The following authors contributed to the article, "FDA's Pharmaceutical Quality Initiatives: Implementation of a Modern Risk-based Approach," in the May 2008 issue: Moheb Nasr (FDA), Gerald Migliaccio (Pfizer), Barbara Allen ( Eli Lilly and Company), Robert Baum (Pfizer), Ronald Branning (Genetech), Chi-wan Chen (FDA), Joseph Famulare (FDA), Richard Friedman (FDA), Musa Ghannam (Schering-Plough), Frank Holcombe (FDA), Nirdosh Jagota (Wyeth), Christopher Joneckis (FDA), Zena Kaufman (Abbott Laboratories), Steven Kozlowski (FDA), LaiMing Lee (FDA), Anthony Lubiniecki (Centocor), Mary Malarkey (FDA), Christine Moore (FDA), Elaine Morefield (FDA), Gene Murano (Genentech), Richard Norgard (Pfizer), Helen Winkle (FDA), and Janet Woodcock (FDA).

Representatives of the US Food and Drug Administration and Industry

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 in 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 an 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 

 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 achievements 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 

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 reduce the regulatory burden in proportion to the manufacturer's efforts to achieve continuous improvement and manufacturing process optimization.

Development of several science-based guidances for industry (e.g., 

PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance; Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice;

Formal Dispute Resolution: Scientific and Technical Issues Related to Pharmaceutical CGMP

). In addition, training programs to support risk-based regulatory decisions and continuous improvement in pharmaceutical manufacturing were established.

Pharmaceutical Quality Initiatives Workshop, 2007

In early 2006, under the auspices of the CPQ, a workshop planning committee was established with key leaders from the pharmaceutical industry and FDA. Industry representatives encompassed a broad range of expertise and experience in the fields of drug, biologic, and biotech discovery, manufacturing, GMPs, and quality assurance. FDA representatives included key leaders from diverse pharmaceutical quality programs (GMP, compliance, new drug, biologic and generic quality assessment, and postmarketing surveillance). The planning committee's goal was to develop a workshop program to highlight the agency's pharmaceutical quality initiatives and continue forging a common vision for a scientific risk-based regulatory process. As noted, the workshop, co-sponsored by AAPS and ISPE and held Feb. 28-Mar. 2, 2007 provided a forum for regulated industry, other stakeholders, and the public to comment on progress made in implementing the intiatives and to assess future needs and implementation challenges. The following sections summarize the work of 10 breakout sessions held during the three-day workshop. The reports were prepared and presented by industry lead moderators based on discussions with participants from industry, FDA, and the public. These reports are not endorsed by FDA and do not represent FDA's position on issues discussed. 

Quality-by-design breakout reports CMC pilot program. 

The concept of QbD, while not new to the pharmaceutical industry, has presented implementation opportunities and challenges to both industry and regulators. To facilitate QbD implementation for innovator products, FDA established the CMC pilot program in 2005 as part of the Pharmaceutical Quality Assessment System. The information obtained from this pilot has enabled FDA and industry to interact and identify key challenges and opportunities tied to QbD implementation. This breakout session focused on lessons learned, to date, from the pilot program. Participants discussed best practices, regulatory submissions, and review of QbD-based applications. They reached consensus on a number of topics, as outlined below. 

Knowledge-rich submissions are the backbone of QbD submissions

The focus of the submission should be on the content and not on the volume of information provided

A summary of the risk assessment performed on the  product/process/facility as related to the product profile (safety, efficacy, and quality) should be included

A clear rationale for the identification of critical quality attributes and critical process parameters as well as noncritical process parameters should be included

Design of experiments (DOE) to understand the process and/or product should be performed and provided as should information regarding edge of failures, if available

Further efforts toward the characterization of active pharmaceutical ingredients (APIs) and raw materials and the impact of their variability on the process and/or product performance should be studied and provided

A control strategy based on product and/or process understanding should be developed and provided. The control strategy should then be managed using a plant quality system. 

Information can be provided to the regulatory agency within the current ICH common technical document, specifically in the quality format section and in various sections where logical and with proper links as needed.

Industry and regulatory authorities emphasized the importance of a pharmaceutical development report that is rich in scientific content. 

Workshop participants expressed that there is a fine balance between information necessary for the submission versus that which can be retained at the manufacturing site. In addition, there was concern about getting more questions related to QbD, which may result in approval delays. Regulatory authorities expressed the desire for a comprehensive quality overall summary (QOS) that would be systematic and rich in technical content. They also emphasized that a mechanism should be available for providing QbD information for currently marketed products.  

Some participants were not certain whether regulatory flexibility would truly result from a QbD approach. A business case, therefore, may be difficult to establish for some companies or for some products. 

In terms of experience coming out of the CMC pilot program, breakout session participants discussed the necessity for some form of a CMC regulatory agreement or CMC postapproval management plan (PMP) to demonstrate that there is a clearly defined regulatory benefit for industry to adopt the QbD approach (see section on "Regulatory Agreement" for more details). Noted benefits of the program, to date, included enhanced communication between FDA and industry, quick resolution of questions, a multi-disciplinary approach to review, and greater information-sharing. 

To facilitate QbD implementation, participants suggested other mechanisms. Specifically, for the implementation of QbD in programs submitted outside the CMC pilot program umbrella, there was consensus around the need for discussions between regulatory authorities and the sponsors during development of the program. Suggested timeframes for such discussions were the end of Phase-2 or mid-Phase 3. 

Risk-based flexible regulatory approaches and regulatory agreements. 

QbD approaches to pharmaceutical development have been advocated by FDA and industry. Submission of such enhanced QbD information in a new drug application (NDA) or biologic license application (BLA) toward the establishment of design space will enable the applicant to propose flexible regulatory approaches for postapproval manufacturing changes. A resultant risk-based regulatory flexibility can be expected such that movement within the approved design space will not require traditional postapproval regulatory submissions. This workshop breakout session focused on possible flexible regulatory approaches, ways to document this flexibility, and types of information to be submitted. Companies and regulators involved with the CMC pilot program shared their experiences during the session. 

A better understanding emerged regarding the purpose of including extensive pharmaceutical development information in QbD-based application and the possible regulatory flexibility as a result of sharing this information. Participants reached consensus on several topics as outlined below. 

In terms of the type of regulatory flexibility proposed or envisioned in a QbD-based application, participants suggested:  

Manufacturing site change, alternate packaging or packaging sites, alternate analytical methods and testing sites, scale-up

Movement within the design space and/or proven acceptance ranges

Replacement of end-product testing with in-process testing

Flexibility would be dependent on what is submitted.

Participants deemed a "regulatory agreement" as both necessary and useful, because it can:  

Capture the commitments of industry and FDA 

Help avoid possible loss of knowledge due to staffing changes

Articles

The US Food and Drug Administration announced its Pharmaceutical GMPs for the 21st Century initiative six years ago. This article reports on the outcome of a recent workshop on this topic and the action plan set forth.