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).
Chester A. Meyers, PhD
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.
COORDINATION ACROSS DEPARTMENTS
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.