We believe quality by design (QbD) will provide the foundation to achieve an agile pharmaceutical industry capable of manufacturing
a growing range of drug products with increased assurance of product quality. With the final signoff of the annex to International
Conference on Harmonization (ICH) Q8(R1) Pharmaceutical Development in November 2008, industry can now take advantage of three harmonized quality guidances: Q8(R1) Pharmaceutical Development, Q9 Quality Risk Management (harmonized in November 2005), and Q10 Pharmaceutical Quality System (harmonized in June 2008). The newly formed ICH Quality Implementation Working Group (IWG) is available to support further
evolution of QbD concepts as they are adopted by an increasing number of manufacturers.
The acceptance of QbD by all ICH parties, including the US Food and Drug Administration, represents an important change in
the way we approach drug quality. For many in industry, the adoption of QbD has been viewed as a departure from a fixed manufacturing
process, usually accompanied by high regulatory burdens for continual improvement. For ICH, the concept has been, in part,
a move away from harmonizing minimal submission standards and a step toward developing higher level guidances focused on ensuring
product quality. For regulatory bodies such as FDA, the move toward QbD has provided an opportunity to obtain relevant scientific
information required to make informed, risk-based regulatory decisions.
The adoption fo ICH Q8 was a watershed in moving QbD to the forefront. Although initially focused on the minimal expectations
for the pharmaceutical development (P2) section of registration submissions, the final Q8 document introduced many important
QbD concepts such as design space, control strategy, and critical quality attributes (CQAs). Design space, according to Q8,
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." Q8 also states that the aim of pharmaceutical development
is to "design a quality product and its manufacturing process to consistently deliver the intended performance of the product,"
that "information from pharmaceutical development studies can be a basis for quality risk management," and that scientific
understanding provided by development studies and manufacturing experience can be used to "support the establishment of the
design space, specifications, and manufacturing controls."
ICH Q9 goes on to describe the principles of quality risk management, which is fundamental to QbD. The guidance provides references
and tools and explains how risk management can be applied to development, materials management, production, and laboratory
ICH Q10 describes a comprehensive approach to an effective pharmaceutical quality system based on International Organization
for Standardization (ISO) concepts. Implementing Q10 throughout a product's life cycle is expected to strengthen the link
between pharmaceutical development and manufacturing activities, another QbD goal.
The most recent ICH guidance to address QbD topics is the Q8 annex, which has been combined with Q8 and published as ICH guidance
Q8(R1). The Q8 annex elaborates and provides examples of many essential QbD concepts. The guidance specifically describes
how a more enhanced approach can be used to develop drug products and discusses various elements of drug development such
as identifying CQAs, linking material attributes and process parameters to CQAs, selecting variables to include in a design
space, describing design space in an application, and implementing a control strategy. The guidance provides recommendations
on how to accommodate the ICH common technical document format when including QbD information in a regulatory application.
ICH Q11, focusing on the development and manufacture of drug substances, is the only additional harmonized quality guideline
planned at this time. In the meantime, IWG will address questions related to Q8, Q9, and Q10. Already, IWG has drafted a question-and-answer
document (available at
http://www.ich.org/) that elucidates elements of QbD not fully addressed by the quality trio. IWG will provide additional clarifications and
training as needed to ensure a harmonized approach to global QbD implementation.
Overall, these guidances and IWG provide industry and regulators with a foundation to implement QbD in the development and
manufacture of drug products. When fully implemented, FDA expects QbD to provide both economic benefits for the manufacturer
and quality assurance benefits for public consumers.
John Smith is associate director for regulatory science, Christine Moore is acting deputy director, and Moheb Nasr is director, all at the Office of New Drug Quality Assessment in FDA's Center for Drug Evaluation and Research, 10903 New
Hampshire Ave., Bldg. 21, Rm. 2630, Silver Spring, MD 20993-0002.
This article represents the views of the authors and not of FDA.