The desired state must be defined first in more detail. The roles of manufacturers and regulatory authorities must also be defined. Under this paradigm, manufacturers have extensive knowledge about product, process, and quality attributes and strive for continuous improvement to reach the desired end point of consistent, safe and effective, pure and potent, drug products. They share this knowledge with FDA. The agency develops the expertise to evaluate products and processes using a science- and risk-based approach through the review of submitted data in applications and performance of prelicense and preapproval facility inspections.
Subsequent, postapproval changes do not need the submission of supplements if these changes are to happen within the design space of critical process parameters as established and approved in the original application. Surveillance inspections are conducted periodically using a risk-based approach to verify the changes. The desired state includes the potential for less inspectional oversight for a facility or firm that has maintained an acceptable compliance status and has reached a state of quality excellence. Therefore, in addition to the expertise that application reviewers need to develop, field investigators also must develop expertise to address the demands of the new desired state. An integrated model of review and inspection should be in place to complement and coordinate the attainment of the desired state for new pharmaceutical products. New guidance documents and compliance program guidance may need to be created.
It appears that the new desired state can be achieved or at least approached with the adoption of two main elements by the pharmaceutical industry and by FDA: QbD and effective, agile quality systems with good quality risk-management principles.
QUALITY BY DESIGN
QbD is not a new concept (4). It was introduced decades ago and adopted by the automobile and food industries to enhance process design and consistency by employing effective and measurable in-process controls with less reliance on end-product testing. The intent was to allow for corrections in real time for the manufacture of quality product with less variability and with the expected attributes. Furthermore, this principle led to Six Sigma processes and lean manufacturing concepts. QbD was introduced relatively recently in the pharmaceutical industry and embraced by FDA as a means to enhance the regulatory process.
QbD is defined in the International Conference on Harmonization (ICH) Q8 guideline as "a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management" (5).
The publication of FDA's guidance, PAT—A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance , initiated an effort that eventually evolved into QbD (6). The underlying principles of science- and risk-based process and product development and commercialization are also reflected in the contents of the quality guidelines ICH Q8 Pharmaceutical Development , ICH Q9 Quality Risk Management, and ICH Q10 Pharmaceutical Quality System as well as by the recently issued guidance on process validation from FDA (5, 7–9). The past five years have seen QbD gaining widespread adoption in the biopharmaceutical industry with several publications attempting to elucidate a path forward for its implementation and resolution of the various issues that serve as detriments to its success (10–12).