Candidate-selection process

The goal ofthe formulation scientist at this stage is to support the candidate selection process by understanding key physicochemical properties and other factors that can affect the delivery and exposure of compounds. Through well designed and executed formulation work, the formulation support helps to select drug candidates with appropriate physicochemical properties to ensure the developability... 

Animal models of disease play a critical role in the drug discovery process and are important in the lead candidate selection process as well. Categories of animal disease models include spontaneous disease, induced models (e.g., chemically, immunologically), xenograft models, infection models, and genetically modified models (e.g., transgenic knockouts (KOs) or knock-ins (KIs), humanized animals (e.g., expressing the human protein or receptor). The sub-... 

Figure 2. DMPK screening paradigm as part of the lead optimization and candidate selection process-application to HCV compound selection.

The descriptor set can then be reduced by eliminating candidates that show such bad characteristics. Optimization techniques such as genetic algorithms (see Section 9.7) are powerful means of automating this selection process. 

Investigations of incidents associated with tolling projects have identified that appropriate selection of a toller based upon proper equipment and expertise is important in reducing the likelihood of future process safety related incidents and environmental releases. It is likewise important to review toller safety, health, and environmental practices (current and past) in the selection process. This review can identify those practices that would need to be modified to be acceptable. Eliminating less qualified candidate firms at an early stage is a best practice. 

In this phase of the toller selection process, we assume the long list became a short list and now one or more candidate tollers from the short list will be given an opportunity to prepare a commercial bid. This by no means indicates the short listed tollers are perfect. There may be deficiencies that need to be corrected in concert with the client. With proper effort, one will be successful and be engaged for the toll. Sometimes it is appropriate to decide on a backup toller, as complications can develop that prevent the primary candidate from executing the project as originally planned, due to an incident in their plant, departure of key personnel, or unexpected production demands on the toller. 

Note that the site selection process need not be lengthy or complex. Team members regular pb responsMities, as well as their PSM work to date, witt have thoroughly acquainted them vdth a range of your company s facilities. It s more than likely that logical candidates for the pilot site will have emerged naturally from the process and may already have been proposed. 

The genesis of in silico oral bioavailability predictions can be traced back to Lip-inski s Rule of Five and others qualitative attempts to describe drug-like molecules [13-15]. These processes are useful primarily as a qualitative tool in the early stage library design and in the candidate selection. Despite its large number of falsepositive results, Lipinski s Rule of Five has come into wide use as a qualitative tool to help the chemist design bioavailable compounds. It was concluded that compounds are most likely to have poor absorption when the molecular weight is >500, the calculated octan-l-ol/water partition coefficient (c log P) is >5, the number of H-bond donors is >5, and the number of H-bond acceptors is >10. Computation of these properties is now available as an ADME (absorption, distribution, metabolism, excretion) screen in commercial software such as Tsar (from Accelrys). The rule-of-5 should be seen as a qualitative, rather than quantitative, predictor of absorption and permeability [16, 17]. 

Only after all these exhaustive tests are a few candidates selected for pre-clinical in vivo studies using animal disease models. The current approach is to perform as many tests as possible based on tissue cultures or cell-based assays, as they are less costly and provide results more readily. At the end of this long process is the availability of selected drug candidates with sufficient efficacy and safety required for human chnical trials. 

III. CAPILLARY ELECTROPHORESIS IN THE DRUG DEVELOPMENT PROCESS, FROM CANDIDATE SELECTION TO THE MARKET... 

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