Active pharmaceutical ingredient specification

Garrett, C.E. and Prasad, K. (2004) The art of meeting palladium specifications in active pharmaceutical ingredients produced by Pd-catalyzed reactions. Advanced Synthesis and Catalysis, 346 (8), 889-900. 

The design of crystallization processes for the manufacture of Active Pharmaceutical Ingredients is a significant technical challenge to Process Research and Development groups throughout the Pharmaceutical and related industries. It requires an understanding of both the thermodynamic and kinetic aspects of crystallization, to ensure that the physical properties of the product will consistently meet specification. Failure to address these issues may lead to production problems associated with crystal size, shape and solubility, and to dissolution and bioavailability effects in the formulated product. 

Reliable quality control in the field of pharmaceutical analysis is based on the use of valid analytical methods. For this reason, any analytical procedures proposed for a particular active pharmaceutical ingredient and its corresponding dosage forms shonld be validated to demonstrate that they are scientifically sonnd nnder the experimental conditions intended to be used. Since dissolntion data reflect drng prod-net stability and quality, the HPLC method used in snch tests shonld be validated in terms of accuracy, precision, sensitivity, specificity, rngged-ness, and robustness as per ICH guidelines. 

An active pharmaceutical ingredient (API) batch fails to conform to established specifications and yet the manufacturer distributed it anyway. Deliberately blending API batches to dilute or hide noxious contaminant or filth or failing to determine actual yield and percentages of expected yields. Contamination of drugs with toxic chemicals, drug residues, airborne contaminants, or filth. 

Part IF Specific requirements of premises, plant, and materials for manufacture of active pharmaceutical ingredients (bulk drugs)... 

World Health Organization (WHO). Good Manufacturing Practices for active pharmaceutical ingredients (bulk drug substances). In WHO Expert Committee on Specifications for Pharmaceutical Preparations (1992). 

While this is a very positive boundary condition for the development of low-dose formulations, the major drawback of the low-dose formulation range is, as mentioned earlier, the potential exacerbation of chemical instability of active pharmaceutical ingredients. Thus, stabilization techniques are of high interest to the formulator dealing with this formulation space. Specifically, stabilizers from various classes of antioxidants have been applied.23,24 It is obvious that the specific knowledge of potential and actual degradation pathways of the drug will be crucial for the development of stable formulations. 

Note that in this theoretical example the specification limit for compound D is set to 7.0% and since no isolated impurity exists the active pharmaceutical ingredient is used for the low level... 

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