Latest issue

At the crossroads: The next decade

Latest issue / 26 April 2012 / J. Paul Robinson, Purdue University Cytometry Laboratories & Weldon School of Biomedical Engineering, Purdue University; Bernd Bodenmiller, Group leader, Institute of Molecular Life Sciences, University of Zurich; Valery Patsekin and Bartek Rajwa, Purdue University Cytometry Laboratories, Purdue University; and V. J. Davisson, Medicinal Chemistry & Molecular Pharmacology, Purdue University

Flow cytometry is the technology that has the most impact on single-cell analysis. Over the past 40 years, it has arguably been the single most important research technique in the fields of basic and applied immunology. Flow cytometry excels in quantitative evaluation of receptor expression, separation of functionally defined cell populations and monitoring of cellular differentiation. For the clinical sciences, flow cytometry has been a key tool for diagnostics whereby aberrant populations are identified, classified and quantified, and in situations such as minimal residual disease, is capable of identifying rare cells indicative of dysplasia.

Despite the importance of its applications, flow cytometry is often seen as an aging technique without new exciting opportunities. The reality could not be further from the truth. The systems biology approach breathes new life into this unique technology. The new challenges of complex analysis of networks and pathways are a natural fit for modern multifactorial flow cytometry. (more…)

Tagged with: Bartek Rajwa, Bernd Bodenmiller, Clinical Immunology, Flow Cytometry, J Paul Robinson, Purdue University, University of Zurich, V J Davisson, Valery Patsekin

Implementing chemometrics in late stage development and manufacturing

Latest issue / 26 April 2012 / Geir Rune Flåten, former Chemometrician Leader in Global Manufacturing and Supply at GlaxoSmithKline

Chemometrics was defined as a research area in 1974 and developed rapidly through the following decades in parallel with the fast paced improvement in analytical technologies and computational power for lab instruments and sensors. Chemometrics is essentially the translation of measured signals characterising a sample or a process into meaningful results. This is achieved by applying a number of powerful multivariate data analytical techniques (MVA) to develop a model from a representative data set, and use this model to predict or quantify the property of interest for new samples or process runs.

In the pharmaceutical industry, chemometrics has been successfully applied at every stage from discovery, through development, and to manufacturing. In this review, the requirements and benefits to applying chemometrics in late stage development and manufacturing will be discussed.

Two main areas of interest in pharma – ceutical development and manufacturing are QbD (Quality by Design) and PAT (Process Analytical Technologies), and chemometrics, i.e. modelling, is a key element of these approaches. Chemometrics is used for simplicity as the label for any model translating data into meaningful output in the following discussion. To maximise the benefit from chemometrics, the very first step is to define the objective of the model. (more…)

Tagged with: Chemometrics, drug development, Drug manufacturing, Geir Rune Flaten, GlaxoSmithKline, Multivariate data analytical techniques (MVA)

Building robust PCR/qPCR assays

Latest issue / 26 April 2012 / Linda Starr-Spires, Director, Nucleic Acid Methods Platform, Global Clinical Immunology Department, Sanofi Pasteur

The process of building robust PCR/qPCR assays is a matter of perseverance and consistency. A few questions that should be answered prior to starting development will help make the process more efficient and effective:

1. Does the assay need to simply detect the presence of the target (qualitative), or must it assign a value to the detected target (quantitative)? The development process for a qualitative or quantitative assay, although similar in many respects, ultimately will take different paths
2. In what type of matrix will samples be? Matrix plays an important role in both development and validation of the assay. If the assay is needed for multiple matrices (whole blood, plasma, serum, differing tissue types, etc.), each matrix must be evaluated individually to determine its impact on assay performance
3. Will extraction be required, and by what method? 4) What throughput will be needed?

Answering these questions early in the process will help prevent ‘reworks’ later. (more…)

Tagged with: Clinical Immunology, Linda Starr-Spires, PCR, PCR assay, qPCR, Sanofi Pasteur

Applications of Raman, CARS and SRS imaging in dosage form development

Latest issue / 26 April 2012 / Clare Strachan, Senior Lecturer Pharmaceutical Sciences, School of Pharmacy, University of Otago

The use of Raman spectroscopy in pharmaceuticals has grown enormously since its appearance on the scene in the 1980s1-4. While typical Raman spectroscopy setups are able to provide chemical and physicochemical information about the sample on the bulk level, most solid samples in the pharmaceutical setting may not be assumed to be homogenous, and many critical quality attributes, such as drug release for example, depend on component distribution. Thus, obtaining chemically and spatially resolved information about pharmaceutical samples is pertinent. Since Raman microscopy imaging made its debut in the pharmaceutical setting, the range of pharmaceutical applications for which the technique has been used has continued to grow5-7.

Briefly, Raman spectroscopy involves the detection of inelastic scattering of light associated with molecular vibrations. The resulting photons have a longer (Stokes scattering) or shorter wavelength (anti-Stokes scattering) than the incident photons. In the most common setup (with spontaneous Raman scattering), the Stokes effect is detected since it is stronger. Raman spectroscopy is related to (near- and mid-) infrared spectroscopy since both techniques probe molecular vibrations, but there are several practical differences, which are due to the different molecular phenomena behind Raman scattering (polarisability change during vibration) and infrared absorption (dipole moment change, for more detail see e.g.8,9,5 for a brief explanation). While near-infrared and mid-infrared micro – scopy may also be used to gain chemically and spatially resolved information about samples, Raman microscopy has some advantages which include: (more…)

Tagged with: Clare Strachan, Coherent anti-Stokes Raman scattering (CARS), Dosage, Imaging techniques, Raman Spectroscopy, simulated Raman scattering (SRS), University of Otago

Discovery chemistry outsourcing

Latest issue / 26 April 2012 / Luigi La Vecchia, Director of the Preparations Laboratories, Novartis Institute for Biomedical Research

In 2002, Novartis decided to create a new research centre in Cambridge, MA. This was accompanied by a significant increase in headcount in medicinal chemistry. Within two years, this resulted in a strongly increased demand for prep-scale synthesis which in turn led to priority issues and to prolonged turnaround times due to lack of resources in our Preparations Laboratories. In order to debottleneck time critical scale-up activities, the Preparations Laboratories was asked in 2004 to introduce outsourcing as an alternative option to an in-house increase of headcount.

Regarding the selection for outsourcing of projects, the following selection criteria should apply:

• ‘Easy’ projects with a good chance of success, i.e. well documented and few process steps
• Shorter time for critical requests
• Non-critical projects with regard to proprietary situation, giving us better control of quality and protection of know-how

In order to differentiate the individual com – panies from each other, the evaluation criteria outlined below were applied: (more…)

Tagged with: Drug discovery, Luigi La Vecchia, Novartis, Outsourcing

Outsourcing in early drug discovery: Evolution and opportunities

Latest issue / 26 April 2012 / Jayshree Mistry, Paul Lloyd, Kevin Oliver and Peter North, GlaxoSmithKline R&D and Duncan Judd, Awridian

This article describes the evolution of outsourcing within early drug discovery at GlaxoSmithKline (GSK), specifically for chemistry services applied to developing a compound from the screening hit through lead optimisation. It will touch on different business models, factors to consider when selecting potential CROs, the benefits of outsourcing and CRO management.

Although pharmaceutical companies have always outsourced some of their activities, the outsourcing of drug discovery research (Figure 1) has grown significantly over the last 10 years.

The enabling factors include a vast improvement in global communications, an opportunity to access talent outside of big pharma and to an increasing number of signatories to Trade Related aspects on Intellectual Property Rights (TRIPS). It is well recognised that drug discovery research is a costly and risky endeavour, estimated to be USD 800 million of the USD 1.8 billion cost of a new chemical entity1. There are many factors that can contribute to reducing these costs: reducing cycle times, minimising late stage failures and making better decisions are imperative, however the use of external flexible resources can also provide significant cost savings. Although outsourcing can facilitate drug discovery research outside of established pharma structures, it needs to be well managed to succeed. (more…)

Tagged with: Awridian, Contract Research Organisations (CROs), Drug discovery, Duncan Judd, GlaxoSmithKline R&D, High Throughput Chemistry (HTC), Jayshree Mistry, Kevin Oliver, Outsourcing, Paul Lloyd, Peter North

GPCR screening and drug discovery: Challenges and latest trends

Latest issue / 26 April 2012 / Sofia M.A. Martins, João R.C. Trabuco, Gabriel A. Monteiro and Duarte Miguel Prazeres, Institute for Biotechnology and Bioengineering, Instituto Superior Técnico, Technical University of Lisbon

G-protein coupled receptors (GPCRs) are one of the most popular drug targets today. Almost one third of the approved drugs currently available rely on some kind of interaction with these receptors. The annual revenues are around USD 30 billion (109) and the fact that one quarter of the top US selling drugs are GPCR-related puts this drug target under the drug discovery spotlight. Also, GPCRs are one of the largest families in the human genome, with nearly 1,000 sequences identified as likely to be GPCRs. Among these, around 100 sequences have been confirmed as receptors, but have no known ligand or function. These so-called orphan receptors harbour the highest drug discovery potential. Still, even amongst the non-orphan receptors, only a handful are actually targeted by drugs1-3.

GPCR function is associated with cell sensing of external factors including odorants, taste ligands, light, metals, neurotransmitters, biogenic amines, fatty acids, amino acids, peptides, proteins, steroids and other lipids. The immense possibilities of ligands associated with the huge quantity of receptors led to the association of GPCRs with a large number of physiological and pathological conditions which include pain, asthma, cancer, cardio vascular diseases, gastrointestinal diseases, CNS diseases and others3. (more…)

Tagged with: Drug discovery, Duarte Miguel Prazeres, Gabriel A Monteiro, GPCRs, Institute for Biotechnology and Bioengineering, Joao C R Trabuco, Sofia M A Martins, Technical University of Lisbon

Rapid micro methods and EMA’s post approval change management protocol

Latest issue / 26 April 2012 / Michael J. Miller, President, Microbiology Consultants, LLC

This is the second paper in our continuing series on Rapid Microbiological Methods that will appear in European Pharmaceutical Review during 2012. In my last article, we discussed a number of myths or misconceptions associated with the validation and implementation of rapid microbiological methods (RMMs). In fact, most RMM myths that have been circulating throughout our industry are not true or have been exaggerated to the point that many companies continue to be hesitant in exploring what RMMs have to offer.

One of the most prominent myths is that the regulators do not understand, accept or even encourage the use of rapid methods. I submit to you that the regulators want to see RMMs implemented, as their use is directly aligned with the future state of pharmaceutical manufacturing, QbD, PAT and continuous process and product improvement. Further – more, recent changes to regulatory guidance and proposed policy have made it easier to implement RMMs than ever before. In my last article, I introduced a relatively new process that the European Medicines Agency (EMA) launched that allows for the review and approval of RMM validation strategies before testing is initiated. A more thorough review of this process, better known as the Post Approval Change Management Protocol (PACMP), is presented herein. (more…)

Tagged with: European Medicines Agency (EMA), FDA Comparability Protocol, Michael J. Miller, Microbiology Consultants LLC, Post approvall change management protocol (PACMP), Rapid microbiological methods (RMMs)

Under the microscope: Aric Meares, CEO, Azbil BioVigilant

Latest issue / 26 April 2012 / Helen Difford, Editor

Want to avoid a devastating drug shortage? Aric Meares, CEO of Azbil BioVigilant, says rapid microbial detection technology is a critical part of the solution.

With more than 20 years of experience in technical roles with technologies ranging from precision measurement equipment to advanced optical systems, Aric Meares joined BioVigilant in 2007 as its Vice President of Operations, and in 2011 became the President and CEO. Founded in 2002 in Tucson, Arizona, originally inventing its instantaneous microbial detection tech nology to detect weaponised bio-agents for the US military and Homeland Security, BioVigilant commercialised the technology for the pharmaceutical market in 2007. Today, the systems detect, instantaneously and in real time, particulate count, size and biological status. (more…)

Tagged with: Aric Meares, Azbil BioVigilant, Rapid Microbiology

In-depth focus – Mass Spectrometry

Latest issue / 25 April 2012 / Ana Rita Angelino, Min Yang, Tasso Miliotis, Constanze Hilgendorf, Anthony Bristow, George McLeod, Detlev Hochmuth, Alessandro Baldi, Gary Harland

This free to view Mass Spectrometry in-depth focus is sponsored by Waters, Bruker, Protea and Dr. Hochmuth and contains the following articles:

• Mass spectrometry in drug discovery – Proteomics, small molecules and metablomics
  (Ana Rita Angelino and Min Yang, Department of Pharmaceutical and Biological Chemistry, UCL School of Pharmacy)
• Quantification of membrane drug transporters and application in drug discovery and development
  (Tasso Miliotis and Constanze Hilgendorf, Innovative Medicines, AstraZeneca R&D)
• Show preview – The 60th annual conference on Mass Spectrometry and Allied Topics
• Anthony Bristow, AstraZeneca, poses the questions for our Mass Spectrometry Leaders Roundtable
  (George McLeod, Market Manager, Pharmaceutical MS, Bruker Daltonics / Detlev Hochmuth, Scientific Consultant and Software Developer for MS and Chemoinformatics, Dr. Hochmuth Scientific Consulting / Alessandro Baldi, VP & General Manager, Protea Biosciences Inc / Gary Harland, Mass Spectrometry Product Manager, Waters Corporation)

(more…)

Tagged with: Alessandro Baldi, Ana Rita Angelino, Anthony Bristow, AstraZeneca R&D, Bruker, Constanze Hilgendorf, Detlev Hochmuth, Dr. Hochmuth, Drug discovery, Gary Harland, George McLeod, Mass spectrometry, Min Yang, Protea, Proteomics, Tasso Miliotis, UCL School of Pharmacy, Waters