bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulations
Authors: Dagher Ramzi , Sridhara Rajeshwari , Chidambaram Nallaperumal , Booth Brian P.
Published: March 2010

The U.S. Food and Drug Administration (USFDA) is a scientific, regulatory, and public health agency that oversees the consumer economy. The agency has jurisdiction over most food products, human and animal drugs, therapeutic biologic agents, medical devices, radiation‐emitting products, cosmetics, and animal feed. This article focuses on the role of the FDA and different scientific disciplines in the marketing approval of drug products in the United States.
Future Challenges in Design and Ethics of Clinical Trials
Authors: Burman Carl‐Fredrik , Carlberg Axel
Published: March 2010

Clinical development faces two major challenges: public trust and productivity. Recent opinion polls show that the public trust in pharmaceutical companies has fallen sharply. If public trust in clinical trials decreases, recruitment of patients for clinical trials will be more difficult, which in turn will result in even poorer productivity. This article clarifies the nature of the ethical challenges that lie ahead and specifies the design features that can increase productivity in individual clinical trials under ethically acceptable standards.
Biomarkers Are Not New
Authors: Dews Ian
Published: March 2010

The word biomarker in its medical context is a little over 30 years old. Urine was for many centuries the focus of attention as biomarker because of its easy availability for inspection. This article discusses the history of establishment of biomarkers in medical sciences.
Enabling Go/No Go Decisions
Authors: Pritchard J. Fred , Jurima‐Romet Mallé
Published: March 2010

Drug development is a process that proceeds through several high‐level decision gates, “go/no go”, from identification of a potential therapeutic agent through to marketing a new drug product. Biomarkers can provide valuable information that can be translated into knowledge to aid decision making at all stages of the drug discovery–development process. This article focuses on major factors affecting three main perspectives of risk in drug development and the role of biomarkers in discovery and preclinical development.
Protein Biomarker Discovery Using Mass Spectrometry–Based Proteomics
Authors: Hunter Joanna M. , Chelsky Daniel
Published: March 2010

Recent advances in biological sample preparation, automated sample handling, and sensitive mass spectrometry with a variety of sample ionization sources have catalyzed the emergence of these methods as tools for clinical proteomic analyses. The global proteomics approach for candidate biomarker discovery using label‐free mass spectrometry‐based methods is able to detect significantly differentially expressed proteins in a variety of biological systems. This article discusses various aspects of protein biomarker discovery using mass spectrometry‐based proteomics.
Use of High‐Throughput Proteomic Arrays for the Discovery of Disease‐Associated Molecules
Authors: Molina Douglas M. , Morrow W. John W. , Liang Xiaowu
Published: March 2010

The high‐throughput proteomics approach is the natural progression of the genome sequencing projects of the 1990s. Organisms such as
M. tuberculosis
with 4000 ORFs, or malaria (
P. falciparum
and
P. vivax
) with even larger genomes, can now be assayed on a whole‐proteome scale. This article focuses on assay miniaturization technology and applications of advances in cloning and gene expression in profiling the immune response to infection, cancer, and autoimmune disease.
Fit‐for‐Purpose Method Validation and Assays for Biomarker Characterization to Support Drug Development
Authors: Lee Jean W. , Wu Yuling , Wang Jin
Published: March 2010

The use of novel biomarkers has become a prominent component of decision‐making processes in drug development. They are used in the in vitro and preclinical models and early clinical phase for quick‐hit and early‐attrition decisions. This article focuses on quantitative method validation and assay for biomarker characterization to support drug development using the fit‐for‐purpose approach.
Molecular Biomarkers from a Diagnostic Perspective
Authors: Lindpaintner Klaus
Published: March 2010

The term molecular biomarker comprises any and all in vitro testing for biologically informative molecules in tissues or body fluids, for purposes of diagnosing disease, preventive health screening applications, and prognostication of the natural history of a disorder. Molecular biomarkers may be useful in a number of applications, including mechanistic studies, early clinical pharmacodynamic assessment, dose‐finding studies, and stratification for efficacy. This article focuses on the diagnostic perspective as relevant to novel biomarker tests that accompany the development of a drug.
Strategies for the Co‐Development of Drugs and Diagnostics:FDAPerspective on Diagnostics Regulation
Authors: Kalush Francis , Gutman Steven
Published: March 2010

One of multiple important parts of the critical path initiative at the FDA has been a growing interest and attention to the issue of biomarkers, particularly with regard to the role they play as tools to aid in development of drugs and other new therapies. The FDA appreciates that the coordination of reviews across these two product lines may be challenging and has both administrative and regulatory tools in place that can contribute to review successes for these products. This article focuses on the strategies for the co‐development of drug and diagnostics from the FDA perspective.
Biomarkers for the Immunogenicity of Therapeutic Proteins and Its Clinical Consequences
Authors: Cornips Claire , Schellekens Huub
Published: March 2010

Therapeutic proteins such as growth factors, hormones, and monoclonal antibodies (mAbs) have increased in use dramatically over the past two decades, although their uses have been associated with immunogenicity in animals. Two classes of biomarkers, general and specific, can be used to indicate the clinical consequences of immunogenicity of therapeutic proteins. This article focuses on biomarkers for the immunogenecity of therapeutic proteins and its clinical consequences.
Translational Medicine—a Paradigm Shift in Modern Drug Discovery and Development: The Role of Biomarkers
Authors: Feuerstein Giora Z. , Alesci Salvatore , Walsh Frank L. , Rutkowski J. Lynn , Ruffolo Robert R.
Published: March 2010

The analysis and utility of biomarkers along the process of drug discovery and development have become an integral part of the “learn and confirm” paradigm of drug discovery and development in leading pharmaceutical organizations. Such analyses are useful to guide the “learn phase” in search for biomarkers that can better assess the benefits and risks associated with manipulation of the molecular target. This article offers a utilitarian approach to biomarkers as well as target selection and validation that is driven by the translational medicine prospect of the target to become a successful drug target.
Clinical Validation and Biomarker Translation
Authors: Lin David , Scherer Andreas , Ng Raymond , Balshaw Robert , Flynn Shawna , Keown Paul , McMaster Robert , McManus Bruce
Published: March 2010

Many of the biomarkers in current clinical use have become accepted via debate, consensus, or merely the passage of time. Biomarkers can no longer become accepted in this way, as they would fail to meet the current regulatory standards of modern medicine. Contemporary biomarkers must be tested in highly regulated human clinical trials. This article focuses on various aspects of discovery, development, clinical validation, and translation of biomarkers.
Predicting and Assessing an Inflammatory Disease and Its Complications: Example from Rheumatoid Arthritis
Authors: Trollmo Christina , Klareskog Lars
Published: March 2010

Chronic inflammatory diseases include a number of rheumatic, neurological, dermatological, and gastrointestinal diseases, which develop as a result of immune and inflammatory reactions. Analyzing the disease course longitudinally reveals several distinct steps during disease progression, for which the presence of biomarkers is of importance, both for identification of disease status and for prediction of disease course and treatment options. This article discusses disease characteristics and potential biomarkers in rheumatoid arthritis (RA).
Pharmacokinetic and Pharmacodynamic Biomarker Correlations
Authors: Marier J.F. , Gallicano Keith
Published: March 2010

Considering the complexity involved in drug discovery and development processes, it is imperative that companies adopt strategies and technologies that will facilitate the identification and development of new therapies. Appropriate PK/PD modeling of biomarkers and surrogate endpoints facilitate proof‐of‐concept demonstrations for target modulation and enhance the rational selection of an optimal drug dose and schedule. This article focuses on the PK/PD correlation assessment of a drug and a biomarker, and the use of PK/PD modeling and simulation to optimize drug development and decision making.
Validating In Vitro Toxicity Biomarkers Against Clinical Endpoints
Authors: Louden Calvert , Roberts Ruth A.
Published: March 2010

There is a compelling need for in vitro toxicity biomarkers for clinical endpoints. Toxicity biomarkers in the in vitro context are defined as quantitative measurable characteristics that serve as indicators of a pathologic process or related biochemical or molecular events. This article discusses validation of in vitro toxicity biomarkers against clinical endpoints.
Biomarkers for Lysosomal Storage Disorders
Authors: Zimran Ari , Fratazzi Candida , Elstein Deborah
Published: March 2010

Biomarkers are a means of better prediction and follow‐up, especially from the perspective of regulatory issues involving diagnostics and novel therapeutic options. In recruiting patients with lysosomal disorders for clinical trials, the use of biomarkers must be clearly related to disease burden in the vast majority of patients and be capable of detection at both ends of the spectrum, from very mild to severe, and equally reactive to specific therapy within the same range. This article reviews the literature and practice of biomarkers in lysosomal storage diseases and uses current practices to discuss guidelines for the use of biomarkers in upcoming clinical trials.
Value Chain in the Development of Biomarkers for Disease Targets
Authors: Richard Charles W. , Tzianabos Arthur O. , Soo Whaijen
Published: March 2010

The continued development of biomarkers and true surrogate markers throughout the drug development value chain in the service of drug registration will remain an important activity to increase efficiency in the drug development process. Academic, pharmaceutical, and regulatory agency partnerships to develop biomarkers collaboratively. This article focuses on biomarker development in preclinical models, in clinical trials, and in partnership with regulatory agencies.
Integrating Academic Laboratories Into Pharmaceutical Development
Authors: Ward Peter A. , Johnson Kent J.
Published: March 2010

Historically, there has been somewhat of an arm's‐length relationship between researchers in academic medical centers and pharmaceutical companies. However, this attitude has undergone a major change over the past three decades and academicians have taken an entrepreneurial approach through the formation of biotech firms. This article discusses the history and development of strong ties between academic scientists and the pharmaceutical industry, including potential pitfalls associated with this association.
Anti‐Unicorn Principle: Appropriate Biomarkers Don't Need to be Rare or Hard to Find
Authors: Bleavins Michael R. , Rahbari Ramin
Published: March 2010

The emphasis on biomarkers as a new approach often has lead to expectations that the ideal biomarker must be novel and/or exotic. To answer the pertinent questions during drug development, teams often embark on the quest for the “unicorn” of biomarkers, sometimes resulting in the best and most practical test being overlooked as the search progresses for elusive methods. This article highlights examples of unicorn, horse, and mule biomarker approaches.
Biomarker Patent Strategies: Opportunities and Risks
Authors: Bott Cynthia M. , Baude Eric J.
Published: March 2010

The discovery and use of biomarkers presents opportunities and risks in the patent area. There are opportunities to patent biomarkers and methods of using biomarkers to further commercial ventures. There is also the risk of infringing third‐party patents when making or using certain biomarkers. This article focuses on various aspects of patenting biomarkers and identifying patent infringement risks.
IT
Supporting Biomarker‐Enabled Drug Development
Authors: Hehenberger Michael
Published: March 2010

It is believed that “biomarker‐enabled” drug development will lead to better and earlier decision making, paving the way toward targeted therapeutics combining “precision drugs” for stratified patient populations. Organizations who believe in biomarker‐enabled R & D are investing in tools and making the necessary organizational changes to implement the new concepts and associated processes. This article focuses on IT standards and architectures to support business strategies, including their implementation.
Redefining Disease and Pharmaceutical Targets Through Molecular Definitions and Personalized Medicine
Authors: Webb Craig P. , Thompson John F. , Littman Bruce H.
Published: March 2010

Personalized medicine treatment strategies in cancer patients include diagnostics, targeted agents with well‐understood mechanisms of action, an understanding of the molecular pathways important in disease progression, and ways of rapidly assessing clinical success. This has especially been enabled by the power of new genomic, biomarker, and informatics technologies. This article focuses on the principles and the potential of personalized medicine in cancer, diabetes, and rheumatoid arthritis.
Ethics of Biomarkers: the Borders of Investigative Research, Informed Consent, and Patient Protection
Authors: Walmsley Heather , Burgess Michael , Brinkman Jacquelyn , Hegele Richard , Wilson‐McManus Janet , McManus Bruce
Published: March 2010

In recent years, there has been increased role of large biobanking projects within biomedical research. These projects reveal major public concerns with the social and ethical implications of these projects: for privacy, indigenous identity and self‐determination, ownership and control over body parts, and medical data for individuals and their families. This article focuses on the diversity of social and ethical issues surrounding biomarker‐related research and biobanks and its applications.
Pathodynamics: Improving Biomarker Selection by Getting More Information from Changes Over Time
Authors: Trost Donald C.
Published: March 2010

Pathodynamics refers to a quantitative approach to disease that includes how the biological system changes over time. In many ways it is analogous to thermodynamics in that it deals with the macroscopic, measurable phenotypic aspects of a biological system rather than the microscopic aspects such as those modeled in mathematical physiology. This article focuses on some approaches to thinking about pathodynamics.
Nanotechnology‐Based Biomarker Detection
Authors: Reineke Joshua
Published: March 2010

Recent developments in genetics, proteomics, and nanotechnology have produced a large number of nanoparticle‐based biomarker detection systems, including nanoparticles, quantum dots, nanowires, nanocantilever, and nanoarrays. They are being used to address various challenges faced in the detection of biomarkers, such as multiplexing ability, specificity, and label‐free detection. This article focuses on nanoparticles and nanodevices currently being developed for the enhanced detection of biomarkers and reviews nanotoxicology issues and other challenges that nanotechnology will present to the biomarker field.
Sequencing the Human Genome: Was it Worth It?
Authors: Zabarovsky Eugene
Published: March 2010

Almost complete human genome information is available and progress in the sequencing of other model organisms is impressive. This sequence information provides enormous possibility for identification of disease genes. This article focuses on the potential applications of human genome sequence.
From Defining Bioinformatics and Pharmacogenomics to Developing Information‐Based Medicine and Pharmacotyping in Health Care
Authors: Vizirianakis Ioannis S.
Published: March 2010

Through sophisticated technological advances have achieved so far, genomic knowledge is being used to analyze complex diseases including cardiovascular diseases, asthma, cancer, and degenerated disorders. The use of automated DNA sequencing techniques and the application of DNA microarray (DNA chip) systems permit the rapid and reliable assessment of a large number of genes implicated in drug response and disease pathogenesis. This article focuses on the influence of bioinformatics and pharmacogenomics, information‐based medicine, and pharmacotyping in health care.
Toxicogenomics
Authors: Cunningham Mary Jane , Shah Mrinal
Published: March 2010

Toxicogenomics is the use of OMICS technologies to assess the safety of new chemical entities or other compounds used in diagnostics or therapeutics. OMICS technologies encompass genomics, proteomics, metabonomics, and pharmacogenomics. This article describes all OMICS methods and shows how they can be applied to studying toxicity in pharmaceutical development.
Preclinical Pharmacokinetics
Authors: Mager Donald E. , Ramanathan Murali
Published: March 2010

The preclinical pharmacokinetics of protein pharmaceuticals is distinctively different from small‐molecule drugs. Understanding the mechanisms and implications of in vivo disposition of macromolecules provides a means for investigating and designing novel drug candidates and delivery systems to optimize exposure‐response relationships or therapeutic efficacy. This article focuses on the different aspects of preclinical pharmacokinetics of protein pharmaceuticals.
Process Validation for Biopharmaceuticals
Authors: Junker Beth
Published: March 2010

Process validation is a methodology to permit organizations to take advantage of process improvement opportunities presenting themselves over the course of a product's lifetime. Process validation continues to be a formidable undertaking, requiring extensive resources and time for full execution. This article focuses on various aspects of process validation for biopharmaceuticals.
Stability Assessment and Formulation Characterization
Authors: Chow Albert H.L. , Tong Henry H.Y. , Zheng Ying
Published: March 2010

A drug needs to be formulated in a safe, consistent, and stable dosage form with proven clinical efficacy before it can be approved for specific therapeutic indications by drug regulatory authorities. Depending on the modes of chemical degradation or physical denaturation, a wide variety of formulation excipients or additives, including buffers, antioxidants, sugars, and polysaccharides, can be used to preserve the structural integrity and biological activity of such vulnerable macromolecules. This article focuses on the stability problems of biopharmaceuticals and their assessment as well as the formulation approaches that can be used to circumvent these problems.
Formulation and Delivery Issues of Therapeutic Proteins
Authors: Balu‐Iyer Sathy V. , Miclea Razvan D. , Purohit Vivek S.
Published: March 2010

The protein therapeutics have unique handling and development requirements relative to the small organic molecule‐based drugs and pose exclusive challenges for the formulation scientist. The formulation and delivery issues of therapeutic proteins can contribute to difficulties in pharmaceutical development such as stability, immune toxicity, and pharmacodynamics‐related problems. This article focuses on formulation and delivery strategies of therapeutic proteins.
Immunogenicity of Therapeutic Proteins
Authors: Hermeling Suzanne , Crommelin Daan J.A. , Schellekens Huub , Jiskoot Wim
Published: March 2010

The introduction of recombinant DNA techniques has made possible to produce proteins on a large scale. These protein therapeutics are potentially immunogenic, inducing antibodies in patients after a certain period of treatment. This article gives an overview of the current knowledge about the immunogenicity of therapeutic proteins.
PlasmidDNAand MessengerRNAfor Therapy
Authors: Pascolo Steve
Published: March 2010

Recent studies performed in animal models and humans show that injection of pDNA or mRNA is safe and can elicit the expected results. Because pDNA and stabilized mRNA have the natural capacity to activate the immune system through the triggering of TLR, pDNA‐ and mRNA‐based therapeutic utilizations are mostly tested in the field of vaccination. This article focuses on therapeutic applications of pDNA‐ and mRNA‐based approaches.
Case Studies—Development of Oligonucleotides
Authors: Chowdhury Ezharul Hoque , Akaike Toshihiro
Published: March 2010

Oligonucleotides have emerged as essential tools in pharmaceutical biotechnology by virtue of their small size, low‐cost chemical synthesis, and precise base pairing capability with other complementary sequences either in the transcriptome or in the genome. Oligonucleotides have the enormous potential to facilitate manufacturing of innovative molecular machinery with the help of molecular biology enzymes, for being used as genomics tools as well as therapeutic tools. This article focuses on various aspects of the development and use of oligonucleotides for therapeutic use.
Growth Factors, Cytokines, and Chemokines: Formulation, Delivery, and Pharmacokinetics
Authors: Cao Heping , Lin Rui
Published: March 2010

Growth factors, such as cytokines, hormones and chemokines, refer to a large class of proteins capable of stimulating cellular proliferation and differentiation. Cytokines stimulate the humoral and cellular immune responses and activate phagocytic cells, where as chemokines induce directed chemotaxis in nearby responsive cells. This article addresses the issues related to the formulation, delivery, pharmacokinetics, and applications of growth factors, cytokines, and chemokines.
Overview of Stem and Artificial Cells
Authors: Soto‐Gutierrez Alejandro , Navarro‐Alvarez Nalu , David Rivas‐Carrillo Jorge , Kobayashi Naoya
Published: March 2010

Research on stem cells allows us to get the information about how an organism grows and develops from a single cell and how healthy normal cells replace damaged cells in adult organisms. Stem cells are capable of renewing themselves for long periods through cell division. This article reviews the nature and potential of embryonic stem cells.
Regulation of Small‐Molecule Drugs Versus Biologicals Versus Biotech Products
Authors: de los Angeles Cortés Castillo María , Di Fabio José Luis
Published: March 2010

Regulation of drugs by health institutions and governments ensures public protection from unsafe products. In parallel with the development of drug regulations, biological regulations were developed to enforce safety concerns of drugs. This article focuses on regulation enforced in development of small molecules, biological (vaccines), and biotech products.
Intellectual Property and Biotechnology
Authors: Bubela Tania , Durell Karen Lynne
Published: March 2010

Intellectual property laws and regulations provide incentives for the production and distribution of new knowledge by establishing a mechanism for the creator of that knowledge to obtain compensation for the use of protected works. Patents are the most prevalent form of intellectual property right (IPR) sought for biotechnological innovation. This article provides an overview of intellectual property rights available for biotechnological innovation and regulations governing those rights.
Enhanced Proteomic Analysis by
HPLC
Prefractionation
Authors: Havugimana Pierre C. , Wong Peter , Emili Andrew
Published: March 2010

Proteomics is the global (genome‐wide) study of protein expression in a given living cell, tissue or organism. Multidimensional Protein Identification Technology (MudPIT), gel electrophoresis (GE) and high performance liquid chromatography (HPLC) are the widely employed approaches to survey protein levels in complex biological samples. This article describes an easily implemented, effective, and highly reproducible dual‐column HPLC prefractionation method that helps in improving routine proteomic analyses.
Bioterrorism
Authors: Shoham Dany
Published: March 2010

Bioterrorism constitutes a counter arena that may amplify or substitute for the natural control mechanisms signified by infectious diseases. Pharmaceutical biotechnology in itself represents a potential key resource for bioterrorism. This article focuses on microbiological, epidemiological, medical, technological, demographical, political, and strategic aspects of bioterrorism.
Regulatory Considerations in Approval of Follow‐On Protein Drug Products
Authors: Oliver Erin , Carl Stephen M. , Morris Kenneth R. , Becker Gerald W. , Knipp Gregory T.
Published: March 2010

Given the rising cost of health care and prescription medications in the U.S. and the expanding role of biologically derived products within the pharmaceutical landscape, multifaceted issues present a challenge to industry, regulators, and legislators alike. Recent FDA approvals provide insight into the technical requirements for approval of well‐characterized FOP products. This article provides an overview of the complex scientific, legal, and policy issues facing the development of biogenerics today.
Sterile Product Manufacturing
Authors: Agalloco James , Akers James
Published: March 2010

The manufacture of sterile products by aseptic processing has long been considered a difficult technical challenge. The production of sterile products requires fastidious design, operation, and maintenance of facilities and equipment. This article reviews the salient elements of sterile manufacturing necessary to provide acceptable levels of risk regarding sterility assurance.
From Pilot Plant to Manufacturing: Effect of Scale‐Up on Operation of Jacketed Reactors
Authors: Bequette B. Wayne
Published: March 2010

Temperature control for laboratory reactors is typically easy because of high heat transfer area – reactor volume ratios, which do not require large driving forces for heat transfer from the reactor to the jacket. Pilot‐and full‐scale reactors, however, often have a limited heat transfer capability. This article provides an overview of scale‐up considerations involved as one moves from bench‐scale reaction calorimetry to larger scale pilot plant and production reactors.
Controlled‐Release Dosage Forms
Authors: Anal Anil Kumar
Published: March 2010

Controlled drug delivery alters the pharmacokinetics and pharmacodynamics of pharmacologically active moieties using novel drug delivery systems or by modifying the molecular structure and/or physiological parameters inherent in a selected route of administration. Recent developments in drug delivery techniques has made it possible to control the rate of drug delivery to sustain the duration of therapeutic activity and/or target the delivery of drug to a specific organ or tissue. This article focuses on design and fabrication of controlled‐release oral dosage forms and the importance of different routes of administration.
Progress in Design of Biodegradable Polymer‐Based Microspheres for Parenteral Controlled Delivery of Therapeutic Peptide/Protein
Authors: Tamilvanan Shunmugaperumal
Published: March 2010

Microspheres prepared from biodegradable polymers are widely recognized for controlled drug delivery following parenteral administration. Polyester polymers such as poly(lactic acid) (PLA), poly(glycolic acid) (PGA), and their copolymer poly(lactic acid‐co‐glycolic acid) (PLGA) are used routinely for the preparation of injectable microspheres due to their biocompatibility, controlled biodegradability, and no toxicity of degradation products. This article focuses on investigations made progressively on the design of injectable peptide/protein‐loaded PLGA microspheres
Nasal Delivery of Peptide and Nonpeptide Drugs
Authors: Thomas Chandan , Ahsan Fakhrul
Published: March 2010

In recent decades, intranasal drug delivery has shown great promise in various fields of medical practice. Drug delivery via the nasal route offers a number of advantages, such as possibility of needle‐free treatment, rapid onset of action, and high bioavailability. This article describes delivery and absorption of drugs by the nasal route and appreciates the factors that may affect it.
Nasal Powder Drug Delivery
Authors: Filipović‐Grčić Jelena , Hafner Anita
Published: March 2010

Intranasal drug administration has been practiced since ancient times. Nasal dry powder formulations have been recognized as efficient nasal delivery systems offering numerous advantages over liquid formulations, such as avoidance of preservatives, improved formulation stability, and prolonged contact with the mucosa. This article focuses on the benefits associated with nasal dry powder formulations and microspheres as nasal drug delivery devices.
Tablet Design
Authors: Castellanos Gil Eddy , Caraballo Isidoro , Bataille Bernard
Published: March 2010

The compression of powders is a complex task due to the variability in particle size and shape, the unknown distribution of the particles in the die, their different ability to flow, and the forces needed to create bonds between them. In tablet design many factors have to be taken into account, such as the physicochemical properties of active compounds and excipients. This article provides a brief description of the main theoretical aspects of tablet design and formulation together with practical examples of tablet development and characterization using different techniques.
Tablet Compression
Authors: Santos Helton M. M. , Sousa João J. M. S.
Published: March 2010

The process of tablet compression involves the rearrangement of particles within the die cavity and initial elimination of voids. Since tablet compression relies on the ability of particulates to be compacted, the need to control the critical properties of the materials with respect to readiness or ability to compact is an important issue to the formulator. This article focuses on tablet compression process.
Oral Extended‐Release Formulations
Authors: Larsson Anette , Abrahmsén‐Alami Susanna , Juppo Anne
Published: March 2010

In order to achieve therapeutic effect, a drug needs to reach the right place in the body at the right time. For some drugs, this may be achieved by simple solutions or solid dosage forms with an instant drug release while, for others, one has to modify the drug release, such as modified‐release (MR) formulations and oral extended‐release (ER) formulations. This article focuses on formulation principles and manufacturing of the different forms of ER formulations, such as insoluble matrix tablets, membrane‐coated oral extended release, and hydrophilic matrix tablets.
Nanotechnology in Pharmaceutical Manufacturing
Authors: Jin Yiguang
Published: March 2010

The application of nanotechnology in pharmacy has a long history. Nanotechnology plays a key role in future pharmaceutical development and pharmacotherapy. This article focuses on the effects of nanotechnology on pharmaceutical manufacturing.
Scale‐Up and Postapproval Changes (
SUPAC
) Regulations
Authors: Sharma Puneet , Ganta Srinivas , Garg Sanjay
Published: March 2010

Regulatory authorities in the U.S., Europe and Latin America require the pharmaceutical industries to follow guidelines on scale‐up and postapproval changes (SUPAC) to maintain the quality of the pharmaceutical products. Apart from these guidelines, there are other checkpoints, such as change control and validation exercises. This chapter describes the regulations imposed by different regulatory authorities.
GMP
‐Compliant Propagation of Human Multipotent Mesenchymal Stromal Cells
Authors: Rohde Eva , Schallmoser Katharina , Bartmann Christina , Reinisch Andreas , Strunk Dirk
Published: March 2010

U.S. regulations demand that tests for potency shall consist of either in vitro or in vivo tests, or both. These tests should be designed specifically for each product so as to indicate its potency in a manner adequate to satisfy the interpretation of potency given by the definition in 21 CFR 600.3(s). This article demonstrates that rapid and standardized expansion of human mesenchymal stromal cells (MSCs) to achieve a reasonable cell dose is feasible within less than four weeks and replacing fetal bovine serum (FBS) with human platelet lysate (HPL) provides one strategy toward a safer cell‐based medicinal product (CBMP).
NationalGMPRegulations and Codes and InternationalGMPGuides and Guidelines: Correspondences and Differences
Authors: Närhi Marko , Nordström Katrina
Published: March 2010

Good manufacturing practices (GMPs) is included as integral part of most of the countries' laws as part of legislation or separate guidelines to ensure safety, identity, and quality of drug products. Some international organizations and trade blocks also have issued their own international GMP guidelines to harmonize the requirements for drug. This article focuses on the U.S. and international GMP regulations, their similarities and differences.
Analytical and Computational Methods and Examples for Designing and Controlling Total Quality Management Pharmaceutical Manufacturing Systems
Authors: Ranky Paul G. , Ranky Gregory N. , Ranky Richard G. , John Ashley
Published: March 2010

Total quality management (TQM) and operation control is an essential criteria in pharmaceutical manufacturing system design engineering. Quality control means establishing and maintaining specified quality standards of products in adherence to accepted criteria. This article provides methods and examples for designing and controlling TQM pharmaceutical manufacturing systems.
Role of Quality Systems and Audits in Pharmaceutical Manufacturing Environment
Authors: Siegel Evan B. , Barquest James M.
Published: March 2010

Quality assurance (QA) and independent audit is critical in the pharmaceutical industry to assure reliability of the products, adherence to approved specifications, and conformation of current good manufacturing practices (cGMP) to regulation. Manufacturers must establish a quality control unit that is responsible for quality‐related activities required by the regulations. This article focuses on role of quality assurance and independent audit in the pharmaceutical manufacturing environment.
Case for Process Analytical Technology: Regulatory and Industrial Perspectives
Authors: Cogdill Robert P.
Published: March 2010

Process analytical technology (PAT) has become an important part of the pharmaceutical manufacturing industry in the recent years. The Food and Drug Administration (FDA) initiative to implement a modern, risk‐based framework for regulation and oversight of pharmaceutical manufacturing has been a major driving force for the increase popularity of PAT. This article provides an overview of PAT in the pharmaceutical industry, summarizes FDA initiatives, and presents a basic plan for PAT implementation.
Process Analytical Technology
Authors: Ulmschneider Michel , Roggo Yves
Published: March 2010

The Food and Drug Administration (FDA) defines process analytical technology (PAT) as a system for designing, analyzing, and controlling pharmaceutical manufacturing through the measurement of critical quality and performance parameters. Process analytical technology encourages technological innovation by the pharmaceutical industry to improve the understanding and control of manufacturing processes. This article provides an overview of PAT and various tools of PAT.
Personnel Training in Pharmaceutical Manufacturing
Authors: Gallup David A. , Domenick Katherine V. , Gillis Marge
Published: March 2010

Competency and efficiency of pharmaceutical manufacturing personnel is critical to a safe and successful manufacturing process. The Code of Federal Regulations (CFR) provides mandatory rules for personnel training, while Food and Drug Administration (FDA) drafts guidance documents and good training practices (GTPs). This article focuses on how to develop and implement a training strategy that is compliant to CFR and FDA guidance.
Quantitation of Markers for Gram‐Negative and Gram‐Positive Endotoxins in Work Environment and as Contaminants in Pharmaceutical Products Using Gas Chromatogaphy–Tandem Mass Spectrometry
Authors: Fox Alvin
Published: March 2010

Lipopolysaccharide (LPS) is an endotoxin present only in gram‐negative bacterial outer membranes, while peptidoglycan (PG), which displays endotoxin‐like activity, is present in the cell wall of gram‐positive and gram‐negative bacteria. Substances are found in LPS and PG that are rarely found elsewhere in nature and serve as chemical markers. This article focuses on detection of the markers for LPS and PG using gas chromatography–tandem mass spectrometry (GC–MS/MS).
Microbiology of Nonsterile Pharmaceutical Manufacturing
Authors: Velagaleti Ranga
Published: March 2010

The U.S. Pharmacopeia (USP) and Food and Drug Administration (FDA) have laid down guidelines for microbiological quality attributes for nonsterile pharmaceuticals. Other international organizations, such as the International Conference on Harmonization (ICH), authorities in Australia, and the World Health Organization (WHO) have also published guidelines on good manucaturing practice (GMP) of nonsterile pharmaceuticals. This article focuses on the U.S. and global guidelines relevant to microbiology of nonsterile manufacturing.
Synthesis of Poly(4‐vinylpyridine) Thin Films by Initiated Chemical Vapor Deposition (iCVD) for Selective Nanotrench‐Based Sensing of Nitroaromatics
Authors: Tenhaeff Wyatt E. , McIntosh Lucas D. , Gleason Karen K.
Published: March 2010

A new nanoscale sensing concept for the detection of nitroaromatic explosives is described. The design consists of nitroaromatic‐selective polymeric layers deposited inside microfabricated trenches. As the layers are exposed to nitroaromatic vapors, they swell and contact each other to close an electrical circuit. The nitroaromatic selective polymer, poly(4‐vinylpyridine) (P4VP), is deposited in the trenches using initiated chemical vapor deposition (iCVD). P4VP is characterized for the first time as a selective layer for the absorption of nitroaromatic vapors. The Flory–Huggins equation is used to model the swelling response to nitroaromatic vapors. The Flory–Huggins interaction parameter for the P4VP–nitrobenzene system at 40 °C is 0.71 and 0.25 for P4VP–4‐nitrotoluene at 60 °C. Sensing of nitrobenzene vapors is demonstrated in a prototype device, while techniques to improve the performance of the design in terms of response time and sensitivities are described. Modeling shows that concentration and mass limits of detection of 0.95 ppb and 3 fg, respectively, can be achieved.
Proinflammatory cytokine expression profile in degenerated and herniated human intervertebral disc tissues
Authors: Shamji Mohammed F. , Setton Lori A. , Jarvis Wingrove , So Stephen , Chen Jun , Jing Liufang , Bullock Robert , Isaacs Robert E. , Brown Christopher , Richardson William J.
Published: March 2010

Objective

Prior reports document macrophage and lymphocyte infiltration with proinflammatory cytokine expression in pathologic intervertebral disc (IVD) tissues. Nevertheless, the role of the Th17 lymphocyte lineage in mediating disc disease remains uninvestigated. We undertook this study to evaluate the immunophenotype of pathologic IVD specimens, including interleukin‐17 (IL‐17) expression, from surgically obtained IVD tissue and from nondegenerated autopsy control tissue.

Methods

Surgical IVD tissues were procured from patients with degenerative disc disease (n = 25) or herniated IVDs (n = 12); nondegenerated autopsy control tissue was also obtained (n = 8) from the anulus fibrosus and nucleus pulposus regions. Immunohistochemistry was performed for cell surface antigens (CD68 for macrophages, CD4 for lymphocytes) and various cytokines, with differences in cellularity and target immunoreactivity scores analyzed between surgical tissue groups and between autopsy control tissue regions.

Results

Immunoreactivity for IL‐4, IL‐6, IL‐12, and interferon‐γ (IFNγ) was modest in surgical IVD tissue, although expression was higher in herniated IVD samples and virtually nonexistent in control samples. The Th17 lymphocyte product IL‐17 was present in >70% of surgical tissue fields, and among control samples was detected rarely in anulus fibrosus regions and modestly in nucleus pulposus regions. Macrophages were prevalent in surgical tissues, particularly herniated IVD samples, and lymphocytes were expectedly scarce. Control tissue revealed lesser infiltration by macrophages and a near absence of lymphocytes.

Conclusion

Greater IFNγ positivity, macrophage presence, and cellularity in herniated IVDs suggests a pattern of Th1 lymphocyte activation in this pathology. Remarkable pathologic IVD tissue expression of IL‐17 is a novel finding that contrasts markedly with low levels of IL‐17 in autopsy control tissue. These findings suggest involvement of Th17 lymphocytes in the pathomechanism of disc degeneration.
Synovial fluid proteins differentiate between the subtypes of juvenile idiopathic arthritis
Authors: Rosenkranz Margalit E. , Wilson David C. , Marinov Anthony D. , Decewicz Alisha , Grof‐Tisza Patrick , Kirchner David , Giles Brendan , Reynolds Paul R. , Liebman Michael N. , Kolli V. S. Kumar , Thompson Susan D. , Hirsch Raphael
Published: March 2010

Objective

Juvenile idiopathic arthritis (JIA) is a heterogeneous group of inflammatory diseases, and no clinically useful prognostic markers to predict disease outcome in children with JIA are currently available. Synovial fluid likely reflects the proteins present in the inflamed synovium. The purpose of this study was to delineate the synovial fluid proteome and determine whether protein expression differs in the different subtypes of JIA.

Methods

Synovial fluid samples obtained from children with oligoarticular JIA, polyarticular JIA, or systemic JIA were compared. Two‐dimensional gel electrophoresis for protein separation and matrix‐assisted laser desorption ionization−time‐of‐flight mass spectrometry and quadripole time‐of‐flight mass spectrometry for protein identification were used for this study. Synovial fluid cells were analyzed by polymerase chain reaction (PCR) for the presence of haptoglobin messenger RNA (mRNA).

Results

The synovial fluid proteome of the samples was delineated. The majority of proteins showed overexpression in JIA synovial fluid as compared with noninflammatory control samples. There were 24 statistically significantly differentially expressed spots (>2‐fold change; P < 0.05) between the subtypes of JIA. PCR analysis revealed haptoglobin mRNA, suggesting that haptoglobin is locally produced in an inflamed joint in JIA.

Conclusion

Despite the similar histologic appearance of inflamed joints in patients with different subtypes of JIA, there are differences in protein expression according to the subtype of JIA. Haptoglobin is differentially expressed between the subtypes of JIA and is locally produced in an inflamed joint in JIA. Haptoglobin and other differentially expressed proteins may be potential biomarkers in JIA.
Large‐scale extraction and characterization of CD271+ multipotential stromal cells from trabecular bone in health and osteoarthritis: Implications for bone regeneration strategies based on uncultured or minimally cultured multipotential stromal cells
Authors: Jones E. , English A. , Churchman S. M. , Kouroupis D. , Boxall S. A. , Kinsey S. , Giannoudis P. G. , Emery P. , McGonagle D.
Published: March 2010

Objective

To test the hypothesis that CD45lowCD271+ bone marrow multipotential stromal cells (MSCs) are abundant in the trabecular bone niche and to explore their functional “fitness” in health and osteoarthritis (OA).

Methods

Following enzymatic extraction, MSC release was evaluated using colony‐forming unit–fibroblast (CFU‐F) and colony‐forming unit–osteoblast assays, flow cytometry, and confocal microscopy. CD45lowCD271+ cells isolated by fluorescence‐activated cell sorting were enumerated and expanded under standard and clonal conditions. Their proliferative and osteogenic potencies were assessed in relation to donor age and compared with those of aspirated CD45lowCD271+ cells. In vitro and in vivo MSC “aging” was measured using quantitative polymerase chain reaction–based telomere length analysis, and standard differentiation assays were utilized to demonstrate multipotentiality.

Results

Cellular isolates from trabecular bone cavities contained ∼65‐fold more CD45lowCD271+ cells compared with aspirates (P < 0.0001) (median 1.89% [n = 39] and 0.029% [n = 46], respectively), concordant with increased CFU‐F release. Aspirated and enzymatically released CD45lowCD271+ cells had identical MSC phenotypes (∼100% CD73+CD105+CD13+, ∼50–60% CD146+CD106+CD166+) and contained large proportions of highly clonogenic multipotential cells. In vitro osteogenic potency of freshly isolated CD45lowCD271+ cells was comparable with, and often above, that of early‐passage MSCs (8–14%). Their frequency and in vivo telomere status in OA bone were similar to those in bone from age‐matched controls.

Conclusion

Our findings show that CD45lowCD271+ MSCs are abundant in the trabecular bone cavity and indistinguishable from aspirated CD45lowCD271+ MSCs. In OA they display aging‐related loss of proliferation but no gross osteogenic abnormality. These findings offer new opportunities for direct study of MSCs in musculoskeletal diseases without the requirement for culture expansion. They are also relevant for direct therapeutic exploitation of prospectively isolated, minimally cultured MSCs in trauma and OA.
Constructing business profiles based on keyword patterns on Web sites
Authors: Vaughan Liwen , Tang Juan , Du Jian
Published: March 2010

The study examined the possibility of constructing business profiles (specifically, product profiles) based on keyword patterns on various types of Web sites, including a company's own Web site, blog sites, and Web sites that have particular keywords and also hyperlinks pointing to company Web sites. To test the proposed methods, we selected China's four major oil companies and two other companies that have related products. We collected three rounds of data over a 7‐month period from these three Web sources and analyzed the numbers of retrieved pages to construct business profiles. The business profiles constructed were checked against business information collected from other sources such as company annual reports and company newsletters to determine the correctness of the profiles and thus the usefulness of the proposed methods. We found that we can construct fairly accurate profiles by examining the frequency distribution of product keywords on company Web sites. Analyzing the frequency distribution of blogs on various topics was very useful in following major business events and developments during particular time periods. We also conducted qualitative content analysis for a sample of 454 Web pages retrieved from the three sources. Findings from the content analysis confirmed the conclusions from the quantitative analysis.
Low‐frequency climate variability in the Atlantic basin during the 20th century
Authors: Tourre Y. M. , Paz S. , Kushnir Y. , White W. B.
Published: March 2010

From joint sea surface temperature/sea level pressure (SST/SLP) EOF analyses, low‐frequency variability modes are compared. The multi‐decadal oscillation (MDO) changed phases twice during the 20th century, with its north Atlantic SST patterns resembling the Atlantic multi‐decadal oscillation (AMO). The quasi‐decadal oscillation (QDO) SST patterns displayed a double tripole configuration over the entire Atlantic basin, leading to tropical inter‐hemispheric out‐of‐phase relationship. From the mid‐1960s onward, while SST anomalies were negative to the north (negative phases of MDO/AMO), the Sahelian drought persisted with a weaker hurricane power dissipation index (PDI). During that period, the QDO modulated the intensity of the Sahelian drought. Copyright © 2010 Royal Meteorological Society