kilomentor | 25 June, 2012 13:51
June 13 and
14th just passed I was
generously provided a Press Pass to attend the Cambridge Healthtech
Institute’s 6th International
Current Process Chemistry Conference in Princeton New Jersey.
This meeting is attended predominantly by very experienced scale up scientists who usually are the team leaders of a group or the directors of a department specializing in process scale up. The content is focused at a level suitable for persons who could write this blog rather than those who are most likely to benefit from reading it! Nevertheless, the general nature of the subject matter being discussed helps me see the trends of the research big pharma and contract research organizations are doing today and the types of background preparation upcoming process development chemists and chemical engineers are going to need.
Most speakers provided a narrative description of the particular issues that arose in the scale up for preparing a particular structure. The emphasis here is on rapid, fit-for-purpose, scale up. This means that the processes were not really optimized in the sense of using a multivariable statistic design to find the overall best combination of all the variables. Rather, in the typical instance, a processes was modified by eliminating potentially serious risks such as the potential difficult in removing metal impurities or immediately vetoing potentially dangerous methodologies or making appropriate provisions to deal with questions about late stage genotoxic impurities. (Issues relating to genotoxic impurities came up regularly throughout the meeting. There are certain functional groups which increase the likelihood that the intermediate or reagent containing them will be found genotoxic. Genotoxic substances cause changes in the transmission of the genome and affect genetic inheritance and must be held below very stringent impurity levels. They do not follow a dose response relationship so there is no completely safe dose. Just developing analytic methods showing that a process controls genotoxic impurities below these levels is difficult. As a result scale up chemists often simply avoid routes that use these late stage intermediates or reagents.)
The main concern of these specialists was as I said fit-for-purpose scale up. The dominate concern was to provide the correct number of kilograms of product, of the required purity, on the required date. The only long range requirement of the method was that there should be no reason why the method could not be run larger and more intensively to provide commercial quantities.
There wa very little mention of minimizing cost at this stage, for these people, except the minimization of solvent usage where it reflects the greenness of the process. Minimization of solvent use of course also helps increase throughput and influences the time needed to deliver their kilograms of drug candidate. It seems that the cost reduction strategies that grind down the costs of API to the lowest level possible are found more among the generic drug substance chemical community.
Another keen interest of these fit-for-purpose process chemists was identifying and demonstrating the effect of critical process variables. It appears still very important for developing process chemists to have an understanding of what constitute critic process parameters. This is part of process validation. Kilomentor has written an article about process validation from a process chemist’s perspective which the emphasis of this conference seems to further recommend. http://kilomentor.chemicalblogs.com/55_kilomentor/archive/1375_the_importance_of_understanding_process_validation_for_pharmaceutical_process_chemists.html
Government regulators are interested in guaranteeing the public’s safety when they take the actual medicine. Therefore, they are only interested that manufacturers control variables which can deleteriously affect the quality of the final drug substance. The companies that make drug substances, on the other hand, are also very interested in parameters that have an impact upon the cost of the drug substance. Although the percentage yield of a drug intermediate is may have no effect on the quality of the final product, a low yield can and most likely will make the ultimate process uneconomic. Thus the companies are very concerned about these parameters which affect the economics. Parameters that do not affect the final product quality but do affect the economics are called key parameters as opposed to critical parameters. Incidentally regulators are interested in knowing about varying yields, even if the yield of a particular intermediate is only a key parameter because it shows that there is at least one significant uncontrolled variable in the process. Unidentified sources of process variation are signs of inadequate process knowledge and potential product difficulties in the future.