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Latest issue / 15 December 2011 / Terry McMahon (PAI Partners), Dr. Marianna Machin, Dr. Lorenz Liesum, Dr. Antonio Peinado (Novartis Pharma AG), Ravindra Dhumal, Tim Gough (Centre for Pharmaceutical Engineering Science, University of Bradford)
The historical development of the FDA’s PAT initiative and its present course (Terry McMahon, PAI Partners)
Implementation of modelling approaches in the QbD framework: Examples from the Novartis experience (Dr. Marianna Machin, Dr. Lorenz Liesum and Dr. Antonio Peinado, Novartis Pharma AG)
Challenges in development and implementation of spectroscopic techniques as PAT Analysers (Ravindra Dhumal and Tim Gough, Centre for Pharmaceutical Engineering Science, University of Bradford) (more…)
Tagged with: Centre for Pharmaceutical Engineering Science, Dr. Antonio Peinado, Dr. Lorenz Liesum, Dr. Marianna Machin, Novartis Pharma AG, PAI Partners, PAT, Ravindra Dhumal, Terry McMahon, Tim Gough, University of Bradford
Latest issue / 13 December 2011 / Michael J. Miller, President, Microbiology Consultants
This is the sixth and final article in our series on Rapid Microbiological Methods (RMMs) that have appeared in European Pharmaceutical Review during 2011. In our last article, we reviewed the world of nucleic acid amplification technologies, including PCR-DNA amplification, RNA-based reverse-transcriptase amplification, 16S rRNA typing and gene sequencing for the detection, identification, and in some cases, the enumeration of microorganisms. In our last article of the year, we will explore one of the most exciting areas in microbiological detection and miniaturisation: Micro-Electro-Mechanical Systems, or MEMS.
Imagine, for a moment, a machine so small that the human eye cannot see it and thousands of these machines are manufactured on a single piece of silicon. Imagine a future where gravity and inertia are no longer important, but atomic forces and surface sciences dominate. This is the world of Micro-Electro-Mechanical Systems (MEMS), and the future is now.
MEMS is the integration of mechanical, electrical, fluidic and optical elements, sensors and actuators on common silicon or other solid substrate through microfabrication technology. This is one of the fastest growing segments in the diagnostics and biomedical applications area, particularly for drug discovery and delivery, DNA testing and diagnostics, biotelemetry and genomics. And now, these same technologies are being introduced into the pharmaceutical sector for the rapid detection of contaminants. Examples of MEMS that have already been developed include Lab-On-A-Chip and microfluidics devices, microarrays, biosensors and other nanotechnology platforms. (more…)
Tagged with: Biosensors, Michael J. Miller, Micro-Electro-Mechanical Systems (MEMS), Microarrays, Microbiology, Microbiology Consultants LLC, Microorganisms, Nanotechnology
Latest issue / 13 December 2011 / Andrew A. Parsons, Vice President Preclinical Drug Development, GlaxoSmithKline and Steve Street, Vice President, Head of Research Centres of Emphasis, Head of WRD Continuous Improvement, Pfizer and William Strohl, Vice President of Biologics Research, Centocor R&D, a division of Johnson & Johnson Pharmaceutical Research & Development and Eckhard von Keutz, Senior Vice President, Head Global Early Development, Bayer HealthCare
Andrew A. Parsons, Vice President Preclinical Drug Development, GlaxoSmithKline
Dr. Parsons has led the Preclinical Development function in the CEDD since its creation. He was previously the Head of Preclinical Development for the Neurology and Gastrointestinal (NGI) Center of Excellence for Drug Discovery (CEDD) and a member of the Executive Leadership Team. Dr. Parsons joined SmithKline Beecham in 1991 as a lead biologist on the Migraine Program and played a key role in the identification and development of Frovatriptan and Tonabersat. He has worked in a number of therapy areas within drug discovery and has led teams that progressed numerous compounds in development. He was also previously the Chairman of the Imitrex (Sumatriptan) International Scientific Advisory Board. Dr. Parsons graduated with a BSc, MSc and PhD in Pharmacology, University of Manchester and is a qualified NLP practitioner and Cognitive Therapist. He worked as a post-doctoral researcher at the Institute of Physiology, University of Munich, Germany. He has authored more than 90 peer-reviewed publications.
Steve Street, Vice President, Head of Research Centres of Emphasis, Head of WRD Continuous Improvement, Pfizer
Steve Street joined Pfizer in 1985 and held a variety of roles within the Chemistry Department in Sandwich UK, before being appointed Head of Chemistry for Sandwich Discovery in 2001. Three years later, at the start of 2004, Steve moved to establish and lead the Chemistry discipline across Worldwide Discovery. Steve held this role through to early 2007 when he was delighted to be asked to take on a new role as Head of the Research Centers of Emphasis, covering a range of activities supporting Worldwide Research including External Research, BioImaging, Computational Sciences and High Throughput Screening. In April 2008, Steve was asked to become Head of Continuous Improvement across all of Pfizer Worldwide Research and Development where his focus was uniquely on improving project and portfolio survival and cycle times. (more…)
Tagged with: Andrew A. Parsons, Bayer HealthCare, Centocor R&D, Drug discovery, Eckhard von Keutz, GlaxoSmithKline, Johnson & Johnson Pharmaceutical Research & Development, Pfizer, Steve Street, William Strohl
Latest issue / 13 December 2011 / Ole Pless and Sheraz Gul, European ScreeningPort GmbH
Multiple Sclerosis (MS) is an autoimmune disease leading to a chronic inflammation and degeneration of the central nervous system. It is one of the major neurological diseases with approximately 2.5 million suffering patients worldwide. Until now, the underlying mechanisms have not been fully elucidated, but the cause of the disease can be modulated to limit progression and severity. Currently, there are no validated biomarkers available to predict the progression of MS or response to a clinical intervention apart from MRI. In order to identify protein biomarkers for MS as well as other diseases, significant infrastructure is required and this is discussed.
The term ‘biomarker’ has been defined as a “characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention”1,2. The measurement of normal and dysfunctional biological processes and their changes in response to therapeutic intervention forms the basis of biomarkers. The advances in genetics and molecular biology leading to the sequencing of the human genome has resulted in the identification of a variety of novel targets implicated in different disease states3-5. Further technological developments including high throughput profiling of various samples using genomics, transcriptomics and proteomics6,7 has led to the identification of gene and protein based markers that characterise disease states for a number of indications including breast cancer8-10, colorectal cancer11 and cardiovascular diseases12. Additional initiatives that have led to the identification of biomarkers with minimal invasive methods such as proteomics technologies13 and systems biology14 have proven extremely effective for discovering potential biomarkers and drug targets. These technologies tend to provide large data sets that can be difficult to deconvolute for biomarker discovery. This bottleneck can be reduced by using several strategies. The first is to constrict the number of potential biomarkers and drug targets by dividing the proteome into smaller, more biologically significant segments. The second is to widen the bottleneck with higheroutput and higher-throughput screening technologies. The third is to incorporate more preliminary validation into the discovery process. New and emerging technologies provide promise for each of these strategies15. (more…)
Tagged with: Biomarkers, European ScreeningPort GmbH, Mltiple Sclerosis (MS), Ole Pless, Sheraz Gul
Latest issue / 13 December 2011 / Henri Xhaard, Head of Computational Drug Discovery Group, Centre for Drug Research, University of Helsinki
The central location of G protein-coupled receptors (GPCRs) at the interface between the interior and exterior of cells, as well as their key role in signalling events, make GPCRs a prominent class of pharmaceutical targets. To date, approximately 40 per cent of known drugs are thought to act on GPCRs either directly or indirectly. GPCRs are for the most part inaccessible to structural determination due to difficulties to express, purify and crystallise them; however, progress of structure determination has led to seven new structures in the last decade. This number is still insufficient to conduct structure-based drug discovery on all available targets. Computational modelling is therefore a very useful surrogate and in this paper I discuss the reliability of atomistic three-dimensional models that are obtained through molecular modelling in light of the GPCRdock 2008 and 2010 competitions organised by the Scripps Institute.
G protein coupled receptors (GPCRs) are key proteins involved in signalling and as such are prominent drug targets1. Ligands that bind to GPCRs include small aminergic neuro – transmitters or hormones such as noradrenaline and adrenaline, dopamine, histamine, small peptides, nucleic acids, lipids or even opsins that contain light-reactive retinal chromophores. Altogether, in the human genome project, about 390 non-olfactory GPCRs have been identified; of which about 100 are orphan proteins without an identified ligand or cellular function. (more…)
Tagged with: Drug discovery, GPCRs, Henr Xhaard, University of Helsinki
Latest issue / 13 December 2011 / Ulrike Korf, DKFZ Heidelberg
In order to advance the identification of new drug targets and disease biomarkers, experimental tools for the systems-level analysis of signalling networks are required. Approaches for a targeted analysis of cellular proteomes have improved in recent years. Notably, the reverse phase protein microarray (RPPA) approach offers great advantages due to properties such as high sensitivity and high sample capacity. This review gives an overview of the principle of RPPA and summarises successful applications that illustrate the potential of RPPA for the analysis of clinical samples, systems biology and for drug discovery concepts. Numerous reports demonstrated the power of this approach to produce higher-order information than is currently possible with any other approach while requiring only minute amounts of sample.
Up-to-date, acquired experience on the application of targeted therapeutics revealed that patients benefit from drugs targeting molecules that are overexpressed by tumours. However, the percentage of patients truly benefiting from the targeted treatment depends largely on the type of tumour. In detail, clinical data obtained from the treatment of solid tumours suggests that our current knowledge is not sufficient to decide beforehand which patients will benefit from a certain treatment and which patients do not. This suggests that overexpression of a particular oncogenic protein by a tumour, such as EGFR, HER2, or oestrogen receptor, does not provide dependable information for treatment decisions. Considerable knowledge has been accumulated on the wiring of those pathways that convey information from cell surface receptors and neighbouring cells as well as the nutritional state and related physiological events. An obvious challenge for proteome research is to convert this knowledge into clinically and pharmaceutically relevant information. However, most drugs target proteins and therefore the realisation of personalised treatment concepts requires a systematic large-scale analysis of individual tumours to identify patterns of deregulation characteristic for subgroups of a certain type of cancer. The identification of reliable disease markers could then be translated into new treatment concepts which have been held back due to technological constraints. (more…)
Tagged with: Antibody Microarrays, Biomarkers, Cellular Proteomes, DKFZ Heidelberg, Microarrays, Oncology, Reverse Phase Protein Microarray (RPPA), Ulrike Korf
Latest issue / 13 December 2011 / Sheraz Gul, Vice President and Head of Biology, European ScreeningPort GmbH
The pre-clinical phase of drug discovery spans a period in the region of five years and requires contributions from multi-disciplinary teams often working at different sites. These teams can generate significant amounts of data which are processed using standard as well as specialist software. The recording of a substantial amount of project related experimental work has historically been performed using paper-based laboratory notebooks completed manually with all files usually being stored locally.
This scenario poses a variety of issues such as delayed access to important information to the project team members which could ultimately reduce its efficiency and thus increase the time taken to complete the project. These paper-based notebooks are now being replaced by an electronic laboratory notebook (eLNB) within research laboratories in industry and academia. Such software allows the documentation of experimental data and its sharing within the multi-disciplinary research team and would be expected to improve data integrity, reduce the time to complete the project and improve communication. This article discusses some of the advantages that would be expected to be achieved upon implementing an eLNB in pre-clinical drug discovery. (more…)
Tagged with: Drug discovery, eLNBs, ELNs, European ScreeningPort GmbH, Sheraz Gul
Latest issue / 13 December 2011 / Nouf N. Laqtom, University of Edinburgh & King Abdulaziz University and Amy H. Buck, University of Edinburgh
microRNAs (miRNA) are a class of non-coding RNA that regulate the precise amounts of proteins expressed in a cell at a given time. These molecules were discovered in worms in 1993 and only known to exist in humans in the last decade. Despite the youth of the miRNA field, miRNA misexpression is known to occur in a range of human disease conditions and drugs based on modulating miRNA expression are now in development for treatment of cancer, cardiovascular, metabolic and inflammatory diseases. In the last six years, an increasing number of reports have also illuminated diverse roles of cellular miRNAs in viral infection and a miRNA-targeting therapy is currently in phase II clinical trials for treatment of the Hepatitis C virus. Here we review the literature related to miRNAs that regulate viral replication and highlight the factors that will influence the use of miRNA manipulation as a broader antiviral therapeutic strategy.
microRNAs (miRNA) are a class of small noncoding RNA that bind to messenger RNAs (mRNA) and regulate the amount of specific proteins that get expressed. These small RNAs are derived from longer primary transcripts that fold back on themselves to produce stem-loop structures which are recognised and processed by Drosha and co-factors in the nucleus followed by Dicer and co-factors in the cytoplasm, resulting in a ~ 22 nucleotide (nt) duplex RNA, for review see1,2. One strand of the duplex is preferentially incorporated into the RNA-induced silencing complex (RISC) where it then mediates binding to target mRNAs. These interactions lead to decreased protein getting produced from the transcript, due to RNA destabilisation and/or inhibited translation3 (Figure 1). miRNA-mRNA recognition generally requires perfect complementarity with only the first 6-8 nt of a miRNA, termed the ‘seed’ site4. Each miRNA therefore has the potential to interact with hundreds of target mRNAs3,4 and the majority of human protein-coding genes contain miRNA binding sites under selective pressure5. Therapeutic interest in miRNAs has been supported by studies in model organisms demonstrating key functions of individual miRNAs in cancer, cardiac disease, metabolic disease, neuronal and immune cell function6. (more…)
Tagged with: Amy Buck, Infection, King Abdulaziz University, microRNA, miRNA, mRNA, Nouf N. Laqtom, Proteins, RNAi, University of Edinburgh, Viruses
Latest issue / 13 December 2011 / Mirco Castoldi. Department of Pediatric Hematology, Oncology and Immunology University of Heidelberg
Cell-free nucleic acids circulating in human blood were first described in 19481. However, it was not until the work of Sorengon and colleagues was published in 19942 that the importance of circulating nucleic acid (cfNA) was recognised. Today, the detection of diverse type of cfNA3 in blood and other body fluids is a valuable resource for the identification of a novel biomarker4,5. Although different types of cfNA have been described (including DNA, mRNA and microRNA), this review focuses on the isolation, detection and clinical utility of circulating microRNAs.
microRNAs (miRNAs) are an abundant class of short single stranded non-coding RNAs (~22 nts) that regulate gene expression at the posttranscriptional level. Interaction between an miRNA and any given of its mRNA targets results in either translation inhibition, mRNA degradation or a combination of both mechanisms. Therefore, miRNAs activity effectively reduces the transcriptional output of a target gene, without affecting its transcription rate. Currently, the sequence of over 60,000 microRNAs are deposited in the miRBase database [Version 17, April 20116]. miRNA activity has been associated with the control of a wide range of basic processes such as development, differentiation and metabolism. Detection of differential expression of miRNAs in many cases have established the basis for miRNA functional analysis and specific miRNA expression patterns can provide valuable diagnostic and prognostic indications, for example, in the context of human malignancies7,8. Moreover, the deregulation of the expression of miRNAs has been shown to contribute to cancer development through various kinds of mechanisms, including deletions, amplification or mutations involving miRNA loci, epigenetic silencing, as well as the dysregulation of transcription factors that target specific miRNAs9,10. (more…)
Tagged with: Biomarkers, Dr. Mirco Castoldi, microRNA, miRNA, PCR, qPCR, University of Heidelberg
Latest issue / 13 December 2011 / Nalini A.L. Mehta & David J. Dow, Molecular and Cellular Technologies, Platform Technology and Science, GlaxoSmithKline and Anthony M. Battram, Molecular and Cellular Technologies, Platform Technology and Science, GlaxoSmithKline & Department of Life Sciences, Imperial College London
In recent years, the development of Next Generation DNA Sequencing (NGS) technology has significantly impacted molecular biology research, resulting in many new insights and discoveries. NGS technology goes beyond traditional DNA sequencing with applications that reach across the central dogma of molecular biology from DNA to RNA and protein science. Drug discovery is beginning to benefit from the diversity of NGS, with applications in evidence across various therapeutic areas, such as oncology, immunology and infectious diseases.
DNA is the molecule of life, containing the information for the synthesis of RNA molecules and proteins, which in turn form structural components of the cell or catalyse essential biochemical processes. Understanding the sequence of DNA, which is made from the four basic building blocks or ‘nucleotides’, A,G,C and T, has resulted in great insights and discoveries in cellular biology, pathology and disease, culminating in the human genome project, which achieved the remarkable feat of determining the sequence of the three billion bases of the human genome.
The field of DNA sequencing has witnessed some key milestones in technology develop – ment since the description of the first revolutionary DNA sequencing techniques in 19771,2. The Sanger dideoxy sequencing method, discovered by the Nobel Laureate Fred Sanger, underwent the most significant improvements and became the first automated sequencing platform in the late 20th century. Advancements in the Sanger process were partly motivated by the advent of the USD 3 billion Human Genome Project, which required the development of high-throughput tech – niques3,4 (Figure 1A). (more…)
Tagged with: DNA, Drug discovery, Next Generation Sequencing, Proteins, RNA, RNA-Seq
Latest issue / 13 December 2011 / Mingshi Yang, Faculty of Pharmaceutical Sciences, University of Copenhagen
Spray drying is a widely used technical method to produce fine particles, coarse powders, agglomerates or granulates in various industries. The characteristics of the particles produced by this method can be controlled and the particle properties can be maintained as constant throughout a continuous operation. The product from this process can readily meet the product specifications that are most desirable for subsequent processing or direct application. Hence, it has been successfully applied in the pharmaceutical industry to process both primary pharmaceuticals like APIs and also the final pharmaceutical formulations. The aim of this review is to present current pharmaceutical applications of this method and share my perspectives from both an industrial and academic point of view. I hope that it can serve as inspiration for some peers in pharmaceutical field.
By definition, spray drying is the transformation of a feed from a fluid state into a dried particu – late form by spraying the feed into a hot drying medium1. The drying medium is typically air, but an inert gas, e.g. nitrogen, can be employed when the liquid is a flammable solvent or the product is oxygen-sensitive. It is a one-step, con – tinuous particle formation process involving drying. The feed can be a solution, suspension, emulsion, dispersion or even paste, and the solvent medium can either be aqueous or organic. The dried product from the process conforms to particles, powders, agglomerates or granules, and the form of which depends upon the physical and chemical properties of the feed, the dryer design and the operation conditions1. (more…)
Tagged with: Mingshi Yang, Spray Drying, University of Copenhagen
Latest issue / 13 December 2011 / Philip Irving, President, FOSS NIRSystems, Inc.
FOSS NIRSystems, Inc. has a long, complicated and rich history tracing back to 1966 when NEOTEC Corporation was founded. Through a number of acquisitions and mergers, NIRSystems was trademarked in 1989 and bought by Perstorp Analytical, before the company was bought by FOSS in 1997, strengthening the company’s pharmaceutical division.
Although Near Infrared (NIR) technology was discovered in the 19th century, the first industrial applications of the technology began in the 1960s, which Irving ascribes to the advent of small affordable computers. “It not only spurred the development of digital instru – mentation, but also made practical the use of chemometrics, the application of mathematics and statistics to spectroscopic analysis,” Irving surmises. So what exactly is NIR technology? It is a spectroscopic method that uses the near infrared region of the electromagnetic spectrum to analyse samples. NIR can be used on-line, at-line and in-line in the pharmaceutical industry. “For at-line analysis, the NIR analyser is placed near the process,” explains Irving. “The operator then takes a process sample and places it in the NIR analyser. For on-line and in-line analysis, an NIR probe is inserted into the process line. This probe is connected via fibre optics back to the NIR analyser. The difference between on-line and in-line is where in the process the NIR probe is placed. For in-line analysis, the probe is placed directly into the main process pipe, reactor, etc. For on-line analysis, the probe is placed in a sidestream off the main process pipe or reactor.” (more…)
Tagged with: FOSS NIRSystems Inc, Near Infrared Spectroscopy, Philip Irving
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