Issue link: http://www.e-digitaleditions.com/i/579724
12 OCTOBER 2015 Inhalation to improve quality and decrease cost to the con- sumer. In order to improve reliability and thus the efficiency and cost-effectiveness of manufacturing through the use of innovative technologies, the FDA started to move towards a "risk-based orienta- tion" incorporating risk management, through its pharmaceutical cGMP (current good manufactur- ing practice) initiative, as well as by guidelines laid dow n b y th e I n ter n a ti o n a l C o n ference o n Harmonization (ICH) (see sidebar). 5, 7, 8 This pro- vided the industry with a framework to apply to both the understanding of new products and the regulatory requirements for both new applications and managing change. Benefits of quality by design QbD has a range of benefits in trial design and prod- uct development 8 that include: • Better-designed products • Enhanced mitigation of risk • Improved manufacturing processes, with fewer issues • More streamlined introduction of new manufac- turing technologies • Opportunity for continuous improvement in manufacturing processes without costly post- approval change processes • Lower-cost, or more cost-effective, manufacturing • Less waste • Faster and/or more f lexible approval process based on enhanced knowledge • Better understanding of processes In addition to receiving encouragement from regu- latory authorities, the biopharma industry has been positive about the adoption of QbD. The approach has enabled the industry to: reduce the risk of attri- tion due to manufacturing issues during the prod- uct development process, especially at later stages; increase flexibility; and add the potential for cost savings. Indeed, the first QbD approval was of a biologic license application (BLA) from Roche for Gazyva (obinutuzumab), an immunomodulator for the treatment of lymphoma. 9 Doing quality by design step by step The overall QbD approach is based on the risk assessment/management process, 5, 7 which involves: • Initial risk assessment of the effects of those dis- cussed variables on the CQAs, based on the expe- rience with similar products • Study design and execution to evaluate the effect of the input variables on the CQAs • Data analysis and trending to understand the cor- relation between the input variables and CQAs over the design space • Finalizing the risk assessment and defining the operating space based on the outcomes of the experiments. Understanding these variables is based on a combina- tion of prior knowledge of all these criteria, along with risk analysis and experiments that have been sta- tistically designed, and helps keep the objective---suc- cessful commercialization---in the mind of all con- cerned in the development process. 8, 10 The first step of the QbD process is to define the quality target product profile (QTPP), which the ICH guidelines describe as "a prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired qual- ity, taking into account safety and efficacy of the drug product." 5 For an inhaled product this might include a range of elements such as target dose range, frequency of dosing, delivery time, portabil- ity, shelf life and storage conditions. The next step is to identify the critical quality attributes (CQAs) that drug developers and manu- facturers will need to achieve the quality target product profile. A CQA is described by the ICH guidelines as "a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or dis- tribution to ensure the desired product quality." 5, 8 Ensuring that the right CQAs, such as aerodynamic particle size or air flow rate to trigger dose deliv- ery, are selected is a vital part of the QbD process. Pivotal to these two steps is an understanding of how components can var y. These components include active pharmaceutical ingredients (APIs), excipients, formulations and deliver y devices (especially in inhaled therapies). The developer will evaluate how the properties of the end prod- uct will be affected by changes in the CQAs, and will look at how the CQAs are related to each other. 1 Once the quality target product profile has been decided, and the critical quality attributes defined, the drug developer's next step is to create the design space. Again using the ICH guidelines defini- tion, a design space is the "multidimensional combi- nation and interaction of input variables (e.g., mate- rial attributes) and process parameters that have been demonstrated to provide assurance of quality." These variables include in-process, drug substance and drug product attributes. The determination of the process design space includes the use of risk analysis, mathematical models where available and design of experiment (DOE) techniques. 5, 8 The role of the design space in QbD is to provide a place to define the range for the process variables. Provided that these variables remain within the pre-determined ranges, process developers can be assured that the performance of the drug product and device will be as expected. Each step that links