http://informahealthcare.com/ddi ISSN: 0363-9045 (print), 1520-5762 (electronic) Drug Dev Ind Pharm, Early Online: 1–7 ! 2013 Informa Healthcare USA, Inc. DOI: 10.3109/03639045.2013.850709 RESEARCH ARTICLE Media milling process optimization for manufacture of drug nanoparticles using design of experiments (DOE) Vijaykumar Nekkanti 1 , Ashwani Marwah 2 , and Raviraj Pillai 2 1 Department of Pharmacy, Western University of Health Sciences, Pomona, CA, USA and 2 Integrated Product Development, Dr. Reddy’s Laboratories Limited, Hyderabad, Andhra Pradesh, India Abstract Design of experiments (DOE), a component of Quality by Design (QbD), is systematic and simultaneous evaluation of process variables to develop a product with predetermined quality attributes. This article presents a case study to understand the effects of process variables in a bead milling process used for manufacture of drug nanoparticles. Experiments were designed and results were computed according to a 3-factor, 3-level face-centered central composite design (CCD). The factors investigated were motor speed, pump speed and bead volume. Responses analyzed for evaluating these effects and interactions were milling time, particle size and process yield. Process validation batches were executed using the optimum process conditions obtained from software Design-Expert Õ to evaluate both the repeatability and reproducibility of bead milling technique. Milling time was optimized to 5 5 h to obtain the desired particle size (d905400 nm). The desirability function used to optimize the response variables and observed responses were in agreement with experimental values. These results demonstrated the reliability of selected model for manufacture of drug nanoparticles with predictable quality attributes. The optimization of bead milling process variables by applying DOE resulted in considerable decrease in milling time to achieve the desired particle size. The study indicates the applicability of DOE approach to optimize critical process parameters in the manufacture of drug nanoparticles. Keywords Bead milling, central composite design, design of experiments, process optimization, QbD History Received 27 April 2013 Revised 31 August 2013 Accepted 20 September 2013 Published online 4 November 2013 Introduction Experimental design has been applied widely to formulation development, and is useful in process optimization and process validation 1 . The manufacturing process can be optimized using the traditional ‘‘trial and error’’ method by evaluating one variable at a time keeping all others constant but this may lead to suboptimal results since the interaction effects of the process variables are ignored and therefore a better process may still prevail in the studied conditions. This invites for the adaptation of rational, systematic, efficient and cost-effective strategies using designing of experiments. With recent quality initiatives and regulatory prospects, implementation of Quality by Design (QbD) has now become an integral part of pharmaceutical industry. A manufacturing process optimized using design of experiments (DOE) should result in a robust process amenable for seamless scale-up and validation 2 . Design of experiments, a component of Quality by Design (QbD), is systematic and simultaneous evaluation of variables (process or formulation) to develop a product with the desired quality attributes 3 . QbD is a broad term that encompasses predefined target quality, physicochemical, physiological, pharmacological and clinical considerations to obtain a product with the desired quality attributes that are safe and effective. For practical considerations, it is expected that variables associated with raw material characteristics, product design, process and scale-up issues will be thoroughly investigated. Therefore, a very useful component of QbD is the understanding of factors and their interaction effects using a desired set of experiments. To understand the variables and their interactions, many statistical experimental designs have been recognized as useful techniques. The concept of DOE methodology is detailed in the following five-step process (Figure 1):  The first step begins with identification of critical quality attributes or responses which can substantially influence the manufacturing process are listed down for evaluation.  The second step involves selection of response variables that may have direct impact on the product quality (e.g. particle size of nanoparticles). Screening of other possible variables shall also be done to identify their prominent influence. The formulation scientists at times, bypass the rigor of screening process by virtue of practical experience, wisdom and previous knowledge or based on the results from the lab experiments. Experimental studies may also be undertaken to define the range of factor levels.  In step three, the response variables and their levels are finalized; a suitable experimental design shall be worked out Address for correspondence: Vijaykumar Nekkanti, Department of Pharmacy, Western University of Health Sciences, Western University, Pomona, CA 91766, USA. Tel: þ909 469 6476. Fax: þ909 469 5600. E- mail: nekkanti_vk@yahoo.com Drug Development and Industrial Pharmacy Downloaded from informahealthcare.com by 172.248.144.104 on 11/04/13 For personal use only.