37


Chromatography Today talks to Howard Hill


by John Lough


Up until now, interviewees featuring in Chromatography Today have been drawn from individuals who have been recipients of Martin or Jubilee Awards of The Chromatographic Society. Illustrious though this group very much is, they do not have exclusive ownership of all comment that is worth making in the field of analysis and separation science. Accordingly, we are more than happy to turn to Howard Hill (of contract researchers HLS) who not only has his finger on the pulse regarding biopharmaceuticals and their analysis but is also the lead of the team charged with nurturing the legacy of the late Eric Reid that is the Reid International Bioanalytical Forum. Howard’s main responsibility is orchestrating the high quality scientific programmes that characterize the Reid meetings; so he knows what he is talking about. Here Howard talks to Chromatography Today not only about biopharmaceuticals but also about what is in store for us in this year's Reid meeting in early July.


(Chromatography Today) Several years ago you noted the increasing proportion of biopharmaceuticals in pharmaceutical company pipelines. What were the drivers and just how far have things gone now?


(HH) In some cases biologics are able to target receptors that are not amenable to small chemical entities; there was and probably still is a school of thought that better designed small molecule mimetics could be identified to target any ligand. However the success of some of the early biologics, mostly recombinant forms of endogenous proteins and other important classes such as monoclonal antibodies have proven to be extremely successful in treating life threatening conditions. These “large” molecules now represent up to 50% of many companies’ development portfolios. Indeed there is common agreement amongst most industry observers that by 2014 the top six block busters will be biologics.


What are the drivers causing the current changes in the Pharma Industry.


There are really a variety of changes, a major one being the move to biologicals as described above; another is reduction in new therapeutics registered year on year for the last ten years. This coupled with the patent cliff i.e. where most blockbusters will become generics in the next few years, initiated a round of mergers which in some cases were designed to buy in existing blockbuster molecule sales while diversifying the merged entities portfolio. However this did not result in an increase in new molecules so together the failure of research and loss of revenues has resulted in the need to cut costs, the most prominent recent casualty being Pfizer in Sandwich. There is an increasing trend to off shoring the early discovery, while maintaining the IP around targets and molecular design,


and/or joint ventures with academia and spin out discovery companies. There is a nice article in the RSC journal which, if not a correct interpretation of current and future events, is one with which I certainly agree


This February, your company staged a "Biologics" symposium at Cambridge. How did things go?


The Biologics symposium in Cambridge sponsored by HLS, was a great success, the auditorium was full and the mix of presentations excited a lot of discussion.


There were over 160 registrants. While this is the first in a series of such symposia, HLS organized a similar meeting at Clare College on Advanced Therapies last year. This year was a wider ranging meeting and attracted a much larger audience and had to be moved to the larger auditorium.


The diversity of monoclonal antibodies was illustrated be Dr Mike Clarke (Cambridge University) who illustrated that even within this single therapeutic class there are many technological variations. This started with the production of monoclonal antibodies around 1980 using hybridoma technology. Monoclonal antibodies now range from genetically engineered chimeric antibodies through humanized and full human antibodies generated using a wide range of approaches including mouse immunization, phage display and human monoclonals produced in mice. In addition, receptor polymorphisms are likely to result in the production of subsets of monoclonal therapies able to meet these needs; variations on a theme seem infinite.


While biological therapies have been around a long time, their diversity and rapid growth has meant that industry is learning and evolving its approach so the development process which is truly on a case by case basis – something that was may have been lost in the


small molecule field which used to be developed in a standard format. The current approach for biologics is more fit for purpose; this means that the industry, pharma companies, CROs are all learning and regulators need to share their understanding and take a proactive science driven and less prescriptive approach to drug development.


At HPLC 2010 in Boston and elsewhere there has been discussion of "top down" and "bottom up" approaches to the analysis of biopharmaceuticals. Are both approaches needed? Is LC-MS already eclipsing immunoassay?


I guess this means how concerned are we about small variations in the actual structure of the molecule compared with methods such as immunoassay that measure only one component of the molecule i.e. the binding epitope. Can you relate small changes in structure to changes in activity-do you need to!?


LC-MS is a long way from eclipsing immunoassay; throughput and sensitivity are the two main pros for immunoassay while LC-MS strictly speaking can be set up relatively quickly and for small proteins / peptides is probably the method of choice for this group of compounds.


If we get to the stage where we can measure routinely 10-20 variants of a molecule all with similar biological activity then we may be over specifying the requirements. However understanding the correlation of structural based assays with other assay types is important to know. At the last Reid Forum we had a session organized by John Smeraglia on essentially this topic where Ezan showed a difference in plasma levels between the LC- MS approach and a ligand based approach. In fact Eric Ezan goes into great detail on this in a recent special edition of Bioanalysis.


Is there a strong regulatory influence on how biologics must be analysed?


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52