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22 July 2017 Tablets & Capsules Select a control strategy approach The control strategy plays an important role in ensur- ing that the QTPP is realized and the CQAs met. It is not just a concept, nor is it optional. It is also not a speci- fication. Each product requires an overall control strat- egy, and there may be more than one approach to creat- ing it. For instance, you may want to develop a control strategy for each unit operation, which can include site- specific details. Regardless whether you develop a control strategy using a traditional or QbD approach, the effort should begin during formulation and process development and continue through commercial manufacture. The identifi- cation and understanding of the links between the CQAs and the formulation and processing variables are key to formulation and process understanding and to risk analy- sis and mitigation. A well-defined control strategy reduces risk but does not change the criticality of the attributes. The goal is to gain product and process understanding and to identify the sources of variability that can affect product quality. Once you understand these sources of variability and their impact on the downstream processes, in-process materials, and drug product quality, you can—if necessary—shift controls upstream and minimize the need for end-product testing. Only by identifying the potential for harm can you estimate the probability of its occurrence. Which approach to developing a control strategy you select will depend on many factors, including, for exam- ple, analytical testing sensitivity, equipment limitations, and processing capabilities. Also, consider sharing your control strategy with regulatory affairs personnel so they can determine whether the risks have been adequately controlled to meet the expectations of health authorities. Once the control strategy is adapted to and implemented at production scale at the manufacturing site, inspectors from the health authority may review it during inspec- tions to ensure its adequacy and determine whether the site's quality system can support it. Control strategy is generally initiated during the clini- cal trial phase and must be refined for use in commercial manufacture as you gain more information and knowl- edge. As part of scale-up and technical transfer, product attributes are assessed to determine their impact on prod- uct quality. This evaluation and refinement should be continuous to ensure a robust control strategy over the lifecycle of the drug product. The control strategy for each drug product should contain an understanding of the chemical and physical characteristics of the API and excipients. It may also involve aspects that are specific to the manufacturing site, such as temperature, humidity, or containment require- ments. Additionally, there may be specific equipment characteristics or operating parameters that are important to product quality. Other considerations may include what controls are needed to adjust the process and/or ensure the quality of intermediates, how to monitor those controls, and what in-process tests are required. Containers/closures and storage conditions may also war- rant consideration. A control strategy can be divided into more than one level. There is the operational level—tied to the manu- facturing process—which would include, for example, processing parameters and material attributes. The qual- ity assurance level would include overseeing the opera- tional level and using risk assessment/risk analysis to determine whether a change in a material attribute or process parameter is within the design space or proven acceptable range. The strategic level relates to regulatory robustness, i.e., what is written in the documentation approved by the FDA. This defines what action may be required to implement changes to approved NDA or ANDA documents. Figure 1 summarizes considerations typical for most control strategies. Don't confuse the control strategy with batch release. The control strategy is an element of batch release, but not the only element needed for making a batch-release deci- sion. The elements of control strategy that contribute to final product quality may include, as discussed above, in- process controls and the controls for input materials such as APIs, excipients, intermediates, and containers/closures. The control strategy also encompasses the drug product, facilities, equipment operating conditions, frequency of monitoring, finished-product specifications, and analytical methods. Clarity in documentation The better you understand and apply QbD concepts when developing the documentation to be included in an NDA or ANDA, the less likely the FDA will require addi- tional information during the review process or when you seek to make a post-approval change. Be sure your docu- ments are written clearly, use easily understandable lan- guage, and meet the required format. The documents should, for instance, define the formu- lation and process studies that were conducted and state what was learned from each experiment. Using this infor- mation, construct a risk evaluation of what may be critical or not critical in defining the unit operations. Provide a detailed flow chart and describe each unit operation. Discuss each processing step, its purpose, and how it affects overall product quality. Identify the critical mater- ial attributes of the API, excipients, and/ or intermediates and the CPPs. Determine how often these attributes and parameters require monitoring and control to ensure a consistently high-quality finished tablet or capsule based on the risk assessments you performed. Explain your reasoning. Provide experimental data that justify your decisions and/or, if necessary, conduct addi- tional studies to provide missing data. Never make any statement that implies that the criticality of a material or process attribute is undetermined or unknown, because that reveals that your development work is insufficient to understand the product, to assess its CQAs, or to propose a suitable control strategy. T&C