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November/December 2009 The Scientific Program

Session 1 - Mixed theme including metabolites in safety testing (Chaired by Derek Stevenson)

Derek Stevenson opened the spring symposium with a welcome address and then passed to Howard Hill speaking on ‘The Changing Face of the Pharmaceutical Industry: Impact on Bioanalysis’. He outlined the drivers influencing the industry including new analytical technologies and the rise in the number of large molecule therapeutics undergoing development. He commented that the regulatory bar is being raised, in part by pharma companies, to exclude new players. Also, the increasing importance of India & China to pharma companies in the market place both as cost effective areas of the world to carry out drug development activities but also, with the emerging wealth of both, potentially huge markets to sell drugs. The closing remarks were directed towards the Bioanalytical Forum itself. As part of the organising committee, Howard invited comments on where the future of the meeting lay

The following two presentations were on the subject of the recently published FDA guidelines on Metabolites in Safety Testing (MIST). Firstly Dennis Smith (Pfizer) outlined the development in thinking that has led to the guidelines and highlighted the danger of using plasma metabolite concentration alone in classifying major and minor metabolites as the volume of distribution may mask the true toxicological potential of a metabolite. He then went on to describe the four classifications of drug side effects, type A, B, C & D and illustrated each with examples. Mark Seymour (Xceleron) described the advantages of using of Accelerator Mass Spectrometry (AMS) in combination with C14 microtracer doses of drug for metabolite identification in Phase 1 studies. This negates

Figure 3. Slide from Anne-Marie Orkild’s presentation on ‘Development of Selective and Sensitive Bioanalytical Methods for Peptide Therapeutics in Human Plasma’.

the requirement for separate mass balance studies saving development time/money. The final presentation of the session was from Michelle Gradley (Novacta Biosystems) who described the synthesis of metabolite reference standards using microbial systems which have been shown to have the capacity to mimic mammalian metabolism of drugs, carrying out the same highly region and stereoselective modifications as seen in the liver and other organs.

Session 2 - Mixed theme including peptide quantification (Chaired by Jaap Wieling)

Figure 2. Slide for Mark Seymour’s presentation on ‘HPLC-AMS: seeing through the MIST’.

Magnus Knutsson (Ferring) presented on ‘Quantification of peptide drugs in biological fluids of low pg/mL levels using LC-MS/MS’. He outlined the generic approach to large molecule analysis employed at Ferring. Molecules 5000 amu remain the realm of immunoassay. With method sensitivity remaining the main challenge with LC- MS/MS analysis of large molecules, he described the use of large sample volume extraction using SPE (Oasis WCX), miniaturisation of coupled LC columns (use of 1.0 mm i.d.) and a Sciex API5000 instrument enabling LLOQs of 5 pg/mL to be achieved for some peptide molecules. However, the potential for non specific binding to some polypropylene plates and solubility of proteins and peptides remain challenges that must be overcome during method development. The final presentation of this first day was from Chris Harrington (University of Surrey) on ‘High accuracy and high sensitivity methods for analysis of platinum cancer drug DNA adducts in cells’. The cytotoxic efficacy of platinum- DNA adducts and the relationship between adduct

concentration in tumour cells and blood is not well understood. By measuring these biomarkers, information on a patient’s clinical drug response could be obtained. By coupling a highly specific enzyme based adduction isolation method with a sensitive detection based on HPLC coupled to inductively coupled plasma mass spectrometry (HPLC-ICP-MS) it was possible to measure platinum-DNA adduct formation from a number of different sample types. The methodology opens up the possibility to tailor cancer treatment to an individual’s potential to form and repair DNA-adducts, making for a targeted treatment regime.

Session 3 - Mixed theme including a number of vendor presentations (Chaired by Robin Whelpton)

This session, covering the Tuesday morning of the conference, included a number of vendor presentations. These included Anne- Marie Orkild (Waters) on ‘A Comprehensive Approach to Developing Selective and Sensitive Bioanalytical Methods for Peptide Therapeutics in Humana Plasma, Klaus Buckendahl (Sigma-Aldrich) on ‘Hybrid SPE in the removal of Phospholipids and Proteins in Biological fluids’, Jonathan Coffey (Shimadzu) on ‘Analysis of impurities in streptomycin and dihydrostreptomycin by hydrophilic interaction chromatography/electrospray ionisation quadrupole ion trap/time-of-flight mass spectrometry’ and Pär Davidsson (DiLab) on Automated Blood Sampling.

Mark Bayliss (Pfizer) presented on ‘Halo Columns; what are they, what are their advantages’ describing the pelicular particles as “inside-out maltesers” i.e. the honeycomb bit on the outside. His practical tips were that a pre-column filter must always be used, they can be used with ballistic gradients, are only 20% less efficient than sub 2 µm columns, can be used back-to-front, up to temperatures of 80oC and in his experience,

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