Control Strategy is a critical concept in formulation and process development and the manufacture of a drug product.
A well-defined control strategy reduces risk
The control strategy plays an important role in ensuring that the Quality Target Product Profile (QTPP) is realized and the Critical Quality Attributes (CQAs) met. It is not just a concept, nor is it optional. It is also not a specification. Each product requires an overall control strategy, and there may be more than one approach to creating 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 identification and understanding of the links between the CQAs and the formulation and processing variables are key to formulation and process understanding and risk analysis and mitigation.
Reducing Risk
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.
Developing your Control Strategy
Which approach to developing a control strategy you select will be depend on many factors, including, for example, analytical testing sensitivity, equipment limitations, and processing capabilities. Also, consider sharing your control strategy with regulatory affairs so they can determine whether the risks have been adequately controlled to meet health authority expectations. Once the control strategy is adapted to, and implemented at, the production scale at the manufacturing site, health authority inspectors may review it during inspections to ensure its adequacy and that the site’s quality system can support it.
Control strategy is generally initiated during the clinical trial phase and must be refined for use in commercial manufacture as you gain more information and knowledge. As part of scale-up and technical transfer, product attributes are assessed to determine their impact on product 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 requirements. 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 warrant consideration.
Multi-Level Approach
A control strategy can be divided into more than one level. There is the operational level—tied to the manufacturing process—which would include, for example, processing parameters and material attributes. The quality assurance level would include overseeing the operational 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 a 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 an approved NDA or ANDA.
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 decision. 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.
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