New approaches to raw-material variability

Under the FDA 21st-century CGMP initiative and ICH Q8(R2), pharmaceutical excipient users are now encouraged to apply QbD principles to develop formulations and processes that are flexible enough to cope with anticipated raw-material variability and to produce products that are robust and provide consistent performance (1, 2). At one extreme, the process could be controlled by input parameters from the raw materials so that incoming variability could be compensated by process control to yield finished product that consistently meets the Quality Target Product Profile (QTPP) (2). At the other extreme, the raw material's critical quality attributes (CQAs) could be specified tightly enough to ensure consistent performance to the QTPP.

Of these two extremes, tighter raw-material control is unlikely to be viable in practice; thus, industry is compelled to consider adjustments during the manufacturing process to compensate for inherent raw-material variability. For example, such compensation is facilitated by moving to end-point control instead of using the traditional fixed-processing times.

"the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory postapproval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval" (2).

Scientists in new-product development need to be aware of the expanded scope for adjustments afforded by QbD as they develop their design of experiments to establish their design space. Adjustments could include changes in the physical grade of the excipient (including any potential use of nonpharmaceutical-grade material in the early non-GMP phase of development), blending different grades, quantitative changes in excipient levels, fractionation of excipients (e.g., sieve cuts) as well as process adjustments. Understanding raw-material characteristics and how they influence product CQAs is necessary to derive the controlling algorithms for implementation of such adjustments within a quality system.

This understanding is essential for establishing a design space. Simply mapping the process and raw-material properties used, without understanding, merely defines the experience space, and no adds no benefit beyond the traditional pharmaceutical-development approach. To use the flexibility afforded by the 21st- century CGMP initiative and the ICH guideline, it is necessary to understand the overall context of excipient manufacture and variability, integrate such materials understanding and process engineering, and switch emphasis from consistent composition to consistent performance.