QbD and GMPs: How the Convergence of Science and Compliance Will Change the Way We Work

The focus on the design space will lead to a new workspace, and will affect staff in the development, manufacturing, and quality functions.
Nov 01, 2009
Volume 22, Issue 11

Chester A. Meyers, PhD
July 2, 2008, marked a significant milestone for the biopharmaceutical industry. That's when the US Food and Drug Administration announced its pilot program for the submission of quality information for biotechnology products consistent with the principles of Quality by Design (QbD).

Debbie Weigl
The greater product and process understanding provided by QbD can help companies in a variety of ways. Greater process understanding means more accurate and thorough validation and more robust processes, thus improving quality. More robustness also helps lower manufacturing costs by increasing yield, reducing manufacturing downtime, and decreasing the amount of rework and rejected batches. By strengthening the manufacturing process, QbD can speed time to market, thus increasing the return on investment. In addition, QbD holds out the promise of reduced regulatory burden, including fewer postapproval submissions, reduced end-product release testing, and the possibility of introducing process improvements without further agency review.

Achieving those many benefits, however, will require adopting new ways of working and a new outlook on good manufacturing practices (GMPs). What will QbD mean in that regard? The answer lies in the convergence of science and compliance at the heart of QbD: (1) robust processes designed to provide statistically defined performance characteristics that ultimately result in products with a defined target product profile, and (2) good biopharmaceutical quality, defined as an acceptably low risk of failing to achieve the target profile. In other words, QbD combines increased scientific understanding of products and processes with the risk-based compliance that such understanding makes possible.

This convergence of science and compliance will profoundly affect all areas of GMPs, including the nearly 20 such areas covered in the International Conference on Harmonization (ICH) Q7 guideline.1 Each GMP could, of course, be the subject of extended discussion in light of QbD, but more generally, the convergence of science and compliance will mean:
  • more integrated, coordinated activities across departments that have traditionally worked in separate silos
  • fundamental changes in focus for many personnel in development, manufacturing, and quality
  • changes in training to establish these new ways of working.

Under QbD, GMPs will be reconceived as a framework, rather than as the driver, for the performance of risk-based, flexible processes. In other words, if biopharmaceutical companies are to maximize the benefits of QbD, the technical and compliance revolution it embodies will need to be accompanied by a cultural and organizational revolution.


Most companies have spent years carefully establishing and elaborating the steps involved in the manufacturing of biopharmaceutical products—from the initial cell culture vial through scale-up, bioreactor production, downstream processing, formulation, filling, and packaging. Not surprisingly, this approach has encouraged the development of functional silos, each narrowly focused on its area of expertise, inhibiting the diffusion and integration of knowledge throughout the organization.

This model of drug production, with little crossfunctional involvement after each hand-off to another function, and with quality ensured through analytical testing near the end of the process, has served biopharmaceutical companies reasonably well for decades. But with tighter regulation and cost pressures that now reach into development and manufacturing, companies are seeking more efficiency in manufacturing processes by improving process understanding and control.

QbD, with its aim of achieving a scientific understanding of manufacturing processes as early in the development process as possible, and of enabling continuous improvement in manufacturing, requires a much more integrated and holistic approach by staff in all functional areas. For example, in elucidating and, in particular, documenting the process design space (defined in ICH Q82), development groups may need to operate with an increased attention to GMP guidelines because the data they develop by using design of experiments (DOE) to define the design space will be used to support manufacturing decisions to the FDA. Analytical and bioanalytical support functions will share in the responsibilities for this key element of process design and control.

In essence, succeeding with QbD requires creating a continuous feedback loop between development and manufacturing, with upstream, downstream, and analytical personnel increasingly looking as far down the production process as possible, and manufacturing personnel reaching back into earlier stages of development, all tied tightly together by improved communication and documentation facilitated through IT groups.

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