Crystallization of Organic Compounds, 2nd Edition

Chapter 6Critical Issues and Quality by Design

6.1 QUALITY BY DESIGN

A crystallization process for a specific compound will be governed by the compound’s inherent properties for nucleation and growth. Both morphological and polymorphic formation are also species‐specific. The resulting crystal, physical, and chemical attributes will also depend on external properties of the surrounding environment such as impurities, solvents, temperature, and the rate of generation of supersaturation and mixing. For organic compounds, these critical properties vary over exceedingly wide ranges that are caused by their inherent structural and external operational differences. The reader is referred to Chapters 2, 3, 4, and 5 for a discussion of these properties.

Direct scale‐up from an underdeveloped laboratory procedure may result in a different product from the expected one. These differences may include purity, crystal forms, particle size, wide and/or bimodal particle size distribution (PSD), needles or plates with difficult downstream processing properties, and lack of consistent results.

As stated in ICH guidelines Q11, control strategy should ensure that each drug substance’s Critical Quality Attributes (CQAs) are within the appropriate ranges, limit, or distribution to assure drug substance quality. The drug substance specification is one part of a total control strategy, and not all CQAs need to be included in the drug substance specification. CQAs can (i) be included on the specification ...