Regulatory starting material

Most process steps involved in the manufacture of drug substances, intermediates, and regulatory starting materials occur in the presence of a solvent or combination of solvents. Depending on the manufacturing process and regulatory requirements, these materials may be tested for the amount of solvent(s) present in the sample by the compendial methods. 

Testing for solvent content in intermediates may need to be performed if a critical amount of residual solvent(s) remaining in the intermediate can alter the next step of the process. Knowledge of the solvent content in regulatory starting materials may help the development chemist to understand the synthetic route and predict potential process-related impurities. Knowing the solvents used in a process allows the development chemist to look for possible compound-solvent interactions which can lead to the formation of impurities. 

Many routes of synthesis proceeded through pyrazole 5. Hence, a pragmatic approach was taken to nominate this material as the proposed regulatory starting material and focus on chemistry downstream of pyrazole 5. The commercial route is shown in Scheme 16.3. 

As previously mentioned, nitropyrazole 5 is one of the regulatory starting materials for sildenafil citrate, so not surprisingly the compound has attracted the attention of fine chemical companies and within Pfizer. The optimization of the condensation reaction to make intermediate 1 has been previously reported. In the medicinal chemistry synthesis, conversion of 1 to compound 3 was accomplished via reaction with hydrazine followed by a methylation reaction. Clearly a more efficient way of making this transformation is to use a regioselective condensation reaction with methylbydrazine. " " ... 

FIGURE 1.4 An outline of stages of solid form development in pharmaceutical industry. RSM is a regulatory starting material. 

Good Manufacturing Practice and certification of starting materials for the industrial manufacture of medicinal products. Concept paper on a Community regulatory framework , 1995 European Commission, Directorate General IE, Industry Consumer Goods Industries III/E/3 Pharmaceuticals, July. 

In early 2007, the EMEA reported the analysis of GMP deficiencies in its document entitled Good Manufacturing Practice An Analysis of Regulatory Inspection Findings in the Centralised Procedure. It detailed the deficiencies reported in 435 inspections of manufacturers of medicinal products and starting materials in the European Union and third countries in the period 1995 to 2005. Altogether there were 9465 deficiencies, of which 193 were critical (2%), 989 major (10%), and 8283 (88%) others. The top 20 deficiencies are presented in Table 10.1. 

Regulation also limits the levels of permitted impurities in color additives. Detailed standards of quality and purity have been incorporated into regulatory requirements, establishing maximum amounts of organic impurities such as subsidiary dyes and residues of starting materials, intermediates, or other contaminants. Each batch of color made must be tested for compliance with chemical specifications in order to be certified (130,142,151). Therefore, there is a need for rapid and reliable techniques to separate the dyes from impurities and to monitor the quality of commercial dyes (154). 

Unacceptable starting materials used in research must be replaced by those which meet the regulatory quality and safety criteria. Reference to standard volumes of pharmaceutical ingredients and excipients should be made to decide whether a certain ingredient can be used. Standards are described in the pharmacopoeias of relevant countries, the "Handbook of Pharmaceutical Excipients" or its Swiss anchestor the "Katalog pharmazeutischer Hilfsstoffe". Fiedler s "Lexikon der Hilfsstoffe" (Lexicon of Excipients) provides many useful informations about the safety and about applications for excipients. (For references see Annex B to the registration requirements chapter.)... 

Excipients manufactured by fermentation processes, such as dextrose, citric acid, mannitol, and trehalose, should be specially controlled for endotoxin levels. Mycotoxin (highly toxic metabolic products of certain fimgi species) contamination of an excipient derived from natural material has not been specifically addressed by regulatory authorities. The German health authority issued a draft guideline in 1997 where a limit was specified for Aflotoxins Mi, Bi, and the sum of Bi, B2, Gi, and G2 in the starting material for pharmaceutical products. 

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