Enhanced process and product understanding are the basic tenets of Quality by Design (QbD). A QbD approach for setting specifications would involve harnessing this understanding not only from clinical and nonclinical data available for the product but also from other similar products. Manufacturing using meaningful, science-based specifications will ensure that we attain the optimal balance between manufacturing flexibility and product safety.
Regulatory procedures that influence specification setting for biotechnology-derived protein products, including the International Conference of Harmonization (ICH) guidelines, have been reviewed in the literature.5,6 In traditional manufacturing, specifications were set based on the small number of large-scale batches that had been manufactured before filing for regulatory approval. Each batch was then tested against those specifications to ensure product safety. In the QbD paradigm, however, prior knowledge can play a major role in setting specifications. This may result in broad specifications for attributes whose relationship to product safety and efficacy is well understood to not be significant through product-specific or platform data and relatively narrow specifications for attributes for which the impact on safety and efficacy is not fully understood or is found to be significant.7,8 Unlike in traditional manufacturing, product specifications under QbD are solely for confirmation of product quality because the process control strategy ensures that the specifications are met.
The concept of a clinical design space can be used to quantify the clinical experience with a product.3 This would be in the form of a multidimensional design space with each critical quality attribute (CQA) serving as a dimension. The size of the clinical design space for a given product will depend on the number of lots put in the clinic, the availability of applicable data from other similar products, and the extent of product heterogeneity that has been introduced during the clinical trials. The clinical design space is expected to be limited in the early phases of clinical development when only a few lots have been introduced into the clinic, but then would grow as the product reaches an advanced stage of product development and more clinical data become available.
The design space concept also can be extended to product quality.3 Similar to the clinical design space, a design space would also be multidimensional, with each CQA serving as a dimension. The product design space will be documented in the regulatory filing in the form of in-process controls and drug substance and drug product specifications that define the acceptable variability in CQAs. The size of the product design space for a given product will depend on a multitude of factors, including: