strategies, for vaccine safety should be implemented.

This paper addresses the relevance of automated content testing for the rapid automated process development (RAPD). Our previous work demonstrated that RAPD allowed a fast and efficient development of a continuous capsule-filling process. Target was the mean weight and the relative standard deviation of the weight. Likewise important are the content and the content uniformity. However, an implementation demands a certain level of automation. In general, technology is available that can detect active pharmaceutical ingredient (API) inside the capsules but the final application is linked to additional development and investment in machinery. To eliminate doubts regarding the benefits of an automated content check within the RAPD we present an application example. First, an X-ray system was used to detect barium sulfate accurately inside capsules. Second, a process was developed where barium sulfate was filled. The concentration of excipients was modified in the experiments, as well as the setting of the process parameter. The obtained model provided an explicit understanding of the process. Subsequently, the content uniformity model was compared to a model of the capsule weight relative standard deviation, confirming the benefits of an automated content check in the RAPD. Moreover, we presented another example illustrating the advantages of a connected continuous filling process, which permits evaluation of all process steps and their interactions (i.e. evaluation of the entire process).

Background: Payers frequently rely on budget impact model (BIM) results to help determine drug coverage policy and its effect on their bottom line. It is unclear whether BIMs typically overestimate or underestimate real-world budget impact., Objective: We examined how different modeling assumptions influenced the results of 6 BIMs from the Institute for Clinical and Economic Review (ICER)., Study Design: Retrospective analysis of pharmaceutical sales data., Methods: From ICER reports issued before 2016, we collected estimates of 3 BIM outputs: aggregate therapy cost (ie, cost to treat the patient population with a particular therapy), therapy uptake, and price. We compared these against real-world estimates that we generated using drug sales data. We considered 2 classes of BIM estimates: those forecasting future uptake of new agents, which assumed "unmanaged uptake," and those describing the contemporaneous market state (ie, estimates of current, managed uptake and budget impact for compounds already on the market)., Results: Differences between ICER's estimates and our own were largest for forecasted studies. Here, ICER's uptake estimates exceeded real-world estimates by factors ranging from 7.4 (sacubitril/valsartan) to 54 (hepatitis C treatments). The "unmanaged uptake" assumption (removed from ICER's approach in 2017) yields large deviations between BIM estimates and real-world consumption. Nevertheless, in some cases, ICER's BIMs that relied on current market estimates also deviated substantially from real-world sales data., Conclusions: This study highlights challenges with forecasting budget impact. In particular, assumptions about uptake and data source selection can greatly influence the accuracy of results., (Copyright © 2019 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Over the last several years, continuous manufacturing of pharmaceuticals has evolved from bulk APIs and solid oral dosages into the more complex realm of biologics. The development of continuous downstream processing techniques has allowed biologics manufacturing to realize the benefits (e.g., improved economics, more consistent quality) that come with continuous processing. If relevant processing techniques and principles are selected, the opportunity arises to develop continuous manufacturing designs for additional pharmaceutical products including liposomal drug formulations. Liposome manufacturing has some inherent aspects that make it favorable for a continuous process. Other aspects such as formulation refinement, materials of construction, and aseptic processing need development, but present an achievable challenge. This paper reviews the current state of continuous manufacturing technology applicable to liposomal drug product manufacturing and an assessment of the challenges and potential of this application., (© 2018 The Authors. Biotechnology Journal Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

The biopharmaceutical industry is evolving in response to changing market conditions, including increasing competition and growing pressures to reduce costs. Single-use (SU) technologies and continuous bioprocessing have attracted attention as potential facilitators of cost-optimized manufacturing for monoclonal antibodies. While disposable bioprocessing has been adopted at many scales of manufacturing, continuous bioprocessing has yet to reach the same level of implementation. In this study, the cost of goods of Pall Life Science's integrated, continuous bioprocessing (ICB) platform is modeled, along with that of purification processes in stainless-steel and SU batch formats. All three models include costs associated with downstream processing only. Evaluation of the models across a broad range of clinical and commercial scenarios reveal that the cost savings gained by switching from stainless-steel to SU batch processing are often amplified by continuous operation. The continuous platform exhibits the lowest cost of goods across 78% of all scenarios modeled here, with the SU batch process having the lowest costs in the rest of the cases. The relative savings demonstrated by the continuous process are greatest at the highest feed titers and volumes. These findings indicate that existing and imminent continuous technologies and equipment can become key enablers for more cost effective manufacturing of biopharmaceuticals., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Globally, there are few vitamin and mineral ingredient manufacturers. To support local, in-country or regional procurement and production of multiple micronutrient supplements (MMS), the following production scenarios are possible: (a) straight ingredients of vitamins and minerals forms imported or locally produced that are mixed, tableted, or encapsulated and packaged by a local manufacturer; (b) import or local production of a vitamin and minerals premix that is tableted or encapsulated and packaged locally; (c) import of a bulk, finished product (tablets or capsules) that is packaged and branded; and (d) or import of a branded packaged product. This paper is a situation analysis of the market, manufacturing, and policy factors that are driving the production of MMS in 12 lower and upper middle-income countries. Key informants completed a self-administered structured questionnaire, which examined the local context of products available in the market and their cost, regulations and policies, in Brazil, Colombia, Guatemala, Mexico, Peru, Bangladesh, India, Vietnam, Ghana, Kenya, Nigeria, and South Africa. Our study found that although most countries have the capacity to produce locally MMS, the major barriers observed for sustainable and affordable production include (a) poor technical capacity and policies for ensuring quality along the value chain and (b) lack of policy coherence to incentivize local production and lower the manufacture and retail price of MMS. Also, better guidelines and government oversight will be required because not one country had an MMS formulation that matched the globally recommended formulation of the United Nations Multiple Micronutrient Preparation (UNIMMAP)., (© 2017 The Authors. Maternal and Child Nutrition Published by John Wiley & Sons, Ltd.)

Ligand-functionalized inorganic nanoparticles, also known as monolayer-protected nanoparticles, offer great potential as vehicles for in vivo delivery of drugs, genes, and other therapeutics. These nanoparticles offer highly customizable chemistries independent of the size, shape, and functionality imparted by the inorganic core. Their success as drug delivery agents depends on their interaction with three major classes of biomolecules: nucleic acids, proteins, and membranes. Here, the authors discuss recent advances and open questions in the field of nanoparticle ligand design for nanomedicine, with a focus on atomic-scale interactions with biomolecules. While the importance of charge and hydrophobicity of ligands for biocompatibility and cell internalization has been demonstrated, ligand length, flexibility, branchedness, and other properties also influence the properties of nanoparticles. However, a comprehensive understanding of ligand design principles lies in the cost associated with synthesizing and characterizing diverse ligand chemistries and the ability to carefully assess the structural integrity of biomolecules upon interactions with nanoparticles.

Objective: In many low- and middle-income countries (LMICs), limited availability, substandard quality and high prices of pharmaceutical products lead to lack of access to essential medicines and poor health outcomes. Manufacturing pharmaceuticals in LMICs may improve access for patients while increasing the market size for manufacturers., Methods: We present a tool for assessment of local manufacturing feasibility of pharmaceuticals, intended for use among key stakeholders during the business development process. The tool consists of five domains: product selection and capacity, market sizing, market entry, funding and quality assurance., Key Findings: The tool is intended to identify barriers and facilitators for local manufacturing and provide a roadmap for decision-making across multiple stakeholders. A case study in Namibia identified key barriers and facilitators to successful manufacturing in that county., Conclusions: Careful consideration of feasibility and potential for success may lead to improved health for the populations of LMIC as well as significant market potential for pharmaceutical manufacturers., (© 2018 Royal Pharmaceutical Society.)

Streptococcus pneumoniae is the leading cause of bacterial pneumonia. Although this is a vaccine preventable disease, S. pneumoniae still causes over 1 million deaths per year, mainly in children under the age of five. The biggest disease burden is in the developing world, which is mainly due to unavailability of vaccines due to their high costs. Protein polysaccharide conjugate vaccines are given routinely in the developed world to children to induce a protective antibody response against S. pneumoniae. One of these vaccines is Prevnar13, which targets 13 of the 95 known capsular types. Current vaccine production requires growth of large amounts of the 13 serotypes, and isolation of the capsular polysaccharide that is then chemically coupled to a protein, such as the diphtheria toxoid CRM 197, in a multistep expensive procedure. In this study, we design, purify and produce novel recombinant pneumococcal protein polysaccharide conjugate vaccines in Escherichia coli, which act as mini factories for the low-cost production of conjugate vaccines. Recombinant vaccine efficacy was tested in a murine model of pneumococcal pneumonia; ability to protect against invasive disease was compared to that of Prevnar13. This study provides the first proof of principle that protein polysaccharide conjugate vaccines produced in E. coli can be used to prevent pneumococcal infection. Vaccines produced in this manner may provide a low-cost alternative to the current vaccine production methodology., (Copyright © 2018. Published by Elsevier Ltd.)

Vonoprazan fumarate is a novel potassium-competitive acid blocker for the treatment of acid-related diseases. In the present study, a simple, fast, and economic reversed-phase liquid chromatography (LC) method was developed for the analysis of ten related substances (raw materials, by-products and degradants) in vonoprazan fumarate. The optimized separation was performed on a Phenomenex Kinetex EVO C 18 (250mm×4.6mm, 5.0μm) column. The mobile phase consisted of (A) 0.03M sodium phosphate buffer (pH adjusted to 6.5) - methanol - acetonitrile (72:25:3, v/v/v) and (B) 0.03M sodium phosphate buffer (pH adjusted to 6.5) - acetonitrile (30:70, v/v). Detection of the analytes was conducted at 230nm using a UV detector. The stability-indicating ability of this method was demonstrated by carrying out forced degradation studies. Vonoprazan underwent significant degradation when subjected to alkaline and oxidative stress conditions, while the drug proved to be stable to acidic, thermal and photolytic degradation. The degradants did not interfere with the detection of vonoprazan fumarate and its impurities. The performance of this method was validated in accordance to the regulatory guidelines recommended by the International Conference on Harmonisation (ICH) and this validation included specificity, linearity, limit of detection (LOD), limit of quantification (LOQ), accuracy, precision and robustness. The method proposed in this paper could be applied for process development as well as quality assurance of vonoprazan in bulk drug, since no monograph is available in official compendia., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Current limitations to on-demand drug manufacturing can be addressed by technologies that streamline manufacturing processes. Combining the production of two or more drugs into a single batch could not only be useful for research, clinical studies, and urgent therapies but also effective when combination therapies are needed or where resources are scarce. Here we propose strategies to concurrently produce multiple biologics from yeast in single batches by multiplexing strain development, cell culture, separation, and purification. We demonstrate proof-of-concept for three biologics co-production strategies: (i) inducible expression of multiple biologics and control over the ratio between biologic drugs produced together; (ii) consolidated bioprocessing; and (iii) co-expression and co-purification of a mixture of two monoclonal antibodies. We then use these basic strategies to produce drug mixtures as well as to separate drugs. These strategies offer a diverse array of options for on-demand, flexible, low-cost, and decentralized biomanufacturing applications without the need for specialized equipment.

Previously, we have discussed the importance of economic incentives in shaping markets for precision medicines. Here we consider incentives for biomarker development, including discovery and establishment. Biomarkers can reveal valuable information regarding diagnosis and prognosis, predict treatment efficacy or toxicity, serve as markers of disease progression, and serve as auxiliary endpoints for clinical trials. Some have multiple uses, while others have a specialized role, resulting in diverse incentives across players in the healthcare system., (© 2017, ASCPT.)

Improved understanding of antigenic components and their interaction with the immune system, as supported by computational tools, permits a sophisticated approach to modern vaccine design. Vaccine platforms provide an effective tool by which strategically designed peptide and protein antigens are modularized to enhance their immunogenicity. These modular vaccine platforms can overcome issues faced by traditional vaccine manufacturing and have the potential to generate safe vaccines, rapidly and at a low cost. This review introduces two promising platforms based on virus-like particle and liposome, and discusses the methodologies and challenges., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

As companies, countries, and governments consider investments in vaccine production for routine immunization and outbreak response, understanding the complexity and cost drivers associated with vaccine production will help to inform business decisions. Leading multinational corporations have good understanding of the complex manufacturing processes, high technological and R&D barriers to entry, and the costs associated with vaccine production. However, decision makers in developing countries, donors and investors may not be aware of the factors that continue to limit the number of new manufacturers and have caused attrition and consolidation among existing manufacturers. This paper describes the processes and cost drivers in acquiring and maintaining licensure of childhood vaccines. In addition, when export is the goal, we describe the requirements to supply those vaccines at affordable prices to low-resource markets, including the process of World Health Organization (WHO) prequalification and supporting policy recommendation. By providing a generalized and consolidated view of these requirements we seek to build awareness in the global community of the benefits and costs associated with vaccine manufacturing and the challenges associated with maintaining consistent supply. We show that while vaccine manufacture may prima facie seem an economic growth opportunity, the complexity and high fixed costs of vaccine manufacturing limit potential profit. Further, for most lower and middle income countries a large majority of the equipment, personnel and consumables will need to be imported for years, further limiting benefits to the local economy., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

People living in Africa face a heavy and wide-ranging burden of disease that takes an incalculable toll on social and economic development as well as shortening life expectancy (life expectancy in Tanzania is about 60 vs. about 80 in the United States and Europe. Further, the pharmaceutical market in developing countries is immature and may not support quality medicines. In many cases, a tender system is used, and medicines are bought by the government at the lowest price. In addition to access to medicines, a number of pharmaceutical sciences problems are apparent. The availability of infrastructure and especially standard instruments such as HPLC and X-ray diffraction is minimal. Additionally, there is an important need to increase access to advanced education for men and women in Africa, especially access to state-of-the-art scientific education. Utilizing the mandate of Nelson Mandela, Purdue's conceptual approach has been to utilize education to combat these problems., (Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Through its Global Action Plan for Influenza Vaccines (GAP), the World Health Organization (WHO) in collaboration with the United States Department of Health and Human Services has produced a checklist to support policy-makers and influenza vaccine manufacturers in identifying key technological, political, financial, and logistical issues affecting the sustainability of influenza vaccine production. This checklist highlights actions in five key areas that are beneficial for establishing successful local vaccine manufacturing. These five areas comprise: (1) the policy environment and health-care systems; (2) surveillance systems and influenza evidence; (3) product development and manufacturing; (4) product approval and regulation; and (5) communication to support influenza vaccination. Incorporating the checklist into national vaccine production programmes has identified the policy gaps and next steps for countries involved in GAP's Technology Transfer Initiative. Lessons learnt from country experiences provide context and insight that complement the checklist's goal of simplifying the complexities of influenza prevention, preparedness, and vaccine manufacturing., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Vaccination is made possible by an interconnected and interdependent ecosystem of vaccine producers, vaccination policy makers and implementers, and vaccine procurers and funders. The future of vaccination depends on the continued health of this ecosystem and its ability to produce, purchase, deliver, and innovate. However, the number of vaccine producers that also do significant research and development has decreased over the last several years. Many of these R&D-based producers have been forced to cease production of critical vaccines, despite global shortages, so that in several cases only one or two producers remain. We discuss the reasons for these changes and what might be done to maintain a healthy vaccination ecosystem.

Drug nanocrystals have rapidly evolved into a mature drug delivery strategy in the last decade, with almost 16 products currently on the market. Several "top-down" technologies are available in the market for generation of nanocrystals. Despite several advantages, very few bottom-up technologies have been explored for commercial purpose. This short communication highlights a novel, bottom-up, spray drying based technology-NanoCrySP-to generate drug nanocrystals. Nanocrystals are generated in the presence of non-polymeric excipients that act as crystallization inducer for the drug. Excipients encourage crystallization of drug by plasticization, primary heterogeneous nucleation, and imparting physical barrier to crystal growth. Nanocrystals have shown significant improvement in dissolution and thereby oral bioavailability. NanoCrySP technology is protected through patents in India, the USA, and the European Union. NanoCrySP can be utilized for (i) pharmaceutical development of new chemical entities, (ii) differentiated products of existing molecules, and (iii) generic drug products. The aggregation of drug nanocrystals generated using NanoCrySP poses significant challenges in the nanocrystal-based product development. Addition of stabilizers either during spray drying or during dissolution has shown beneficial effects.

The ongoing digital revolution is no longer limited to the application of apps on the smart phone for daily needs but starts to affect also our professional life in formulation science. The software platform F-CAD (Formulation-Computer Aided Design) of CINCAP can be used to develop and test in silico capsule and tablet formulations. Such an approach allows the pharmaceutical industry to adopt the workflow of the automotive and aircraft industry. Thus, the first prototype of the drug delivery vehicle is prepared virtually by mimicking the composition (particle size distribution of the active drug substance and of the excipients within the tablet) and the process such as direct compression to obtain a defined porosity. The software is based on a cellular automaton (CA) process mimicking the dissolution profile of the capsule or tablet formulation. To take account of the type of dissolution equipment and all SOPs (Standard Operation Procedures) such as a single punch press to manufacture the tablet, a calibration of the F-CAD dissolution profile of the virtual tablet is needed. Thus, the virtual tablet becomes a copy of the real tablet. This statement is valid for all tablets manufactured within the same formulation design space. For this reason, it is important to define already for Clinical Phase I the formulation design space and to work only within this formulation design space consisting of the composition and the processes during all the Clinical Phases. Thus, it is not recommended to start with a simple capsule formulation as service dosage form and to change later to a market ready tablet formulation. The availability of F-CAD is a necessary, but not a sufficient condition to implement the workflow of the automotive and aircraft industry for developing and testing drug delivery vehicles. For a successful implementation of the new workflow, a harmonization of the equipment and the processes between the development and manufacturing departments is a must. In this context, the clinical samples for Clinical Phases I and II should be prepared with a mechanical simulator of the high-speed rotary press used for large batches for Clinical Phases III & IV. If not, the problem of working practically and virtually in different formulation design spaces will remain causing worldwide annually billion of $ losses according to the study of Benson and MacCabe. The harmonization of equipment and processes needs a close cooperation between the industrial pharmacist and the pharmaceutical engineer. In addition, Virtual Equipment Simulators (VESs) of small and large scale equipment for training and computer assisted scale-up would be desirable. A lean and intelligent management information and documentation system will improve the connectivity between the different work stations. Thus, in future, it may be possible to rent at low costs F-CAD as an IT (Information Technology) platform based on a cloud computing solution. By the adoption of the workflow of the automotive and aircraft industry significant savings, a reduced time to market, a lower attrition rate, and a much higher quality of the final marketed dosage form can be achieved., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Key Message: The first Good Manufacturing Practices production of a purification-free rice-based oral cholera vaccine (MucoRice-CTB) from transgenic plants in a closed cultivation system yielded a product meeting regulatory requirements. Despite our knowledge of their advantages, plant-based vaccines remain unavailable for human use in both developing and industrialized countries. A leading, practical obstacle to their widespread use is producing plant-based vaccines that meet governmental regulatory requirements. Here, we report the first production according to current Good Manufacturing Practices of a rice-based vaccine, the cholera vaccine MucoRice-CTB, at an academic institution. To this end, we established specifications and methods for the master seed bank (MSB) of MucoRice-CTB, which was previously generated as a selection-marker-free line, evaluated its propagation, and given that the stored seeds must be renewed periodically. The production of MucoRice-CTB incorporated a closed hydroponic system for cultivating the transgenic plants, to minimize variations in expression and quality during vaccine manufacture. This type of molecular farming factory can be operated year-round, generating three harvests annually, and is cost- and production-effective. Rice was polished to a ratio of 95 % and then powdered to produce the MucoRice-CTB drug substance, and the identity, potency, and safety of the MucoRice-CTB product met pre-established release requirements. The formulation of MucoRice-CTB made by fine-powdering of drug substance and packaged in an aluminum pouch is being evaluated in a physician-initiated phase I study.

A perspective analysis on the technological innovation in pharmaceutical engineering of Chinese medicine unveils a vision on "Future Factory" of Chinese medicine industry in mind. The strategy as well as the technical roadmap of "Chinese medicine industry 4.0" is proposed, with the projection of related core technology system. It is clarified that the technical development path of Chinese medicine industry from digital manufacture to intelligent manufacture. On the basis of precisely defining technical terms such as process control, on-line detection and process quality monitoring for Chinese medicine manufacture, the technical concepts and characteristics of intelligent pharmaceutical manufacture as well as digital pharmaceutical manufacture are elaborated. Promoting wide applications of digital manufacturing technology of Chinese medicine is strongly recommended. Through completely informationized manufacturing processes and multi-discipline cluster innovation, intelligent manufacturing technology of Chinese medicine should be developed, which would provide a new driving force for Chinese medicine industry in technology upgrade, product quality enhancement and efficiency improvement., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

The success of Gavi, the Vaccine Alliance depends on the vaccine markets providing appropriate, affordable vaccines at sufficient and reliable quantities. Gavi's current supplier base for new and underutilized vaccines, such as the human papillomavirus (HPV), rotavirus, and the pneumococcal conjugate vaccine is very small. There is growing concern that following globalization of laws on intellectual property rights (IPRs) through trade agreements, IPRs are impeding new manufacturers from entering the market with competing vaccines. This article examines the extent to which IPRs, specifically patents, can create such obstacles, in particular for developing country vaccine manufacturers (DCVMs). Through building patent landscapes in Brazil, China, and India and interviews with manufacturers and experts in the field, we found intense patenting activity for the HPV and pneumococcal vaccines that could potentially delay the entry of new manufacturers. Increased transparency around patenting of vaccine technologies, stricter patentability criteria suited for local development needs and strengthening of IPRs management capabilities where relevant, may help reduce impediments to market entry for new manufacturers and ensure a competitive supplier base for quality vaccines at sustainably low prices., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Ink-jet printing is a versatile, precise and relatively inexpensive method of depositing small volumes of solutions with remarkable accuracy and repeatability. Although developed primarily as a technology for image reproduction, its areas of application have expanded significantly in recent years. It is particularly suited to the manufacture of low dose medicines or to short production runs and so offers a potential manufacturing solution for the paradigm of personalised medicines. This review discusses the technical and clinical aspects of ink-jet printing that must be considered in order for the technology to become widely adopted in the pharmaceutical arena and considers applications in the literature., (Copyright © 2014 Elsevier B.V. All rights reserved.)

With interest in microneedles as a novel drug transdermal delivery system increasing rapidly since the late 1990s (Margetts and Sawyer Contin Educ Anaesthesia Crit Care Pain. 7(5):171-76, 2007), a diverse range of microneedle systems have been fabricated with varying designs and dimensions. However, there are still very few commercially available microneedle products. One major issue regarding microneedle manufacture on an industrial scale is the lack of specific quality standards for this novel dosage form in the context of Good Manufacturing Practice (GMP). A range of mechanical characterisation tests and microneedle insertion analysis techniques are used by researchers working on microneedle systems to assess the safety and performance profiles of their various designs. The lack of standardised tests and equipment used to demonstrate microneedle mechanical properties and insertion capability makes it difficult to directly compare the in use performance of candidate systems. This review highlights the mechanical tests and insertion analytical techniques used by various groups to characterise microneedles. This in turn exposes the urgent need for consistency across the range of microneedle systems in order to promote innovation and the successful commercialisation of microneedle products.

Aging facilities have become a concern in the pharmaceutical and biopharmaceutical manufacturing industry, so much that task forces are formed by trade organizations to address the topic. Too often, examples of aging or obsolete equipment, unit operations, processes, or entire facilities have been encountered. Major contributors to this outcome are the failure to invest in new equipment, disregarding appropriate maintenance activities, and neglecting the implementation of modern technologies. In some cases, a production process is insufficiently modified to manufacture a new product in an existing process that was used to produce a phased-out product. In other instances, manufacturers expanded the facility or processes to fulfill increasing demand and the scaling occurred in a non-uniform manner, which led to non-optimal results. Regulatory hurdles of post-approval changes in the process may thwart companies' efforts to implement new technologies. As an example, some changes have required 4 years to gain global approval. This paper will address cases of aging processes and facilities aside from modernizing options., (© PDA, Inc. 2015.)

Objectives: To identify the factors that influence the Scottish Medicines Consortium (SMC) in deciding whether to accept pharmaceutical technologies for use within the Scottish health care system., Methods: A database of SMC submissions between 2006 and 2013 was created, containing a range of clinical, economic, and other factors extracted from published health technology assessment reports. A binomial outcome variable was used, defined as the decision to "accept for use" or "not recommend" a technology. Univariate and multivariate analyses were conducted to assess the impact by means of odds ratios (ORs) of the submitted evidence on the recommendation decision., Results: Out of 463 applications, 265 were accepted for use (57%) and 198 (43%) were not recommended for use within National Health Service Scotland. Univariate analyses showed that 13 variables significantly affected the SMC decision. Of these 13 variables, 7 variables were shown to have a meaningful impact in the multivariate analysis. Four of these concerned the outcome of cost-effectiveness analyses; the fact that a submission was supported by a cost-minimization analysis was the strongest positive variable (OR = 10.30) and a submission showing a product not being cost-effective (i.e., incremental cost-effectiveness ratio above £30,000/quality-adjusted life-year gained) was the strongest negative predictor (OR = 0.47). The other variables concerned whether the submission was related to a product indicated for a nervous system disease (OR = 0.41), whether it was indicated for nonchronic use (OR = 1.66), and whether the submission was performed by a big company (OR = 2.83)., Conclusions: This study demonstrated that the outcome of cost-effectiveness analyses is an important factor affecting the SMC's reimbursement recommendation decision., (Copyright © 2015. Published by Elsevier Inc.)

This paper examines the opportunities and challenges facing the pharmaceutical industry in moving to a primarily "continuous processing"-based supply chain. The current predominantly "large batch" and centralized manufacturing system designed for the "blockbuster" drug has driven a slow-paced, inventory heavy operating model that is increasingly regarded as inflexible and unsustainable. Indeed, new markets and the rapidly evolving technology landscape will drive more product variety, shorter product life-cycles, and smaller drug volumes, which will exacerbate an already unsustainable economic model. Future supply chains will be required to enhance affordability and availability for patients and healthcare providers alike despite the increased product complexity. In this more challenging supply scenario, we examine the potential for a more pull driven, near real-time demand-based supply chain, utilizing continuous processing where appropriate as a key element of a more "flow-through" operating model. In this discussion paper on future supply chain models underpinned by developments in the continuous manufacture of pharmaceuticals, we have set out; The significant opportunities to moving to a supply chain flow-through operating model, with substantial opportunities in inventory reduction, lead-time to patient, and radically different product assurance/stability regimes. Scenarios for decentralized production models producing a greater variety of products with enhanced volume flexibility. Production, supply, and value chain footprints that are radically different from today's monolithic and centralized batch manufacturing operations. Clinical trial and drug product development cost savings that support more rapid scale-up and market entry models with early involvement of SC designers within New Product Development. The major supply chain and industrial transformational challenges that need to be addressed. The paper recognizes that although current batch operational performance in pharma is far from optimal and not necessarily an appropriate end-state benchmark for batch technology, the adoption of continuous supply chain operating models underpinned by continuous production processing, as full or hybrid solutions in selected product supply chains, can support industry transformations to deliver right-first-time quality at substantially lower inventory profiles., (© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.)

This white paper focuses on equipment, and analytical manufacturers' perspectives, regarding the challenges of continuous pharmaceutical manufacturing across five prompt questions. In addition to valued input from several vendors, commentary was provided from experienced pharmaceutical representatives, who have installed various continuous platforms. Additionally, a small medium enterprise (SME) perspective was obtained through interviews. A range of technical challenges is outlined, including: the presence of particles, equipment scalability, fouling (and cleaning), technology derisking, specific analytical challenges, and the general requirement of improved technical training. Equipment and analytical companies can make a significant contribution to help the introduction of continuous technology. A key point is that many of these challenges exist in batch processing and are not specific to continuous processing. Backward compatibility of software is not a continuous issue per se. In many cases, there is available learning from other industries. Business models and opportunities through outsourced development partners are also highlighted. Agile smaller companies and academic groups have a key role to play in developing skills, working collaboratively in partnerships, and focusing on solving relevant industry challenges. The precompetitive space differs for vendor companies compared with large pharmaceuticals. Currently, there is no strong consensus around a dominant continuous design, partly because of business dynamics and commercial interests. A more structured common approach to process design and hardware and software standardization would be beneficial, with initial practical steps in modeling. Conclusions include a digestible systems approach, accessible and published business cases, and increased user, academic, and supplier collaboration. This mirrors US FDA direction. The concept of silos in pharmaceutical companies is a common theme throughout the white papers. In the equipment domain, this is equally prevalent among a broad range of companies, mainly focusing on discrete areas. As an example, the flow chemistry and secondary drug product communities are almost entirely disconnected. Control and Process Analytical Technologies (PAT) companies are active in both domains. The equipment actors are a very diverse group with a few major Original Equipment Manufacturers (OEM) players and a variety of SME, project providers, integrators, upstream downstream providers, and specialist PAT. In some cases, partnerships or alliances are formed to increase critical mass. This white paper has focused on small molecules; equipment associated with biopharmaceuticals is covered in a separate white paper. More specifics on equipment detail are provided in final dosage form and drug substance white papers. The equipment and analytical development from laboratory to pilot to production is important, with a variety of sensors and complexity reducing with scale. The importance of robust processing rather than overcomplex control strategy mitigation is important. A search of nonacademic literature highlights, with a few notable exceptions, a relative paucity of material. Much focuses on the economics and benefits of continuous, rather than specifics of equipment issues. The disruptive nature of continuous manufacturing represents either an opportunity or a threat for many companies, so the incentive to change equipment varies. Also, for many companies, the pharmaceutical sector is not actually the dominant sector in terms of sales., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

This white paper provides a perspective of the challenges, research needs, and future directions for control systems engineering in continuous pharmaceutical processing. The main motivation for writing this paper is to facilitate the development and deployment of control systems technologies so as to ensure quality of the drug product. Although the main focus is on small-molecule pharmaceutical products, most of the same statements apply to biological drug products. An introduction to continuous manufacturing and control systems is followed by a discussion of the current status and technical needs in process monitoring and control, systems integration, and risk analysis. Some key points are that: (1) the desired objective in continuous manufacturing should be the satisfaction of all critical quality attributes (CQAs), not for all variables to operate at steady-state values; (2) the design of start-up and shutdown procedures can significantly affect the economic operation of a continuous manufacturing process; (3) the traceability of material as it moves through the manufacturing facility is an important consideration that can at least in part be addressed using residence time distributions; and (4) the control systems technologies must assure quality in the presence of disturbances, dynamics, uncertainties, nonlinearities, and constraints. Direct measurement, first-principles and empirical model-based predictions, and design space approaches are described for ensuring that CQA specifications are met. Ways are discussed for universities, regulatory bodies, and industry to facilitate working around or through barriers to the development of control systems engineering technologies for continuous drug manufacturing. Industry and regulatory bodies should work with federal agencies to create federal funding mechanisms to attract faculty to this area. Universities should hire faculty interested in developing first-principles models and control systems technologies for drug manufacturing that are easily transportable to industry. Industry can facilitate the move to continuous manufacturing by working with universities on the conception of new continuous pharmaceutical manufacturing process unit operations that have the potential to make major improvements in product quality, controllability, or reduced capital and/or operating costs. Regulatory bodies should ensure that: (1) regulations and regulatory practices promote, and do not derail, the development and implementation of continuous manufacturing and control systems engineering approaches; (2) the individuals who approve specific regulatory filings are sufficiently trained to make good decisions regarding control systems approaches; (3) provide regulatory clarity and eliminate/reduce regulatory risks; (4) financially support the development of high-quality training materials for use of undergraduate students, graduate students, industrial employees, and regulatory staff; (5) enhance the training of their own technical staff by financially supporting joint research projects with universities in the development of continuous pharmaceutical manufacturing processes and the associated control systems engineering theory, numerical algorithms, and software; and (6) strongly encourage the federal agencies that support research to fund these research areas., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

New drugs and biologics have had a tremendous impact on the treatment of many diseases. However, available measures suggest that pharmaceutical innovation has remained relatively flat, despite substantial growth in research and development spending. We review recent literature on pharmaceutical innovation to identify limitations in measuring and assessing innovation, and we describe the framework and collaborative approach we are using to develop more comprehensive, publicly available metrics for innovation. Our research teams at the Brookings Institution and Deerfield Institute are collaborating with experts from multiple areas of drug development and regulatory review to identify and collect comprehensive data elements related to key development and regulatory characteristics for each new molecular entity approved over the past several decades in the United States and the European Union. Subsequent phases of our effort will add data on downstream product use and patient outcomes and will also include drugs that have failed or been abandoned in development. Such a database will enable researchers to better analyze the drivers of drug innovation, trends in the output of new medicines, and the effect of policy efforts designed to improve innovation., (Project HOPE—The People-to-People Health Foundation, Inc.)

The sales and financial returns realized by pharmaceutical companies are a frequent topic of discussion and debate. In this study we analyzed the economic returns for four cohorts of new prescription drugs launched in the United States (in 1991-94, 1995-99, 2000-04, and 2005-09) and compared fluctuations in revenues with changing average research and development (R&D) and other costs to determine patterns in rewards for pharmaceutical innovation. We found that the average present values of lifetime net economic returns were positive and reached a peak with the 1995-99 and 2000-04 new drug cohorts. However, returns have fallen sharply since then, with those for the 2005-09 cohort being very slightly negative and, on average, failing to recoup research and development and other costs. If this level of diminished returns persists, we believe that the rewards for innovation will not be sufficient for pharmaceutical manufacturers to maintain the historical rates of investments needed to sustain biomedical innovation., (Project HOPE—The People-to-People Health Foundation, Inc.)

Vaccination is still the most efficient measure to protect against influenza virus infections. Besides the seasonal wave of influenza, pandemic outbreaks of bird or swine flu represent a high threat to human population. With the establishment of cell culture-based processes, there is a growing demand for robust, economic and efficient downstream processes for influenza virus purification. This study focused on the development of an economic flow-through chromatographic process avoiding virus strain sensitive capture steps. Therefore, a three-step process consisting of anion exchange chromatography (AEC), Benzonase(®) treatment, and size exclusion chromatography with a ligand-activated core (LCC) was established, and tested for purification of two influenza A virus strains and one influenza B virus strain. The process resulted in high virus yields (≥68%) with protein contamination levels fulfilling requirements of the European Pharmacopeia for production of influenza vaccines for human use. DNA was depleted by ≥98.7% for all strains. The measured DNA concentrations per dose were close to the required limits of 10ng DNA per dose set by the European Pharmacopeia. In addition, the added Benzonase(®) could be successfully removed from the product fraction. Overall, the presented downstream process could potentially represent a simple, robust and economic platform technology for production of cell culture-derived influenza vaccines., (Copyright © 2014 Elsevier B.V. All rights reserved.)

SCHWABE Company in German is the first and largest manufacturer of Ginkgo biloba preparation. The company not only has leading technology in this field, but also protects its own market effectively through the high quality of patent drafting and exactly patent layout. Based on multi-angle analysis for patent portfolio of G. biloba preparation at application time, legal status, globally layout, Chinese layout, the article provides technical reference of research and development of G. biloba, also provides valuable experience of traditonal Chinese medicine patent portfolio layout for Chinese enterprises.