FDA's pharmaceutical quality initiatives: implementation of a modern risk-based approach.(Quality Initiatives)

Representatives of the US Food and Drug Administration and Industry*

The US Food and Drug Administration announced its Pharmaceutical CGMPs for the 21st Century initiative six years ago. Since that time, FDA and industry have held a number of joint workshops to work through the issues and challenges behind implementing this science- and risk-based approach to drug and biological drug development and manufacturing. One of the most recent workshops discussed progress made to date and ways to further build upon FDA's pharmaceutical quality initiatives. This article reports on the outcome of that workshop and the action plan set forth.

A major pharmaceutical quality workshop was held February 28-March 2, 2007, to highlight the US Food and Drug Administration's pharmaceutical quality initiatives and to continue forging a common vision for a scientific risk-based regulatory process. The workshop was cosponsored by FDA, the American Association of Pharmaceutical Scientists (AAPS), and the International Society of Pharmaceutical Engineers (ISPE). The workshop provided a forum for regulated industry, other stakeholders, and the public to comment on progress made and to assess future needs and implementation challenges since the April 2003 inaugural workshop, "A Drug Quality System for the 21st Century." The program highlighted progress on FDA's pharmaceutical quality initiatives, building upon the themes from the agency's 2004 report, "Pharmaceutical CGMPs for the 21st Century--A Risk-Based Approach." Diverse representation from industry--including the areas of quality, regulatory affairs, development, and manufacturing--and review and compliance staff from FDA engaged in an open exchange of ideas during the plenary panel discussions and 10 breakout sessions conducted over the three day workshop. Implementation challenges and overall regulatory and scientific issues and concerns were identified for topics covering: product and process development, manufacturing and quality operations, good manufacturing practices (GMP), quality systems, and quality assurance.

Participants proposed the following action plan:

* Publish a process validation guidance in 2008 that includes what process validation would look like under quality-by-design (QbD)

* Work with generic stakeholders to develop a model example for design space

* Determine how to leverage comparability protocols and QbD for short-term regulatory relief for biotech products in 2008

* Implement scientific approaches and guidance in 2008 for more risk-based regulatory flexibility for postapproval changes and annual reports

* Continue to share experiences from the chemistry, manufacturing, and controls (CMC) pilot program and establish additional pilot programs for both postapproval and for biotech to highlight successes and identify areas for improvement

* Hold a workshop ill 2009 on the holistic impact of Q8 pharmaceutical development, Q9 quality risk management, and Q10 quality systems, the quality guidelines of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), and of the pilot programs to review status, highlight successes, and identify areas for improvement.

Background: pharmaceutical quality in the 21st century--the path ahead for discovery, development, and delivery

On Aug. 21, 2002, FDA announced a significant new initiative: "Pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century: A Risk-Based Approach." This initiative set forth a plan to enhance and modernize FDA's regulations governing pharmaceutical manufacturing and product quality for human and veterinary drugs and select human biological products. The goal was to ensure that:

* The most up-to-date concepts of risk-management and quality systems approaches were incorporated

* The latest scientific advances in pharmaceutical manufacturing and technology were used

* The Chemistry, Manufacturing, and Controls (CMC) review and inspection programs operated in a coordinated and synergistic manner

* Regulation and manufacturing standards were applied consistently

* Management of the programs encouraged and did not impede innovation in the pharmaceutical manufacturing sector

* Resources were used most efficiently to address the most significant health risks.

In April 2003, the Product Quality Research Institute (PQRI) and FDA held all inaugural workshop on "A Drug Quality System for the 21st Century." This workshop offered a rare opportunity for FDA and industry to share experiences and ideas to create a common vision for a scientific risk-based regulatory process. Topics addressed at the 2003 workshop included: a pharmaceutical inspectorate, changes without prior review, 21 CFR Part 11, manufacturing science, technical issue resolution, and risk-based CGMPs. This workshop provided the necessary forum to develop a framework to facilitate innovation, application of cutting-edge scientific and engineering knowledge, and implementation of modern quality management systems in pharmaceutical manufacturing.

Pharmaceutical CGMPs for the 21st Century--A Risk-Based Approach, Final Report 2004

In September 2004, FDA released its final report on achieve ments and future plans of the initiative known as the "Pharmaceutical CGMPs for the 21st Century--A Risk-Based Approach." Sixteen multi-disciplinary groups comprising scientific and regulatory practice experts from the Center for Drug Evaluation and Review (CDER), the Center for Biologics Evaluation and Review (CBER), the Center for Veterinary Medicines (CVM), the Office of Regulatory Affairs (ORA) and the Office of the Commissioner (OC) within FDA shaped and implemented the initiative under the oversight of the CGMP Steering Committee. Their findings put the agency on a path to develop a product quality regulatory system for the future by creating a system intended to streamline the quality review of pharmaceutical products. This system would allow FDA to use its resources in a more efficient manner while retaining flexibility to accommodate complex products.

Participating groups envisioned a highly educated, well-trained, integrated team of individuals throughout FDA who would use risk-based and science-based approaches for regulatory decision-making throughout the entire life cycle of a product. To move toward this new system, the agency established the Council on Pharmaceutical Quality (CPQ) and charged it with policy development, coordination, and continuing change management, including the ongoing implementation of certain quality management systems within FDA. Key accomplishments of the council were announced in the 2004 final report, including:

* Adoption of a quality systems model for agency operation, developed under FDA's Management Council and published in the FDA Staff Manual Guide. The guide defines the essential quality elements to consider as part of any system that controls an internal FDA regulatory activity.

* Development of a quality systems guidance for CGMP regulation. The draft guidance for industry, Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations, is intended to encourage industry to implement the use of quality-management systems and risk-management principles. The guidance explains how manufacturers implementing a comprehensive quality system can ensure full compliance with CGMP regulations (21 CFR Parts 210 and 211).

* Adoption of risk-management principles to enhance the agency's inspection and enforcement program, which is focused on protecting the public health. For example, FDA began using a risk-based approach for prioritizing domestic manufacturing site inspections for certain human pharmaceuticals. This approach will help the agency predict where its inspections are likely to achieve the greatest public health impact.

* Establishment of a new risk-based pharmaceutical quality assessment system to replace the CMC review system in the Office of New Drug Chemistry within CDER. The new assessment system has the potential to …