Benchmarking biopharmaceutical process development and manufacturing cost contributions to R&D.

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.

Good design practices for an integrated containment and production system for advanced therapies.

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.

Situation analysis of procurement and production of multiple micronutrient supplements in 12 lower and upper middle-income countries.

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).

[Chinese medicine industry 4.0：advancing digital pharmaceutical manufacture toward intelligent pharmaceutical manufacture].

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.

[SCHWABE Company's patent portfolio of Ginkgo biloba preparation].

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.

Lessons learned from the fate of AstraZeneca's drug pipeline: a five-dimensional framework.

Maintaining research and development (R&D) productivity at a sustainable level is one of the main challenges currently facing the pharmaceutical industry. In this article, we discuss the results of a comprehensive longitudinal review of AstraZeneca's small-molecule drug projects from 2005 to 2010. The analysis allowed us to establish a framework based on the five most important technical determinants of project success and pipeline quality, which we describe as the five 'R's: the right target, the right patient, the right tissue, the right safety and the right commercial potential. A sixth factor - the right culture - is also crucial in encouraging effective decision-making based on these technical determinants. AstraZeneca is currently applying this framework to guide its R&D teams, and although it is too early to demonstrate whether this has improved the company's R&D productivity, we present our data and analysis here in the hope that it may assist the industry overall in addressing this key challenge.

[Strategy and core technologies for the secondary development of Chinese patent medicine].

Secondary development of Chinese Patent Medicine (CPM) is an effective and innovation-driven way for the leaping development of Chinese medicine industry with less investment and faster return. Aim to improving the efficacy, safety and batch-to-batch consistency of CPMs, the theory and methodology for the secondary development of CPMs, mode for cultivating superior CPM, approaches to reforming the pharmaceutical technology and the corresponding core technologies were proposed in this paper, which is summarized as 'One objective, Three analyses, Five definitudes and Seven improvements'.

[Industry of traditional Chinese patent medicine science and technology development and review].

"Fifteen" since, our country Chinese traditional medicine industry science and technology has made remarkable achievements. In this paper, the development of science and technology policy, Chinese medicine industry, platform construction and other aspects were analyzed, showing 10 years of Chinese traditional medicine industry development of science and technology innovation achievement and development, and on the current development of traditional Chinese medicine industry facing the main tasks and guarantee measures are analyzed.

Improving the efficiency of the development of drugs for stroke.

The mortality and morbidity associated with stroke makes the development of new drugs a research priority. Recent unsuccessful clinical trials have reduced enthusiasm for the development of neuroprotective drugs. Here, we use empirical evidence derived from systematic reviews of stroke drug development to identify stages of drug development which might be improved. We then propose exemplar strategies which may be helpful, along with some basic economic modelling of what the impact of such strategies might be. This suggests that relatively straightforward measures might reduce the costs of drug development by $5·8 bn or 31%.

Increase in viral yield in eggs and MDCK cells of reassortant H5N1 vaccine candidate viruses caused by insertion of 38 amino acids into the NA stalk.

BACKGROUND: The H5N1 subtype of highly pathogenic avian influenza viruses has spread to over 63 countries in Asia, Europe, and Africa and has become endemic in poultry. Since 2004, vaccination against H5N1 influenza has become common in domestic poultry operations in China. Most influenza vaccines have been produced in embryonated chicken eggs. High yield is the essential feature of a good vaccine candidate virus. OBJECTIVE: Therefore, the large-scale manufacture of such a vaccine requires that the viral yield of H5N1 reassortant vaccine viruses in eggs and MDCK cells be increased. METHODS: We generated two sets of reassortant H5N1 viruses based on backbone viruses A/Chicken/F/98 (H9N2) and A/Puerto Rico/8/34 (H1N1) using reverse genetics. The HAs and NAs of the reassortants were derived from the three epidemic H5N1 strains found in China. We compared the replication properties of these recombinant H5N1 viruses in embryonated chicken eggs and MDCK cells after inserting either 20 or 38 amino acids into their NA stalks. RESULTS: In this study, we demonstrated that inserting 38 amino acids into the NA stalks can significantly increase the viral yield of H5N1 reassortant viruses in both embryonated chicken eggs and MDCK cells, while inserting only 20 amino acids into the same NA stalks does not. Hemagglutinin inhibition testing and protection assays indicated that recombinant H5N1 viruses with 38 aa inserted into their NA stalks had the same antigenicity as the viruses with wt-NA. CONCLUSION: These results suggest that the generation of an H5N1 recombinant vaccine seed by the insertion of 38 aa into the NA stalk may be a suitable and more economical strategy for the increase in viral yield in both eggs and MDCK cells for the purposes of vaccine production.

[Comparison of microwave-assisted and conventional extraction of Corydalis yanhusuo].

OBJECTIVE: To compare the extraction yield and economic cost in the microwave-assisted extraction and conventional extraction of Corydalis yanhusuo. METHODS: Both of the extractions of Corydalis yanhusuo were optimized by orthogonal design. The contents of tetrahydropalmatine and total alkaloids were determined by HPLC and ultraviolet spectrophotometer, respectively. Meanwhile, the electricity consumption was determined in the extraction process. RESULTS: Comparing with conventional extraction, the microwave-assisted extraction saved time and money, and provided higher extraction yield of tetrahydropalmatine and total alkaloids. CONCLUSION: The microwave-assisted extraction has advantages in high efficiency and low cost.

Antibiotic resistance--action to promote new technologies: report of an EU Intergovernmental Conference held in Birmingham, UK, 12-13 December 2005.

The increase in microorganisms that have developed resistance to currently available antimicrobial agents has become a major cause for concern worldwide. These organisms are widespread in hospitals but also occur increasingly in the community. Some of these strains are multiresistant and the agents available to treat infections caused by them are few and dwindling. Over recent years there have been a number of responses by national, international and professional bodies to this situation, many aimed at curbing this unprecedented growth in resistance, but there is an increasing recognition that a major problem in the management of infections caused by such organisms is the paucity of new drugs, vaccines and diagnostic aids. A conference, organized by the Specialist Advisory Committee on Antimicrobial Resistance (SACAR) on behalf of the UK Department of Health and sponsored by the BSAC, was held in Birmingham in December 2005 with the aim of addressing these problems. Conference attendees included those from academia, industry, funding agencies, healthcare management, the European Medicines Agency (EMEA), the European Centre for Disease Prevention and Control (ECDC), European Directorates and representatives of EU governments. Following a number of keynote presentations which identified major issues, there were a series of workshops which addressed specific questions and produced a number of recommendations. These recommendations were discussed by all delegates. The lack of new anti-infectives and the reasons for this were discussed in some detail. Major pharmaceutical companies no longer find this area as financially rewarding as other therapeutic areas while smaller biotechnology companies, who are seen as more innovative, are hampered by a lack of funding. In spite of a few marked successes, the use of vaccines has had minimal impact in the field of bacterial infections, and progress in this field also suffers from a lack of funding. Diagnostics could aid in the better use of antibacterials but need greater acceptance in the healthcare system, which does not generally appreciate their cost-efficacy. The major recommendations were as follows: (i) Increased efforts are needed to reduce the spread of resistant strains both in the environment and in hospitals--these include improved hygiene and decreased use of some antimicrobials. (ii) Surveillance of resistance is a key factor and improved technology (e.g. IT systems) is needed to improve the potential for surveillance data to inform clinical practice. (iii) Rapid, sensitive and specific diagnostics are urgently needed and the issue of reimbursement needs to be addressed. (iv) More accurate estimates of the cost-efficacy of using anti-infectives and diagnostics are urgently needed. (v) Vaccine technology is available but is underused for the prevention of bacterial infections, particularly those caused by organisms resistant to antimicrobials. (vi) Incentives are required to encourage large pharmaceutical companies to partner small biotechnology companies, which are more innovative and have the potential to deliver the new drugs, diagnostics and vaccines. Modifications to the international regulatory requirements for drug licensing could have a major impact on the time and thus the costs of developing new agents.

The power of pharmacological sciences: the example of proton pump inhibitors.

Critics have questioned the foundational principles of pharmacological sciences and modern drug therapy; they also claim that drug therapy is often too expensive or of uncertain value. Contemporaneously, alternative medicine has bloomed. Yet the US government began to pay for drug therapy under Medicare in 2006, an explicit recognition of the value of modern drug therapy. To clarify this confusion, we review the philosophical and scientific foundations of pharmacology, drug discovery and development, the attendant strategies and successful results. We also review and answer the major attacks on the philosophical and scientific foundations of modern pharmacology and drug therapy. Finally, we define the characteristics of an ideal drug. As an example of the principles and strategies of modern pharmacological sciences and their successful application, we focus on the discovery and development of proton pump inhibitors (PPIs) of stomach acid production. This class of drugs approaches the ideal and exemplifies successful application of modern pharmacological principles to drug discovery and development. Moreover, the use of PPIs as a pharmacological tool allowed the resolution of important scientific questions, e.g., the role of stomach acid in peptic diseases of the stomach, duodenum and esophagus.

Finding new tricks for old drugs: an efficient route for public-sector drug discovery.

With the annotation of the human genome approaching completion, public-sector researchers - spurred in part by various National Institutes of Health Roadmap Initiatives - have become increasingly engaged in drug discovery and development efforts. Although large and diverse chemical libraries of 'drug-like' compounds can be readily screened to yield chemically novel scaffolds, transforming these 'chemical probes' into drugs is a daunting endeavour. A more efficient approach involves screening libraries of approved and off-patent medications; both phenotypic- and molecular target-based screening of 'old drugs' can readily yield compounds that could be immediately used in clinical trials. Using case studies, we describe how this approach has rapidly identified candidate medications suitable for clinical trials in disorders such as progressive multifocal leukoencephalopathy and amyotrophic lateral sclerosis. This approach has also led to the discovery of the molecular targets responsible for serious drug side effects, thereby allowing efficient 'counter-screening' to avoid these side effects.

Gene expression profiling for pharmaceutical safety assessment.

Toxicogenomics is the application of gene expression profiling technology to toxicology. This results in the generation of very large and complex gene expression data sets associated with the development of toxicities. It is widely assumed that this data can be deconvoluted to reveal novel insights into toxicological processes that are of value to the task of risk assessment. More specifically, it is hoped that toxicogenomics will aid in the prediction of the toxic potential and mechanisms of toxicity of novel chemical entities. On the basis of such promise, the pharmaceutical industry has invested heavily in this area, as the perceived rewards in terms of improved pipeline efficiency and safer drugs are immense. Consequently, a great deal of groundwork has been done over the past several years to establish working methods in toxicogenomics, both within industry and academia, demonstrating utility in proof-of-concept studies, generating the databases on which some approaches depend, and developing new data analysis tools. Despite such activity, there is little reported evidence to suggest that toxicogenomics is making a significant impact on the discovery and development of drugs. This may partly reflect the understandable reluctance of pharmaceutical industries to share information in a competitive environment. It may also partly reflect difficulties in bridging the gap between theory and practice, as is required to deliver real value to the industry. This review will assess the successes and shortcomings of toxicogenomics, and consider how it can be usefully applied to a drug discovery pipeline.

Affinity-based screening techniques for enhancing lead discovery.

Contemporary, rational small-molecule lead discovery methods, comprising target identification, assay development, high-throughput screening (HTS), hit characterization and medicinal chemistry optimization, dominate early-stage drug discovery strategies in many pharmaceutical companies. There is a growing disparity between the increasing cost of funding these methods and the decreasing number of new drugs reaching the market. New strategies must be adopted to reverse this trend. The use of genomics- and proteomics-based target discovery efforts can aid the process by dramatically increasing the number of novel, more highly validated targets entering the discovery process, but HTS must meet this increased demand with faster, cheaper technologies. Although activity-based screening strategies are typically efficient, allowing one scientist to interrogate tens of thousands of compounds per day, affinity-based screening strategies can allow much greater efficiency in the overall process. Affinity-based methods can play a role in both facilitating the screening of a greater number of targets and in efficiently characterizing the primary hits discovered.