Pharmaceutical profiling, definition

Since the final product is a pharmaceutical, high purity of the product is definitely required. Furthermore, the amount of any impurities in the final product has to be rigorously regulated under ICH guidelines. Rejection of impurities related to cyclopropylacetylene (37) was difficult throughout this whole process [28]. Thus, not only the isolated yield but the impurity profile of 37 was critical. 

Given these definitions, FOPs would likely be considered pharmaceutical alternatives if one presumes that pioneer and follow-on proteins are identical at a precursor stage, prior to potential post-translational modification. This presumption may also be consistent with the similarity standard the agency applies to ascertain orphan drug status (see discussion in Section 1.2.6). Follow-on proteins cannot be considered to be therapeutic equivalents since they are not pharmaceutical equivalents and cannot be expected to have the same clinical effect and safety profile in the absence of testing. This assertion is supported by the following ... 

In a 12-week, double-blind, randomized, placebo-controlled study in 40 patients with treatment-resistant schizophrenia (funded by Johnson Johnson Pharmaceutical Research Development), the addition of risperidone to clozapine improved overall symptoms and positive and negative symptoms (49). The adverse events profile of clozapine + risperidone was similar to that of clozapine + placebo. Clozapine + risperidone did not cause additional weight gain, agranulocytosis, or seizures compared with clozapine + placebo. All the patients completed 12 weeks of treatment however, the small sample size precluded definitive conclusions. 

Analytical chemists generally run a series of different assays (orthogonal assays) to confirm that they have sufficiently characterized the sample and have identified all impurity peaks found in the sample. Furthermore, they ensure that peaks which may co-elute using one technique can be detected with an orthogonal method (see Chapter 10). Analytical HPLC is the most common technology employed for assay and impurity profiling of pharmaceuticals. When the sample has been analyzed, the impurity may need to be isolated (for structural characterization, for instance). While techniques such as LC-MS may give an indication of the compound identification from the bulk assay, the definitive proof is always obtained from an independent analysis of the isolated compound. 

Characterization starts once the synthetic route has been selected, although there will be opportunities to modify the route if the changes do not impact the final solid state or impurity profile of the final active pharmaceutical ingredient. The primary objective is to understand, through experimentation, the chemical and physical chemical processes involved in the transformation of raw materials to intermediates and products. The primary outcome is a process definition that includes the order of manufacturing steps, process parameter control methodology, process parameter limits, raw material specification, and diagnostic metrics. 

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