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40 March 2018 Tablets & Capsules patients, particularly those on long-term management therapies, by reducing the administration burden and improving compliance. this also benefits pharmaceutical companies by extending patents, reducing manufacturing costs compared to single-API drug products, and shortening regulatory approval time and expense compared to NCE development. T&C References 1. Divyakant Desai, Jennifer Wang, Hong Wen, Xuhong Li, and Peter Timmins, "Formulation design, challenges, and development considerations for fixed dose combination (FDC) of oral solid dosage forms," Pharmaceutical Development and Technology, Vol. 18, No. 6, pages 1,265-1,276. 2. Nazaneen Pourkavoos, "Unique risks, benefits, and challenges of developing drug-drug combination products in a pharmaceutical industrial setting," Combination Products in Therapy, Vol. 2, No. 1. 3. US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), "Guidance for Industry: Fixed Dose Combinations, Co-Packaged Drug Products, and Single-Entity Versions of Previously Approved Antiretrovirals for the Treatment of HIV," Available at http://www.fda.gov/cder/guidance/index.htm. 4. Kyu Chan Kwon and Chulung Lee, "Analysis of Fixed-Dose Combination Products Approved by the US Food and Drug Administration, 2010-2015: Implications for Designing a Regulatory Shortcut to New Drug Application." Therapeutic Innovation & Regulatory Science, Vol. 51, No. 1, pages 111-117. 5. Jagannath Kota, Phaninatha Sarma Ayalavajjala, and Rama Sivasubramanian, "Development of orally administered fixed dose combination (FDC) products: Pharmacokinetic and biopharmaceutical considerations," International Journal of Pharmaceutical Sciences and Research, Vol. 6, No. 8, pages 3,161-3,173. 6. Adeline Siew, "Tackling challenges in the development of fixed-dose combinations," Pharmaceutical Technology, Vol. 38, No. 4. 7. Adeline Siew, "Fixed-Dose Combinations," Pharmaceutical Technology, Vol. 39, No. 12, pages 30-31. Amar Patel and Bruhalkumar Shah are senior formulation scientists, Deep Patel is a formulation scientist, Satish Shetty is director of formulation development, and Anthony Qu is vice president of scientific affairs at Halo Pharmaceuticals (866 888 4256, services@halopharma.com). Quality by design A quality-by-design (QbD) approach is critical when developing an FDC dosage form to meet the FDA's requirement for a robust formulation and manufacturing process. Although the application of QbD will be similar to the application for a single-API formulation, it will be more complex due to the presence of multiple APIs. The first and most important step is to define the target product profile (TPP), which describes the use, safety, and efficacy of the product. An in-depth understanding of formulation, excipients, and process is advantageous when defining the TPP and will reduce the amount of experimentation and analytical testing required and, consequently, the manufacturing and testing costs. The next step is to design the formulation and identify the critical quality attributes (CQA) of the final product that must be controlled to meet the TPP. To achieve the final product's critical quality attributes, it's important to identify and control critical process parameters (CPP). Throughout development, scale-up, and commercial- ization, establish a control strategy that includes raw- material and API controls (for particle size distribution, moisture, polymorphs, and impurities, among other characteristics), process controls (such as hardness, thickness, friability, tablet weight during compression, inlet temperature, spray rate, and exhaust temperature during tablet coating), and design space around individual or multiple unit operations (such as granulation, compression, coating, encapsulation, and packaging). It's equally important to monitor these controls and update the process to ensure target product profile. To achieve successful target product profile by QbD approach, it is important to use design of experiment (DOE), risk assessment, and process analytical technology (PAT). A QbD approach provides several advantages, including: • negligible chance of batch failure because the batches are manufactured in a design space defined during product development; • enhanced understanding of the formulation and manufacturing processes; • the development of a robust process that leads to greater regulatory confidence; • continuous improvement in the manufacturing process during development, validation, and post- commercialization in a defined design space doesn't require resubmission to the FDA; • increased product quality, improved yields, reduced investigations and testing, and lower manufacturing costs; • guaranteed therapeutic equivalence of each batch of generics manufactured; • a better, less expensive, and safer drug product. By using a QbD approach, pharmaceutical companies can develop safe and effective FDCs that optimize the pharmacokinetics, bioavailability, and therapeutic effect of existing approved drug products. This benefits