By Garnet G. Smith, N/A
Start with the Ultimate Goal Process Characterization Creative Problem Solving About the Author About SP Pharmaceuticals LLC
Although many factors determine success in the transition of a sterile drug from laboratory to commercial production, process scalability is an area of unique importance. When the process has been properly developed for scaleup, it ensures that a product's transition time from research to commercial production is minimized. This is an important advantage in view of the pressing competition most pharmaceutical companies encounter as rivals bring out competing products ever more quickly. However, the disadvantages are equally important if a process has not been developed properly for scaleup. A flawed process may result in an initially high rejection rate, costly schedule revisions, or excessive labor needs. In some cases, the process may not satisfactorily produce the drug product in order to be approved by regulatory agencies.
Start with the Ultimate Goal (Back to Top) The best approach is to create and design the process with the ultimate goal of making a commercially viable product. The laboratory process should be a scaled-down version of the commercial process and must meet the requirements of high production volume and precise product control, while ensuring the chemical and physical integrity of the product.
Conversely, starting with a process because it works at the bench-scale level may be convenient for the short term, but it may not work well at the production level, at least not without significant modifications to product or process. Industry-wide, this happens too frequently.
Process Characterization (Back to Top) Characterizing the process is a principal step in assuring that it can be translated to manufacturing on a routine production basis. Generally, the step involves characterizing both technique and equipment. This includes identifying variables and assessing their effect on the formulation requirements. It also determines how product quality and manufacturing productivity will be affected.
With sterile products, development scientists are primarily concerned with unit operations such as liquid processing, sterilization, filtration, batch size, stirring rate, shear rate, dispersion of active bulk drugs, and emulsification. Filtration parameters may be affected by surface area, flow rate, viscosity, surface tension, and type of vehicle, any of which can affect product stability. Dispersion parameters may be affected by vehicle surface tension; bulk drug particle size, shape, and electrical charge; and settling rate.
Creative Problem Solving (Back to Top) There may be more than one solution to a problem, and it is important for the development scientist to identify critical variables. For example, when a high-viscosity liquid is scaled up air may be entrapped during mixing, resulting in non-uniform fill volumes. This problem may be minimized by reducing agitator speed, proper selection of impeller design, by inserting tank baffles, or processing in an enclosed tank under vacuum.
Another example: formulations prepared by multiple passes through a laboratory-scale colloid mill, or by prolonged exposure to a vertical homogenizer, may yield a dispersion that is very different in properties from large production batches using an in-line unit. The development scientist must evaluate alternate equipment to maximize product elegance at a reasonable production output rate.
Despite the critical role that process design plays in successful new drug development, it is important to recognize that it does not occur in a vacuum. In addition to process design, successful scale-up depends on a number of factors that are distinct yet intimately related, including the characteristics of the bulk drug, formulation and dosage form, and process control. Only when each of these factors are properly addressed can the product development program result in a quality product that can be manufactured consistently with a validatable process.
About the Author (Back to Top) Garnet G. Smith is director of pharmaceutical research at SP Pharmaceuticals. His employment history includes extensive senior management experience in manufacturing, process development and research. He earned his Ph.D. at Purdue University in Industrial and Physical Pharmacy, and a B.S. and M.S. at the University of Toronto. He also has an MBA from Western Michigan University. During his career, Smith has launched dozens of new products, developed new processes, and designed several new pilot and production manufacturing facilities. He is a member of the Parenteral Drug Association, the American Academy of Pharmaceutical Scientists, and the Pharmaceutical Manufacturers Association.
About SP Pharmaceuticals LLC (Back to Top) SP Pharmaceuticals LLC is a contract manufacturer and product developer specializing in liquid and lyophilized parenterals. SP offers a complete range of services under one roof, including: pharmaceutical formulation and development, regulatory assistance, and production of large or small commercial batches. Privately held, SP emerged from the management buyout of Pharmacia & Upjohn's small-volume sterile injectables division in 1988. Since becoming independent SP has produced several of Pharmacia's chemotherapeutic and AIDS therapy products.
For more information: Garnet G. Smith, Director, Pharmaceutical Research, N/A, 4272 Balloon Park, NE, Albuquerque, NM 87109. Tel: 505-345-0500. Fax: 505-761-9229.
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