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May/June 2011


There are minimal regulatory influences on how you measure a broad range of molecules such as biologics. Although the FDA BMV Guidance provides guidance on the use of ligand based assays there is general acceptance that such assays, while more variable than LC-MS assays, can be made robust and reproducible. Much has been written about ligand based assays and will continue to be so apparently without a regulatory acknowledged consensus.


I think the word “must” is always fraught with difficulty in such a rapidly developing area and where the technologies used to measure them are developing equally as fast – the best that can be done is to set some criteria and issues that must be addressed to provide useful and relevant data using best practices at the time.


Are CRO's leaders in the field?


Biologics represent such a broad range of products and therapies that it would be difficult to say CROs were leaders in this field – I could say they have a broader range of experiences than Pharma who inevitably concentrate on certain areas of expertise and as such CROs are probably more experienced at putting together a broader range of development packages together. One of the objectives of the HLS Biologics meeting was to illustrate the diversity of approaches.


Historically there has been seen to be a “competition” between in-house and outsourced services – not unnaturally job preservation. This is breaking down; we all succeed together or fail together – models change and we must change to survive. Pressure to produce “cost effective” but still sophisticated therapies is becoming the norm.


Turning to the analysis of biopharmaceuticals, is it wrong to 'lump' all large biomolecules together or do different types present different problems?


It is definitely wrong to “lump” all “large” biomolecules together. Biologicals encompass a wide range of therapeutics, ranging from recombinant proteins which together with blood proteins represent the earliest group of biologicals, the peptide Insulin being the first such product. Next are the monoclonal antibodies which by number and sales are the biggest group of biological therapeutics followed by proteins, peptides, oligonucleotides, cell therapies, DNA vaccines and vaccines in general. These have been variously described as biopharmaceuticals, biotechnology products, biotherapeutics and last and perhaps most inappropriately bioceuticals or perhaps more appropriately biological therapies, many of the Advanced Therapies such as gene therapy and stem cells are complex not only in format but in the development process - our company has been involved in the development of one of the few gene therapies.


From an analytical perspective there are specific analytical challenges associated with different product types, ranging from vaccines where the objective is to generate an immune response, as such monitoring the presence of the “vaccine” is not a primary endpoint, through to evaluating protein structures that can be measured by LC-MS.


Biologicals now represent over 30% - 50% of all molecules in development. Biologicals are not new given that vaccines have been around for over 200 years, blood products such as clotting agents were developed in the last century and in the 1930s Insulin was identified, although it was not until Sanger developed amino acid sequencing in the 1950s that its structure could be fully elucidated.


The progress of Insulin as a therapeutic agent could be said to represent the history of biologics molecules. Although of unknown structure its purity was assessed using classical chemistry approaches e.g. crystallization while potency was a measured using in vivo methods of blood glucose lowering. Then later it could be quantified by ligand based assays (developed in the 1950s), only recently have the USP replaced in vivoassays with a chromatographic assay to measure Insulin purity and has the ability to separate it from closely related molecules like the desamido insulin.


Likewise in vivomeasurement of blood kinetics for Biologicals relied largely on immunoassays the range of which has over the years reflected development in antibody production the main reagent in immunoassays, latterly chromatographic assay using LC-MS has been able to achieve sub ng/mL concentrations of insulin in blood driven by the development of insulin analogues with changes in their primary amino acid structure.


Turning to the Reid International Bioanalytical Forum, there seems to have been some confusion over the past year in UK "bioanalysis" meetings. Biopharmaceutical analysis meetings have included small molecule drug bioanalysis and vice versa. The Reid meeting has always ("eclectic mix" or not!) primarily been an analysis of drugs in biological fluids meeting. Will presentations on


biopharmaceuticals only deal with the analysis of biopharmaceuticals in biological fluids?


An eclectic group of questions if I may say so, so lets try one at a time.


Some of this confusion arises from terminology as mentioned earlier Biologics and Biotherapeutics should be regarded as synonymous I see the term


Biopharmaceuticals, (NOT biopharmaceutics, a different beast altogether) as a generic term for all therapeutic agents be they small molecules or large molecules.


Confusion is rife over terminology, Bioanalysis


itself was coined over 30 years ago as the study of science used to measure drugs (of no fixed size) in biological fluids, by the way the Reid Forum and the proceedings generated by it went a long way to cementing this concept. However the terminology has been hijacked by the analytical science used to characterise biological molecules. That said there is a lot to be said for including as many sciences and perspectives in one meeting AND for getting the scientists to interact and get out of their silos.


The Reid Bioforum was always known for its unique character. Just how difficult has it been to retain some of that character that made the meeting so popular while still moving with the times?


I think this has been the biggest and continues to be the biggest challenge. The early meetings were ones where the big boss invariably attended and brought along his younger acolytes to share how they have solved problems in what was termed a “friendly” understanding environment. I think to some extent this has declined in the formal forum but the informal / social part of the meeting continues to be the arena for sharing best practices as such the “campus” nature of the meeting is integral to “encouraging” such discourse, although with the passage of time the use of student accommodation has lost favour with some – albeit with en suite accommodation as universal offering.


As an avowed anti-siloist, I feel that we should include everything from small molecules to large molecules from discovery assays to pivotal clinical bioequivalence assays. We need to break the barriers of Innovator Pharma to CROs, the former is a group I belonged to in the 1970s and where CROs were almost deemed to be pariahs. Now we have moved to a stage where CROs predominate where large Pharma are in the minority and mini/micro Pharma / biotech is a growth industry.


In addition we need now include biomarkers (as measures of PD), something the forum has being doing for over 15 years; after all, PK studies are surrogate for Response. I would like to see the Reid Forum as complimentary to the European Bioanalytical Forum, EBF – if there isn’t a differentiator then its future is in doubt. If it does not develop a symbiotic relationship with the EBF then the Reid Forum needs to develop more presence than just once every two years e.g. with workshops on specific topics – this is especially so in a rapidly developing environment.


The Forum, held every two years over a four day period, has many disadvantages. Today two years can see the rise and fall of a new technology and four days can seem a lifetime – while problem solving and sharing problems can be done over the internet using such sites


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