Drug substance and excipient properties
To consistently achieve the drug-product quality specified in the label, the drug substance needs to be thoroughly characterized
with respect to its physical, chemical, biological, and mechanical properties such as solubility, polymorphism, stability,
particle size, and flow properties (2). It is well recognized that excipients could be a major source of variability. Characterization
and understanding of excipients' pharmaceutical properties depend on the function and utility of excipients. Drug-excipient
compatibility knowledge and information are valuable in the design of formulation and manufacturing processes. Such information
may be gained through theoretical investigation and experimental studies. It was noted during the workshop that mechanistic
understanding of degradation kinetics provides more value in predicting stability than experimental data collected under artificial
stress conditions.
Formulation design and development
Not all prototype formulations can be evaluated in human subjects, which means that developing sensitive in vitro dissolution methods is crucial to an effective development program (4). FDA's recommended in vitro dissolution method is generally used for quality control. Generic-drug sponsors report using in-house methods for pharmaceutical
development (some mentioned using as many as five biorelevant dissolution conditions) to evaluate formulations and processes
before performing bioequivalence studies. FDA participants in the workshop found it compelling that pharmaceutical scientists
develop a battery of biorelevant dissolution methods to accelerate drug-product development. Further, generic-drug industry
participants noted that the Biopharmaceutics Classification System is valuable in guiding formulation development (2).
To establish formulation robustness, sponsors of abbreviated new drug applications (ANDAs) generally evaluate relevant quality
attributes of product manufactured at the laboratory scale. The availability of drug substance may influence the number of
studies and therefore, product understanding. It was suggested during the workshop that QbD should rely on the relevance of
individual studies rather than the number of studies because one of the objectives of QbD is to understand how the material
attributes of the drug substance and excipient influence product quality. ANDA sponsors generally agreed that a formulation
design space (preapproved ranges) would be valuable to industry if appropriate regulatory flexibility is granted. However,
the establishment of formulation design space should not delay FDA's approvals. It was suggested that FDA consider the establishment
of formulation design space as a postapproval activity.
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