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Abstract. This review further clarifies the concept of pharmaceutical quality by design (QbD) and describes its objectives. QbD elements include the following: (1) a quality target product profile (QTPP) that identifies the critical quality attributes (CQAs) of the drug product; (2) product design and understanding including identification of critical material attributes (CMAs); (3) process design and understanding including identification of critical process parameters (CPPs), linking CMAs and CPPs to CQAs; (4) a control strategy that includes specifications for the drug substance(s), excipient(s), and drug product as well as controls for each step of the manufacturing process; and (5) process capability and continual improvement. QbD tools and studies include prior knowledge, risk assessment, mechanistic models, design of experiments (DoE) and data analysis, and process analytical technology (PAT). As the pharmaceutical industry moves toward the implementation of pharmaceutical QbD, a common terminology, understanding of concepts and expectations are necessary. This understanding will facilitate better communication between those involved in risk-based drug development and drug application review.

Heparin has been used clinically as an anticoagulant for over 60 years. Typically isolated from porcine intestine, heparin is a mixture of dimeric glycosidic sequences generating complex polysaccharide glycosaminoglycan chains. Recently, certain lots of heparin have been associated with an acute, rapid onset of significant side effects indicative of an allergic-type reaction. To identify potential causes for this serious rise in side effects, we examined lots of heparin that correlated with adverse events using orthogonal high resolution analytical techniques. Through comparison of these results with those obtained on reference lots, suspect lots were found to contain a highly sulfated chondroitin sulfate contaminant. Through detailed structural analysis, the contaminant was found to contain a disaccharide repeat unit of glucuronic acid linked β1→3 to a β-galactosamine. Surprisingly, the disaccharide unit contains an unusual sulfation pattern and is sulfated at the 2-O and 3-O positions of the glucuronic acid as well as at the 4-O and 6-O positions of the galactosamine. The presence of such a contaminant could elicit a biological response as highly sulfated polysaccharides, such as dextran sulfate, are known to be potent mediators of the immune system. Given the nature of the contaminant, traditional screening tests -such as those present as part of the current United States Pharmacopeia heparin monograph -cannot differentiate between affected and unaffected lots. Our analysis suggests effective screening methods that can be employed to determine whether or not heparin lots contain the contaminants reported here.