The health of our citizens depends on the availability of safe, effective and affordable medicines. In the future, pharmaceutical manufacturing will need to employ innovation, cutting edge scientific and engineering knowledge, and the best principles of quality management to respond to the challenges of new discoveries (e.g., complex drug delivery systems and nanotechnology) and ways of doing business such as individualized therapies or genetically tailored treatments.

“Pharmaceutical cGMPs for the 21st Century” was intended to enhance and modernize the regulation of pharmaceutical manufacturing and product quality. This report provides an overview of the PAT Team’s and Manufacturing Science Working Group’s collaborative efforts, accomplishments, and points to consider as the initiative moves into its next phase (implementation and continuous improvement).

The FDA Science Board and the Advisory Committee for Pharmaceutical Science (ACPS) discussions provided information on the current state of pharmaceutical manufacturing, challenges faced, and opportunities for improvement. These discussions are the primary basis of this report.

Pharmaceutical manufacturing operations are inefficient and costly. The cost of low efficiency is generally not understood or appreciated (e.g., manufacturing costs far exceed those for research and development operations). Low efficiency is predominantly due to “self-imposed” constraints in the system (e.g., static manufacturing processes, focus on testing as opposed to quality by design, approach to specifications based on discrete or the so called “zero tolerance” criteria, a less than optimal understanding of variability, etc.). These constraints keep the system in a corrective action mode.

Continuous improvement is an essential element in a modern quality system and it aims at improving efficiency by optimizing a process and eliminating wasted efforts in production. In the current system continuous improvement is difficult, if not impossible.

Reducing variability provides a “win-win” opportunity from both public health and industry perspectives, therefore continuous improvement needs to be facilitated. The PAT Team and the Manufacturing Science Group cooperated internationally to develop a framework to facilitate innovation, application of cutting edge scientific and engineering knowledge, and the principles of modern quality management systems in pharmaceutical manufacturing. A systems approach was adopted to support the initiative’s objectives and conform to its guiding principles. The “desired state” for pharmaceutical manufacturing in the 21st Century was articulated and international consensus established. A regulatory framework to support innovation was developed and described in the PAT Guidance document. The principles of this framework are being incorporated into the emerging ICH guidance on Pharmaceutical Development (ICH Q8).

Quality by design and process understanding principles were used to develop a flexible regulatory system to support innovation in the PAT Guidance. A team approach to CMC review and CGMP inspections, a recognized best practice (e.g., Team Bio), was used to create the PAT Team to provide appropriate risk coverage. Team building and joint training processes were successful in reducing organizational and communication barriers that existed at the beginning of the initiative. Two assignments, a PAT inspection and pre-operational site visit, have been successfully completed by this team.

The pharmaceutical community was asked take on the responsibility for developing standards to support the introduction of innovative tools and technologies under the PAT framework. The ASTM International provided the process to develop these standards using technical expertise in all relevant disciplines from the pharmaceutical community and other industrial sectors. A significant support infrastructure for the desired state is emerging in several academic and scientific organizations and associations.

A second PAT team is planned and will include CDER’s Office of Biotechnology, Office of Compliance and ORA Team-Bio representatives. Formation of the second PAT Team will provide an additional opportunity to develop close collaboration and cooperation between the PAT team and Team-Bio. Lessons learned from the PAT Team and Team Bio should also be utilized to identify best practices and to develop recommendations for a broader team approach.

ICH Q8 will describe the suggested contents for the 3.2.P.2 Pharmaceutical Development section of a regulatory submission in the ICH M4 Common Technical Document (CTD) format. It is not intended to be a “how to” guidance. It will provide sponsors of drug applications an opportunity to present knowledge gained during development of a product and its manufacturing process and relevant prior knowledge. It will indicate areas where the provision of greater understanding of pharmaceutical and manufacturing sciences can create a basis for flexible regulatory approaches to support continuous improvement.

The PAT framework and ICH Q8 will provide a basis for risk mitigation. Risk management principles and tools being developed under ICH Q9 will be necessary to describe and communicate the level of risk-mitigation achieved through quality by design and process understanding.

Although to a large degree consensus has been established on the “desired state,” it is recognized that there is often a tendency for a consensus on collective ends to attenuate when specifics are addressed. This is often due to divergent understanding of the problem being addressed and/or differences in interests and issues in representation of the problem being addressed.

Under the ACPS Manufacturing Subcommittee a working group will be formed to identify specific steps needed to move towards the desired state. The group will also develop illustrative case studies to support the ICH Q8 document and CPG 7132c.08.

ICH Q8 and illustrative examples should then be a basis to develop the draft comparability guidance to facilitate continuous improvements.

The combined work products of the CGMP Initiative are positioned well to provide a comprehensive set of regulatory tools to facilitate a move towards the desired state. Only companies that achieve a high level of process understanding will have the opportunity to use their information to justify a more flexible regulatory path towards continuous improvement. The proposed ICH Q10 should utilize these regulatory polices to provide additional guidance on quality system for change control under CGMPs to facilitate continuous improvement.

Significant challenges lie ahead for the pharmaceutical community and for regulators to move to the “desired state” for pharmaceutical manufacturing in the 21st century. Nevertheless, critically important steps have already been taken.
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