"Quality by design" (QbD) and "quality risk management" at long last seem to be moving from the buzzword stage to becoming
important influences on drug development and manufacturing. A series of quality standards issued by the International Conference
on Harmonization (ICH) is encouraging the adoption of common quality-based drug manufacturing approaches designed to reach
the "desired state" of drug manufacturing (i.e., more efficient, agile, flexible operations that can reliably produce high-quality drug products with less regulatory oversight).
These developments reflect increased pressure to make pharmaceutical manufacturing more efficient and less wasteful and to
encourage regulators in all regions to focus on the most critical issues affecting product quality and patient safety.
Out with the old. Pharmaceutical manufacturing has not been "state of the art," observed Janet Woodcock, deputy commissioner of the US Food
and Drug Administration and prime mover behind the agency's manufacturing modernization campaign. At a December conference
on implementing ICH Q8 and Q9 sponsored by the International Society for Pharmaceutical Engineering (ISPE) and the Parenteral
Drug Association (PDA), Woodcock described why drug manufacturing is running up costs as high as research and development
(R&D) investments at many companies. Woodcock asserted that factory utilization rates often are a low 15% because of batch-production
processes, waste may top 50% for some products, scale-up is unpredictable, global operations are fragmented, and manufacturers
often don't know the reasons for production failures.
Under the traditional manufacturing model, companies have submitted extensive chemistry, manufacturing, and controls (CMC)
data to FDA that set tight product specifications. The aim has been to establish a production process able to meet those specifications
consistently. Process change is costly and may result in drug shortages, delays in new product development, and the need for
more oversight than FDA can afford to provide.
Testing new approaches
Defining a design space. The new approach calls for manufacturers to use modern statistical and analytical methods to define the critical sources
of variability in a production system and establish appropriate quality controls. Manufacturers that can demonstrate to regulatory
authorities a sufficiently high level of understanding and control may benefit from a smoother application-approval process
and reduced oversight through the product life cycle. Risk management can help companies identify activities that require
closer monitoring and those that merit less attention.
Woodcock expressed optimism that industry is beginning to move toward this more efficient and science-based process. She envisions
pharmaceutical manufacturing systems based on extensive company knowledge about critical production and process parameters
that define a "design space." Instead of reviewing massive amounts of data, checking batches, and spending days inspecting
facilities, FDA would shift its role to initially verify a quality production operation, followed by periodic audits of systems
for ensuring product quality.
The bottom line for FDA is a big reduction in manufacturing supplements. Companies must now inform the agency when they make
relatively minor changes in production processes and suppliers. The goal is to limit such filings to major changes (e.g., developing a new formulation) and end supplements for the vast number of modifications and improvements that occur within
The shift to such QbD approaches also provides an opportunity to move away from disparate regulatory requirements and put
everyone "on the same page," Woodcock commented. To this end, ICH participants from the United States, Europe, and Japan have
developed a series of guidances for establishing a more science-based approach to ensure the quality of products and processes.
The ICH Q8 guidance on product development has been adopted by the European Union, Japan, and the United States. An FDA guidance
was published in May 2006. The Q9 guidance (issued in June 2006) on risk management has been adopted by Japan and the United
States, but still awaits final implementation in Europe.
A third document (Q10), which is still under development, will link product development and risk management to assist manufacturers
in establishing pharmaceutical quality systems. Such programs will include systems for monitoring process and product, for
taking corrective actions, and for managing change in the postmarket environment.