The knowledge gained through appropriately designed development studies culminates in the establishment of a control strategy. As shown in the picture, control strategy could include three levels of controls as follows:
Level 1 utilizes automatic engineering control to monitor the CQAs of the output materials in real time. This level of control is the most adaptive.
Input material attributes are monitored and process parameters are automatically adjusted to assure that CQAs consistently conform to the established acceptance criteria.
Level 1 control can enable real-time release testing and provides an increased level of quality assurance compared to traditional end-product testing. It should be noted that adoption of process analytical technology (PAT) is not the only way to implement real-time release testing.
Level 2 consists of pharmaceutical control with reduced end-product testing and flexible material attributes and process parameters within the established design space.
QbD fosters product and process understanding and facilitates identification of the sources of variability that impact product quality. Understanding the impact that variability has on in-process materials, downstream processing, and drug product quality provides an opportunity to shift controls upstream and to reduce the reliance on end-product testing.
Level 3 is the level of control traditionally used in the pharmaceutical industry. This control strategy relies on extensive end-product testing and tightly constrained material attributes and process parameters.
Due to limited characterization of the sources of variability and inadequate understanding of the impact that CMAs and CPPs have on the drug product CQAs, any significant change in these requires regulatory oversight.
A hybrid approach combining levels 1 and 2 can be used.
ICHQ8 (R2) defines a control strategy as a planned set of controls, derived from current product and process understanding that ensures process performance and product quality.
The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control.
A control strategy can include, but is not limited to, the following:
- Control of input material attributes based on an understanding of their impact on process ability or product quality
- Product specification(s)
- Controls for unit operations that have an impact on downstream processing or product quality
- In-process or real-time release testing in lieu of end-product testing (e.g., measurement and control of CQAs during processing)
- A monitoring program for verifying multivariate prediction models
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