Pharmaceutical quality by design: product and process development, understanding, and control

Pharmaceutical Research, Vol. 25, No. 4, April 2008 (# 2007) DOI: 10.1007/s11095-007-9511-1

Research Paper Pharmaceutical Quality by Design: Product and Process Development, Understanding, and Control
Lawrence X. Yu1,2

Received September 9, 2007; accepted November 26, 2007; published online January 10, 2008 Purpose. The purpose of this paper is to discuss the pharmaceutical Quality byDesign (QbD) and describe how it can be used to ensure pharmaceutical quality. Materials and Methods. The QbD was described and some of its elements identified. Process parameters and quality attributes were identified for each unit operation during manufacture of solid oral dosage forms. The use of QbD was contrasted with the evaluation of product quality by testing alone. Results. The QbD is asystemic approach to pharmaceutical development. It means designing and developing formulations and manufacturing processes to ensure predefined product quality. Some of the QbD elements include: – – – – Defining target product quality profile Designing product and manufacturing processes Identifying critical quality attributes, process parameters, and sources of variability Controlling manufacturingprocesses to produce consistent quality over time

Conclusions. Using QbD, pharmaceutical quality is assured by understanding and controlling formulation and manufacturing variables. Product testing confirms the product quality. Implementation of QbD will enable transformation of the chemistry, manufacturing, and controls (CMC) review of abbreviated new drug applications (ANDAs) into ascience-based pharmaceutical quality assessment. KEY WORDS: pharmaceutical quality by design; pharmaceutical quality by testing; process control; process design; process parameter; process variability; product design; quality attribute; question-based review.

INTRODUCTION The Food and Drug Administration (FDA) Office of Generic Drugs (OGD) has developed a question-based review (QbR) for its chemistry,manufacturing, and controls (CMC) evaluation of abbreviated new drug applications (ANDAs). QbR is a new quality assessment system that is focused on critical pharmaceutical quality attributes. It is a concrete and practical implementation of some underlying concepts and principles outlined by the FDA’s Pharmaceutical CGMPs for the twenty-first century and quality by design (QbD) initiatives (1).This new QbR system incorporates some elements of QbD (2). It recommends that ANDAs be submitted using the common technical document (CTD) and include the quality overall summary (QOS) that addresses all the QbR questions. The main benefits of this QbR system are to (1) assure

product quality through design and performance-based specifications, (2) facilitate continuous improvement and reduce CMCsupplements, (3) enhance the quality of CMC reviews through standardized review questions, and (4) reduce CMC review time when applicants submit a QOS that addresses the QbR questions. This commentary focuses on the QbD for generic drugs. The concept of QbD was mentioned in the ICH Q8 guidance (3), which states that “quality cannot be tested into products, i.e., quality should be built in bydesign”. This paper discusses the pharmaceutical quality by design and describes how it can be used to ensure pharmaceutical quality with emphasis on solid oral dosage forms of small molecules. PHARMACEUTICAL QUALITY BY TESTING Figure 1 shows a simplified quality control diagram under the current quality by testing (QbT) regulatory framework for generic drugs. In this system, product quality is ensuredby raw material testing, drug substance manufacturing, a fixed drug product manufacturing process, in-process material testing, and end product testing. The quality of raw materials including drug substance and excipients is monitored by testing. If they meet the manufacturer’s proposed and FDA approved specifications or other
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