Tolerability of risk: A commentary on the nitrosamine contamination issue.

For decades, regulators have grappled with different approaches to address the issue of control of impurities. Safety-based limits, such as permissible daily exposure (PDE), acceptable intake (AI), threshold of toxicological concern (TTC) and less than lifetime limits (LTL) have all been used. For many years these safety-based limits have been recognized as virtually safe doses (VSDs).

Short commentary on NDMA (N-nitrosodimethylamine) contamination of valsartan products.

A range of generic valsartan products have been found to be contaminated with nitrosamines (principally N-nitrosodimethylamine; NDMA). We present information and discuss various elements of this phenomenon including: actions taken by regulatory agencies, source of the nitrosamine impurities, range of possible risk assessments based mainly on ICH M7 criteria, epidemiological assessment and analytical aspects.

Medicines for Pediatric Patients-Biopharmaceutical, Developmental, and Regulatory Considerations.

This commentary reflects current developments in pediatric medicine. The underpinning legislation in both Europe and the United States has led to the initiation of an increased number of clinical trials in the pediatric population, but there are still a number of outstanding issues within this field. These include the differences in the physiology between adults and the very heterogeneous nature of pediatric patients.

Antibiotic Resistance: The Need For a Global Strategy.

The development of antibiotic resistance is a major problem for mankind and results in fatal consequences on a daily basis across the globe. There are a number of reasons for this situation including increasing globalization with worldwide travel, health tourism, over use and ineffective use (both in man and animals), and counterfeiting of the antimicrobial drug products we have available currently. Although there are huge economical, demographic, legal and logistic differences among the global communities, there are also differences regarding the best approach to dealing with antibiotic resistance.

Recent advances and potential applications of modulated differential scanning calorimetry (mDSC) in drug development.

Differential scanning calorimetry (DSC) is frequently the thermal analysis technique of choice within preformulation and formulation sciences because of its ability to provide detailed information about both the physical and energetic properties of a substance and/or formulation. However, conventional DSC has shortcomings with respect to weak transitions and overlapping events, which could be solved by the use of the more sophisticated modulated DSC (mDSC). mDSC has multiple potential applications within the pharmaceutical field and the present review provides an up-to-date overview of these applications.

Pharmaceutical excipients - quality, regulatory and biopharmaceutical considerations.

Practically all medications contain excipients, which are added for the purpose of production enhancement, patient acceptability, improving stability, controlling release etc. Typically excipients are the major components of a drug product, with the active molecule only present in relatively small amounts. Historically, excipients were termed inactive components.

Analytical advances in pharmaceutical impurity profiling.

Impurities will be present in all drug substances and drug products, i.e. nothing is 100% pure if one looks in enough depth.

Methodology of oral formulation selection in the pharmaceutical industry.

Pharmaceutical formulations have to fulfil various requirements with respect to their intended use, either in the development phase or as a commercial product. New drug candidates with their specific properties confront the formulation scientist with industrial challenges for which a strategy is needed to cope with limited resources, stretched timelines as well as regulatory requirements. This paper aims at reviewing different methodologies to select a suitable formulation approach for oral delivery.

The solid-state continuum: a perspective on the interrelationships between different solid-state forms in drug substance and drug product.

Objective: The objective of the review is to provide an overview of the nomenclature used in the solid-state continuum and relate these to the development of drug substances and drug products.

Key Findings: The importance of a rational approach to solid-state form selection, including integrated decision making (ensuring equal weight is given to the needs of the drug substance and the drug product), is vital for the effective development of a drug candidate. For example, how do secondary processing considerations influence the selection of drug substance solid-state form and resulting formulation, and how can drug substance solid-state form be used to optimise secondary processing? Further, the potential use of 'crystal' engineering to optimise stability, purity and optical resolutions, and the linked regulatory requirements, will be discussed.

Use of pharmaceutical salts and cocrystals to address the issue of poor solubility.

Salt and cocrystal formation are the most commonly used method of increasing solubility and dissolution rate of pharmaceutical compounds, and are of particular interest for compounds with an intermediate to low aqueous solubility. However, selection of the most appropriate form does not necessarily equate to selection of the salt/cocrystal with the optimal aqueous solubility, but rather a balance between the best solubility and the best physicochemical properties. This review provides a presentation of salt and cocrystal selection, from a high throughput screening perspective and then an assessment of counter ion properties, common ion effects and the potential impact on the biopharmaceutical performance of the compound.

The utility of sulfonate salts in drug development.

The issue of controlling genotoxic impurities in novel active pharmaceutical ingredients (APIs) is a significant challenge. Much of the current regulatory concern, has been focused on the formation and control of genotoxic sulfonate esters. This is linked with the withdrawal of Viracept (Nefinavir mesilate) from European markets in mid-2007, over concerns about elevated levels of ethyl methanesulfonate (EMS).

Drug substances presented as sulfonic acid salts: overview of utility, safety and regulation.

Objectives: Controlling genotoxic impurities represents a significant challenge to both industry and regulators. The potential for formation of genotoxic short-chain alkyl esters of sulfonic acids during synthesis of sulfonic acid salts is a long-standing regulatory concern. This review provides a general overview of the utility of sulfonic acids as salt-forming moieties and discusses strategies for effectively minimizing the potential for alkyl sulfonate formation during the synthesis and processing of sulfonate salt active pharmaceutical ingredients.

Development and validation of an automated static headspace gas chromatography-mass spectrometry (SHS-GC-MS) method for monitoring the formation of ethyl methane sulfonate from ethanol and methane sulfonic acid.

An automated sample preparation and analysis procedure was developed to monitor the formation of ethyl methane sulfonate from reaction mixtures containing ethanol and methane sulfonic acid. The system is based on a liquid handling robot combined with a static headspace module. The formed ethyl methane sulfonate is analysed after derivatisation with pentafluorothiophenol using static headspace-gas chromatography-mass spectrometry (SHS-GC-MS).

Development, validation and transfer into a factory environment of a liquid chromatography tandem mass spectrometry assay for the highly neurotoxic impurity FMTP (4-(4-fluorophenyl)-1-methyl-1,2,3,6-tetrahydropyridine) in paroxetine active pharmaceutical ingredient (API).

This work describes the development of a liquid chromatography tandem mass spectrometry (LC-MS/MS) assay for a highly toxic impurity, FMTP (4-(4-fluorophenyl)-1-methyl-1,2,3,6-tetrahydropyridine), in paroxetine active pharmaceutical ingredient (API), followed by the subsequent validation of the methodology and transfer into a global production/quality control environment. The method was developed to achieve a detection limit of 10ppb mass fraction of FMTP in paroxetine API. An LC-MS/MS method was chosen because it provided the required sensitivity and selectivity with minimal sample preparation.

Developing paediatric medicines: identifying the needs and recognizing the challenges.

There is a significant need for research and development into paediatric medicines. Only a small fraction of the drugs marketed and utilized as therapeutic agents in children have been clinically evaluated. The majority of marketed drugs are either not labelled, or inadequately labelled, for use in paediatric patients.