Starting materials guidance

SM-goal. A potential starting material for retrosynthetic guidance. 

The FDA guidance document on impurities in drug substances recommends that individual impurities greater than 0.1% should be fully characterized and quantified by a validated analytical method. In addition, the USP permits up to 2% of ordinary nontoxic impurities in APIs. Such impurities may include residual starting materials, intermediates, reagents, by-products, degradation products, catalysts, heavy metals, electrolytes, filtering aids, and residual solvents. 

The procedure that follows specifies a certain proportion of 1-butanol, sodium bromide, sulfuric acid, and water defines the reaction temperature and time and describes operations to be performed in working up the reaction mixture. The prescription of quantities is based upon considerations of stoichiometry as modified by the results of experimentation. Before undertaking a preparative experiment you should analyze the procedure and calculate the molecular proportions of the reagents. Construction of tables (see p. 178) of properties of starting material, reagents, products, and by-products provides guidance in regulation of temperature and in separa-... 

The company should designate and document the rationale for the point at which production of the API begins. For synthetic processes, this is known as the point at which API starting materials are entered into the process. For other processes (e.g., fermentation, extraction, and purification), this rationale should be established on a case-by-case basis. Table 9 gives guidance on the point at which the API starting material is normally introduced into the process. 

Activated phosphors are used in fluorescent lights, older TV screens, and other light sources because they emit light when they are hit with radiation. They are often made of a metal oxide with trace amounts of another substance, or dopant. They appear to exist on the border between solid solutions and unique chemical substances. When the EPA was compiling the initial Inventory, it accepted some submittals for activated phosphors, but rejected others as mixtures that cannot be listed on the Inventory. The EPA also issued informal guidance letters concluding that activated phosphors are solid solutions. However it later concluded that activated phosphors cannot be manufactured without chemical reactions and therefore they are unique substances and are not solid solutions. Emthermore, the EPA pointed out that the ratio of starting materials is closely controlled and that supports the conclusion that activated phosphors are substances with chemical formulas. 

See Chapter 3, The Inventory. Note that the polymer exemption for polyesters does not disregard starting materials that are charged or present at less than two percent. Polymer Exemption Guidance Manual, 43 (question 37). 

The EPA implied in draft guidance that a chemical manufactured under this exemption cannot be further reacted or used as a starting material without filing a PMN, although that appears to be an overstatement. 

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