International Conference on Harmonisation (ICH)
U.S. Food and Drug Administration (FDA)
European Medicines Agency (EMA)
Australian Therapeutic Goods Administration (TGA)
Japanese Pharmaceuticals and Medical Devices Agency (PMDA)
Regulatory Perspectives on Changing Acceptance Levels and Specifications
ICH Q8; Pharmaceutical Development, and ICH Q9; Quality Risk Management, describe a systematic process for the assessment, control, communication and review of risk to the quality of drug product. These guidances encourage the industry to move toward the implementation of “real time” quality control, leading to a reduction of end-product release testing.
ICH Q8 teaches that during the development of drug product, we should apply sound science, quality risk management principles, and the knowledge gained from the early stages of the product life cycle. More specifically, pharmaceutical development should include, at a minimum, the following elements:
RMMs can certainly play a role in achieving these goals.
QbD is a systematic approach to developing formulations and manufacturing processes to ensure predefined product quality. This concept supports a continuous improvement model, emphasizes product and process understanding and process control, and is based on sound science and quality risk management principles.
One of the basic fundamentals of the GMPs is that quality should be built-in or should be by design, and product cannot be tested into compliance. In essence, when an appropriate QbD product development and manufacturing strategy exists, release testing should seldom result in an out of specification result. Furthermore, if we properly design and validate our processes and include analytical testing points throughout manufacturing, release testing can be reduced or eliminated. This is the basis for Process Analytical Technology (PAT), and RMMs can also serve to support this initiative.
The PAT initiative (FDA, 2004) describes a regulatory framework that encourages the voluntary development and implementation of innovative approaches in pharmaceutical development, manufacturing and quality assurance. PAT is a system for designing, analyzing, and controlling manufacturing through timely measurements of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring predefined product quality and improving manufacturing efficiencies.
The term “analytical” in "PAT" is viewed broadly to include chemical, physical, microbiological, mathematical, and risk analysis. Many new technologies are currently available that provide information on these attributes to improve process understanding and to measure, control and/or predict product quality and performance. Companies that introduce PAT into their routine operations may realize reduced production cycle times by using on-, in-, and/or at-line measurements and controls, an elimination of rejects, scrap, and re-processing, the use of real-time release, and an increase in automation that improves operator safety and the reduction of human errors. Actually, RMMs are now being used in support of the PAT initiative. In fact, the very first FDA PAT approval was for an ATP bioluminescence rapid method that replaced the compendial Microbial Limits Test.
The FDA also understands that to enable successful implementation of PAT, flexibility, coordination, and communication with manufacturers is critical. The recommendations provided in the PAT initiative are intended to alleviate the fear of delay in approval as a result of introducing new manufacturing technologies, including RMMs. Therefore, PAT may be implemented through reduced reporting strategies, the use of comparability protocols, and by way of inspections by the PAT team or PAT-certified inspectors.
From a microbiological control perspective, the industry can benefit from utilizing RMMs to: