A key challenge in successfully implementing Quality by Design (QbD) is achieving a thorough understanding of the product
and the process. This knowledge base must include understanding the variability in raw materials, the relationship between
the process and the critical quality attributes (CQAs) of the product, and finally the relationship between the CQAs and the
clinical safety and efficacy of the product. Part 1 of this article presented a stepwise approach to defining a design space.
This Part 2 explains how to validate, file, and monitor the design space. It also discusses how to implement QbD for existing
products and how to integrate QbD with process analytical technology (PAT).
Quality by Design (QbD) is receiving significant attention in both the traditional pharmaceutical and the biopharmaceutical
industry subsequent to the FDA's publication of the International Conference on Harmonization (ICH) Q8 guidance, Pharmaceutical Development in May 2006.1 In the traditional approach to process validation, companies use process understanding from process characterization studies
to define critical, key, and non-key process parameters. The critical process parameters are then controlled within a narrow
range, and the process is validated to ensure it operates within the defined ranges for these process parameters. In the QbD
paradigm, identifying critical process parameters and critical quality attributes (CQAs) will still be required in defining
the design space for a process. However, companies will need to go further in developing their understanding of both the CQAs
and how they relate to clinical performance, as well as in their understanding of how the process will ensure these identified
properties are controlled.2 Online monitoring has been successfully demonstrated in some aspects of biopharmaceutical processes such as fermentation
processes,3–5 and possibilities for future applications in raw materials,6 and downstream processing7,8 are currently under investigation. Once a design space has been defined it will be continually reassessed and changed, pending
regulatory acceptability, based on process understanding.9 This is part of continuous improvement within the quality systems approach.10,11
This article is the fourteenth in the "Elements of Biopharmaceutical Production" series. In this Part 2 of the article, we
present a stepwise approach to validating, filing, and monitoring a design space. Industrial case studies from industry, both
biotech and traditional small-molecule pharmaceutical manufacturing, are used to illustrate the key aspects. We also discuss
how to implement QbD for existing products and how to integrate QbD with process analytical technology (PAT).
Anurag S. Rathore, PhD
QbD IMPLEMENTATION FOR PHARMACEUTICALS
Validating and Filing a Design space
Since a design space "assures quality" of the drug product, the limits defined in the design space could also provide the
basis of the validation acceptance criteria.9 After the design space has been created, process validation becomes an exercise to demonstrate 1) that the process will
deliver a product of acceptable quality if operated within the design space; and 2) that the small- or pilot-scale systems,
scale-up parameters, or models used to establish the design space accurately model the performance of the manufacturing scale
process. Thus, unanticipated manufacturing excursions that remain within the design space should not jeopardize the success
of the validation exercise. After the design space has been established and validated, the regulatory filing would include
all critical process parameters including material attributes (i.e., those included in the design space) and could also include
key process parameters along with the corresponding acceptable and operating ranges.