Feature

API Scale-Up During Research and Development

Nandita P. Shetgiri is head of the department of chemistry and Mahesh S. Phansalkar, Sandeep Patil, and Rupesh Kelaskar are research students at the Institute of Science, 15, Madam Cama Road, Mumbai, India 400 032, emesp03@yahoo.co.in

The ultimate goal of drug synthesis is to scale up from producing milligram quantities in a laboratory to producing kilogram to ton quantities in a plant, all while maintaining high quality and reproducibility at the lowest cost. The term process in the pharmaceutical industry is broad and can apply to the process development work that leads to the efficient, reproducible, economical, safe, and environmentally friendly synthesis of the active pharmaceutical ingredient (API) in a regulated environment. The increasingly stringent regulatory requirements and the global nature of the pharmaceutical business are continuously presenting new challenges to the pharmaceutical industry, resulting in increased competition and a need to produce high-quality APIs. API process development has subsequently gained more attention because of the potential to establish early control over the process at the research and development (R&D) stage by identifying and addressing problematic issues a priori. Thus, a systematic and prospective approach during R&D is key to achieving a successful prospective validation and scale-up. These activities are important and are frequently under scrutiny by the Food and Drug Administration. Prerequisites The data generated in an R&D laboratory must be accurate, reproducible, and dependable. Therefore, it is imperative to establish and follow standard operating procedures (SOPs) for important activities such as the qualification and calibration of instruments and equipment (e.g., weighing balance, standard weights, temperature indicators, and reference standards). It also is necessary to keep proper detailed records of these qualification and calibration activities and other laboratory experiments, observations, and related analytical data. Process considerations API development. Current literature about the API and about its possible future developments should be kept in one place. Challenges to overcome at this stage include: patent infringement; inconsistent raw material quality and supply; hazardous or nonregulated raw materials; costly raw materials; unsafe or environmentally hazardous reactions; low yields; difficult-to-achieve levels of purity (e.g., for enantiomers); scale-up; difficult-to-handle processes; polymorphism-related issues; stability of intermediates or products. R&D chemists must devise a route that can address as many of these challenges as possible. Cost. Raw materials, packaging materials, processes, and labor are major cost factors. R&D chemists can help reduce process expenses by: suggesting cheaper alternative reagents or synthetic routes; reducing raw material consumption (e.g., by conducting process-optimization studies); shortening process time cycles; recycling materials when possible. Environmental friendliness. Today, R&D chemists are expected to use environmentally benign (i.e., green) chemistry. Ideally, high-yielding processes should be developed so that by-products are not pollutants or are treatable to eliminate pollution. Further processing of the spent materials should be attempted to recover the unreacted materials, by-products, and solvents. For example, a recovered solvent can be treated so that it can again match the desired quality specifications and thus be recycled in the same process step. Gaseous products should be scrubbed effectively. The final spent materials from the scrubber and the other processes should be assessed for their load on the environment and be handled appropriately, causing no environmental damage. Solvent selection. The International Conference on Harmonization (ICH) guidelines have classified solvents on the basis of their risk to human health (1). Class 1 solvents should not be used during the manufacture of APIs. Such solvents include: benzene (carcinogenic); carbon tetrachloride (a toxic and an environmental hazard); 1,2-dichloroethane (toxic); 1,1-dichloroethane (toxic); 1,1,1-trichloroethane (an environmental hazard). Class 2 solvents should be limited because of their inherent toxicity. These compounds include: toluene; hexane; methanol; dichloromethane; chloroform; acetonitrile. Solvents in Class 3 may be regarded as less toxic and of lower risk to human health. These include: acetone; ethanol; ethyl acetate; ethyl ether; 1-butanol; acetic acid. Process adaptability. R&D chemists should modify their techniques to fit manufacturing environments. For example, to isolate a product, R&D chemists should avoid evaporating the solvents to dryness because it is difficult to follow such procedures in the plant. Instead, a suitable technique such as crystallization or precipitation should be developed because, in such cases, the product can be isolated by centrifugation or filtration in the plant. Similarly, the purification of a product should be achieved by means of crystallization or selective precipitation because other typical laboratory techniques such as column chromatography have operational limitations at the plant scale. Methods of handling viscous materials in a plant also must be taken into account because the large surface area of plant equipment and piping can pose problems during material transfer. Solutions to these problems include performing one-pot reactions using a suitable solvent to transfer such materials. In addition, reactions involving low temperatures or high pressures could be difficult to handle in the plant, and an alternative route should be considered. (continued)