US Initiatives to Link Regulation to Good Science
In the US, several initiatives have been undertaken to link regulatory expectations to good science. These include the promulgation
of several guidance documents, such as ICH Q8, Product Development, ICH Q9 Quality Risk Management, and the process analytical technology (PAT) guidance. FDA also undertook an initiative on manufacturing science, formed
the pharmaceutical inspectorate, and is involved in the development of the ICH Q10 guidance on continuous improvement.
Product Development Report (ICH Q8)
The ICH Q8 guideline describes the the Product Development Report (section 3.2.P.2 of the CTD), which can be a valuable tool
for firms that perform adequate and focused product formulation research. The use of this report encourages and allows firms
to share with regulatory reviewers the evolution and refinement of their products. When properly executed, it can elucidate
the design, understanding, and control of the production process and the choice and control of excipients, as well as provide
a basis for identifying Critical Quality Attributes. The report provides an expanded knowledge document that defines the product
and process such that regulatory flexibility becomes "built-in"—from both an understanding and decision perspective. For most
dosage forms, the document does not have to be expansive, but rather a concise historical synopsis.
Quality Risk Management (ICH Q9)
The ICH Q9 document, Quality Risk Management16 has recently been adopted and implemented by FDA, and agreement on terminology and compilation of risk assessment tools
has been accomplished. The document was not intended to be a step-by-step manual, but rather defines and suggests strategies
for examining risks in production and discusses implementation. It represents a collection of tools that can be used to analyze
production risks (e.g., Failure Mode Effects Analysis, FMEA) for incorporation into existing quality systems. The concepts
of risk management can be adopted during research and development, and when they are applied to R&D as part of an expanded
knowledge base, problems and setbacks that are endemic to CMC development can be minimized.
Continuous Improvement (ICH Q10)
Although it is not yet finalized or adopted, ICH Q10 represents some of the most current thinking with respect to pharmaceuticals
manufacturing and control. It is an attempt to capture the concept that cGMPs or the ISO 9000s alone cannot provide effective
systems for allowing process improvements over the life of the product in a less burdensome manner. It shifts responsibility
for managing "low-risk" changes to the manufacturer's quality system. The FDA has responded by publishing a companion guidance
on quality systems17 that details a more holistic approach to quality management for pharmaceutical manufacturing. In the future, pharmaceutical
producers would be well advised to use product development as a tool to map out and support possible product changes and variations
based on product and process knowledge. Forethought can neatly tie together product development, process development, process
analytical technologies, and risk-based decision making.
Process Analytical Technology (PAT)
The 2004 publication of the FDA's guidance on process analytical technology, PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance
7 represented the first time the FDA formally emphasized process understanding as central to controlling product quality. PAT
emphasizes the incorporation of in-line, at-line or on-line analytical methods (e.g., NIR, Raman, micro-chromatography, etc.)
that allow for real-time monitoring of production. Coupled with appropriate data collection and analysis systems, product
quality can be monitored and controlled during the manufacturing process, thus reducing the amount of release testing required
at the end of the manufacturing process. It allows for continuous quality monitoring as well as better process control. The
caveat is that one must understand the formulation and how it is manufactured. The FDA has assembled, trained and certified
a PAT Team that includes CMC and microbiology reviewers (for new and generic drugs), compliance staff, and field investigators
for the purpose of evaluating these types of product applications.