Design Space in QbD — Definitions

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If you are new to QbD, here are the basic definitions of “Design Space” in QbD. If you have to explain the terminologies to your colleagues, you can refer them to this page as a resource. I’m building a resource page (Start Here) for QbD newcomers.

ICH Q8 (R2) defines Design Space as:

“Design Space: 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.”

As with most guidelines, it is verbose. For the scientist, Design Space is a Y(Quality Attributes) = F (Process Parameters, Material Attributes) — a function or a relationship between (critical) process parameters and (critical) quality attributes /material attributes.

When discussing Design Space in QbD,  four other words come up often: Set Point, Operating Range, Accepted Range and Characterization Range.

I explain them in the video below.
[leadplayer_vid id=”538F3ECED89D0″]

Here are other references:

• Workshop Slides on Design Space (2010, ICH.org)
• If you’d like the ICH Q8 definitions, (Pages 13 – 14 of ICH Q8 (R2), see below)

Contains Nonbinding Recommendations

D. Design Space (2.4)
The relationship between the process inputs (material attributes and process parameters) and the critical quality attributes can be described in the design space (see examples in Appendix 2).

1. Selection of Variables (2.4.1)
The risk assessment and process development experiments described in Section 2.3 can lead to an understanding of the linkage and effect of process parameters and material attributes on product CQAs and also help identify the variables and their ranges within which consistent quality can be achieved. These process parameters and material attributes can thus be selected for inclusion in the design space. A description should be provided in the application of the process parameters and material attributes considered for the design space, those that were included, and their effect on product quality. The rationale for inclusion in the design space should be presented. In some cases, it is helpful to provide also the rationale as to why some parameters were excluded. Knowledge gained from studies should be described in the submission. Process parameters and material attributes that were not varied through development should be highlighted.

2. Describing a Design Space in a Submission (2.4.2)
A design space can be described in terms of ranges of material attributes and process parameters, or through more complex mathematical relationships. It is possible to describe a design space as a time dependent function (e.g., temperature and pressure cycle of a lyophilization cycle), or as a combination of variables such as components of a multivariate model. Scaling factors can also be included if the design space is intended to span multiple operational scales. Analysis of historical data can contribute to the establishment of a design space. Regardless of how a design space is developed, it is expected that operation within the design space will result in a product meeting the defined quality. Examples of different potential approaches to presentation of a design space are presented in Appendix 2.

3. Unit Operation Design Space(s) (2.4.3)
The applicant can choose to establish independent design spaces for one or more unit operations, or to establish a single design space that spans multiple operations. While a separate design space for each unit operation is often simpler to develop, a design space that spans the entire process can provide more operational flexibility. For example, in the case of a drug product that undergoes degradation in solution before lyophilization, the design space to control the extent of degradation (e.g., concentration, time, temperature) could be expressed for each unit operation or as a sum over all unit operations.

4. Relationship of Design Space to Scale and Equipment (2.4.4)
When describing a design space, the applicant should consider the type of operational flexibility desired. A design space can be developed at any scale. The applicant should justify the relevance of a design space developed at small or pilot scale to the proposed production scale manufacturing process and  discuss the potential risks in the scale-up operation. If the applicant proposes the design space to be applicable to multiple operational scales, the design space should be described in terms of relevant scale-independent parameters. For example, if a product was determined to be shear sensitive in a mixing operation, the design space could include shear rate, rather than agitation rate. Dimensionless numbers and/or models for scaling can be included as part of the design space description.

5. Design Space Versus Proven Acceptable Ranges (2.4.5)
A combination of proven acceptable ranges does not constitute a design space. However, proven acceptable ranges based on univariate experimentation can provide useful knowledge about the process.

6. Design Space and Edge of Failure (2.4.6)
It can be helpful to determine the edge of failure for process parameters or material attributes, beyond which the relevant quality attributes cannot be met. However, determining the edge of failure or demonstrating failure modes are not essential parts of establishing a design space.