Elements of Quality by Design in Development and Scale-Up of Freeze-Dried Parenterals

Jan 01, 2008


A key concept in the Quality by Design paradigm is design space—a multidimensional space that encompasses combinations of product design and processing variables that provide assurance of suitable product performance. This article discusses design space in the context of developing, scaling up, and transferring freeze-dried products to a manufacturing setting. Smooth technology transfer starts with a robust formulation and an appropriate container and closure system. The design space is developed as an envelope in a graph of sublimation rate, shelf temperature, and chamber pressure. One boundary of the design space is established by failure of the formulation under aggressive cycle conditions. Other boundaries of the design space are determined by equipment performance, including refrigeration capacity, condenser capability, heating capacity, or limitations of the dynamics of water vapor flow within the system. Definition of this design space assures a thorough understanding of both the product and the process, and it minimizes the probability of unpleasant surprises in the technology transfer process.

The US Food and Drug Administration's Quality by Design (QbD) initiative is a new regulatory philosophy based on pre-defined quality targets and a deep understanding of how formulations and processes interact to influence critical quality attributes of pharmaceutical products.1 This understanding is based on: prior knowledge of unit operations used in manufacturing a product, experimental data from development work, and published literature. In contrast, many submissions are based on empirical determination of performance criteria from analysis of experimental data. Table 1 briefly contrasts the Quality by Design paradigm with the current regulatory environment.

The intended benefits of QbD are:

1. Regulatory relief throughout the product life cycle, because post-approval changes don't require prior approval.

2. Potential reduction in the volume of data submitted; empirical data replaced by knowledge-based submissions.

3. Facilitation of continuous process improvement, because these process improvements don't require pre-approval.

4. Elimination of a need for current model of process validation.

A key element of QbD is the concept of design space, which is a multidimensional space that encompasses combinations of product design and processing variables that provide assurance of suitable product performance. Product and process changes that fall within the design space can be implemented without prior approval. Design space is proposed by the applicant and is subject to regulatory review and approval.

Although the principle of QbD is simple and appealing, the actual development, scale-up, and commercialization of pharmaceutical products presents a significant challenge to pharmaceutical scientists and engineers. This article will illustrate how the concept of design space might be applied to the development, scale-up, and transfer of freeze-dry processes for injectable pharmaceuticals.

Process analytical technology is an integral part of Quality by Design, because the paradigm relies on the use of real-time process monitoring and control as a part of an overall control strategy. In addition, a new development in process analytical technology—tunable diode laser absorption spectroscopy (TDLAS)—can be applied to define the design space for a freeze-dry process.2


Figure 1
A paper published by Chang and Fischer in 1995 includes a graph that, although not the point of the article, suggests an approach to establishing a design space for a freeze-dry process.3 A simplified sketch of this graph is redrawn in Figure 1, with sublimation rate shown on the y-axis and chamber pressure shown on the x-axis, illustrating the functional relationships among sublimation rate, product temperature, and the two independently controlled variables in the process: shelf heat-transfer fluid inlet temperature and chamber pressure.

Chamber pressure has a complex effect on product temperature and sublimation rate, as follows: