The concept of "design space" requires that a biotech product is designed so that it will meet its desired clinical performance,
and the process is designed to consistently deliver a product that meets the quality attributes necessary for this clinical
performance. The primary benefit of an approved design space is regulatory flexibility, most notably the potential to make
process improvements within the design space without regulatory oversight. To achieve the required level of process knowledge,
however, process characterization studies will need to be extensive and encompass a wide range of process parameters.
Anurag S. Rathore
The concept of design space has been receiving a lot of attention lately in the biotech community. One of the foundational
documents for this concept is the ICH Q8 guideline, which was finalized in November 2005 and went into effect in May 2006.
This document provides guidance for the Pharmaceutical Development report (Section 3.2.P.2) contained in Module III of the
Common Technical Document (CTD). ICH Q8 encourages manufacturers of pharmaceutical products to include a comprehensive understanding
of a drug product and its manufacturing process based on "scientific approaches and quality risk management." It recommends
including additional information in order to demonstrate a high degree of understanding of the manufacturing process, which
can lead to more flexible regulatory overview. Most notably, this deeper understanding of process control allows for the development
of an expanded design space, which is defined as:
"...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 post-approval change
process. Design space is proposed by the applicant and is subject to regulatory assessment and approval."1
This article is the eighth in the "Elements of Biopharmaceutical Production" series2and shows how three of the major biotech companies are approaching the application of the design space concept with respect
to various aspects of development and manufacture of biotech products, such as process characterization, process validation,
process monitoring, commercial manufacturing, and regulatory filings.
DEFINING DESIGN SPACE
A well-designed process is expected to be robust, and to enable predictable productivity and product of consistent quality.
The primary source of variability in complex processes, especially biological systems such as cell-culture-based production,
is the interaction of two or more variables. The terms space and multidimensional combination in the above-mentioned definition
imply the need for extensive use of design of experiments (DoE) to map primary effects and interactions between variables
during process characterization (robustness) studies. As seen in Figure 1, first the acceptable variability in product quality
and process performance attributes is established based on clinical exposure of the product, knowledge from other similar
products, and general scientific understanding about the molecule. Next, process characterization studies are performed to
explore the characterization ranges and establish acceptable ranges for key and critical operational parameters. Operating
within these acceptable ranges, the combination of which will ultimately define the design space, provides the "assurance
of quality." It is desirable to have the operating space nested comfortably within the design space, as illustrated in Figure
1. The characterization studies should cover wide ranges for product quality and process performance attributes, extending
beyond what is typically tested based on manufacturing logistics and practicality alone.
Figure 1. Illustration of the creation of design space from process characterization studies and the relationship between
design space and the characterized and operating spaces.