FDA's Pharmaceutical Quality Initiatives: Implementation of a Modern Risk-based Approach

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Pharmaceutical Technology, Pharmaceutical Technology-05-02-2008, Volume 32, Issue 5

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.

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 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 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 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 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; and 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.

Type of QbD information:

  • 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.

Presentation of QbD information:

  • 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.

Challenges and opportunities. 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:

  • No postapproval filings for:

  • 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

  • Document the relationship between quality attributes and design space

  • Facilitate life-cycle management.

The scope of a regulatory agreement might include original NDAs (i.e., NDAs with QbD information, traditional NDAs) and legacy products (i.e., previously approved NDAs). The agreement's content, including possible product life-cycle management, might include identification of critical quality attributes, agreement on the design space, a regulatory reporting mechanism for postapproval changes, product life cycle changes envisioned for the future, and change control strategy (i.e., the plan and evaluation criteria).

Several apparent challenges to industry and FDA concerning a regulatory agreement came up as well. For example, how will a company anticipate all the changes envisioned from a life-cycle viewpoint? Industry does not have any current guidance or case studies to use as a model and would have to think differently. Finally, industry may be concerned about delayed approval time and maintaining a living document. On the FDA side, there might be more upfront work, although it could be balanced by fewer supplements. In addition, there may be additional burden for field investigators, and it was brought up that if there is no information on commercial-scale design space, it may be a leap of faith for a reviewer to agree to design space based only on lab- or pilot-scale experiments.

Biological and biotech product breakout reports

Product and process development design. QbD refers to a product and process that consistently delivers a product with the desired product quality attributes. A well-designed product and process requires extensive knowledge of a product's quality attributes, how these attributes impact clinical performance, and how the process impacts the critical product-quality attributes (CPQAs). Product- and process-development design can be streamlined by using existing data and knowledge in conjunction with risk-management tools and statistically valid designed experiments to define acceptable operating ranges for both critical and noncritical parameters. This breakout session explored the development of a robust quality system and its role in documenting data and knowledge to facilitate the definition of design space and the impact of QbD on validation, product approval, and postapproval process changes.

QbD provides a more structured approach to the identification of critical product quality attributes and how the process parameters (both critical and noncritical), which define the design space, affect them. Firms should understand and control variability in this design space using risk-based process development as defined in ICH Q8, Q9, and Q10. By using QbD concepts, industry may obtain postmarketing regulatory submission relief.

Cross-functional teams select molecules based on the potential therapeutic efficacy of specific protein structures. The essential elements that are responsible for the protein's safety and efficacy are defined as CPQAs. The design space is based on the combination and interaction of process parameters, which consistently produce product that meets CPQAs. Design space must account for the inherent variability of raw materials, facilities, equipment, utilities, and processing conditions in manufacturing operations, which all can influence product. The company's development team should conduct a formal risk assessment (covered in ICH Q9) that will determine the critical process parameters (CPPs), that have a significant impact on the drug product. These CPPs are defined by well-controlled experiments, preferably a statistically valid design of experiments (DOE).

The derivation of design space can be applied practically via product specific scientific knowledge gained during development, data-mining across similar products, and/or statistically designed experiments based to define operating parameters. Once adequately defined, the design space has the potential to be expanded, based on additional knowledge, across similar products and operating platforms or unit operations such as chromatography columns. The final list of those items critical to drug product quality is part of process development; once complete, the data can be used to identify CPQAs and CPPs. Given the scientific basis for design space, much of the additional postdevelopment, technology transfer, and validation effort will be significantly reduced, if not eliminated.

A quality system (covered in ICH Q10) is an essential umbrella for all development, facility, equipment, technology transfer, and production activities. The quality system also creates and governs planning, protocol development, test requirements, data generation, and data-assessment structure.

The power of QbD is in the partnership between FDA and industry to streamline the process of product development and regulatory approval. Such a transformation will require an unparalleled level of communication and trust between the parties. The most important communications will be contained in a firm's development summary report. This report includes: a definition of the product's CPQAs and the rationale for their criticality; risk-assessment summaries for all facilities, utilities, equipment, raw materials and processing conditions; and scientific data in support of the identification of CPPs. CPQAs should be incorporated in the development section of the regulatory submissions and CPPs should be incorporated in the manufacturing section.

The practical application of QbD principles will be the upfront agreement between FDA and industry to establish a well-defined design space approach, including an agreed-upon definition and examples, a pilot program for biotechnology products that can build on the success of the CMC pilot, an assessment of the use of comparability protocols as an interim approach, and QbD submission expectations for a preapproval inspection both from FDA reviewers as well as Team Bio in the Center for Biologic Evaluation and Research, and inspectors in the Office of Regulatory Affairs.

The hopeful outcome of the QbD initiative and industry investment is better product and process understanding and a smoother, if not faster, path to product approval. The real payoff will be safe and efficacious drugs that are reliably supplied to the patients we serve.

Process control and postapproval product life-cycle considerations. Application of a comprehensive, scientifically sound approach to product design and process development should result in an efficient and well-controlled manufacturing process that facilitates postapproval changes and product improvements. The inherent diversity and complexity of biotech and biological products present challenges in the development and implementation of QbD approaches. Nevertheless, for many products, leveraging existing knowledge and experiences operating in defined design space, in conjunction with risk-assessment and risk-management tools could result in the implementation of manufacturing changes in a timely fashion with minimal burden on resources.

An overview of the relationship between the ability to establish an understanding of biopharmaceutical drug substance and drug product, mechanism of action and toxicity, and product interaction related to medical indication (efficacy and safety) with QbD was presented at a high level during this breakout session. It is clear that establishing these relationships may be easier where there is greater understanding. Session participants addressed issues and potential impacts of QbD on the implementation of postapproval process changes for biological and biotech products. These issues are described below.

Design space. As a living document, design space should be periodically reviewed as part of industry's quality system. Risk assessment and growing knowledge (e.g., failures and investigations) should be used to reassess and update the design space.

Operations. Operations can be adjusted within the design space. For example, design space may be expanded with continued experience and FDA approval. A nested relationship was envisaged among design space, normal operating ranges, and control ranges. Participants suggested that operations outside the normal operating ranges but within design space should be investigated, but need not be reported. Based on additional knowledge for a robust design space, tests may be eliminated and specifications modified with FDA agreement. New control parameters may also be found. Industry was comfortable periodically reporting (e.g., annual report) changes within a design space to FDA.

Case-by-case applications. A case-by-case approach to biotech and biological products was considered appropriate, depending on several factors including manufacturing process control, mechanism of action, level of characterization, and linkage to clinical studies. Platform technologies may be helpful to allow experience from related processes and products to be used to help define design space, but risk assessments need to be product-specific. Some process-specific data may also be needed for each product.

Comparability protocols. Workshop participants felt that such protocols were useful and appropriate, especially for unit operation changes or more involved new-facility or large-scale changes. The relationship of product quality attributes to clinical experience can affect the design space. In establishing a design space, one must consider that process capability and process robustness that may limit the design space. For implementation of QbD with biopharmaceutical products, uncertainty should be identified and controlled to establish a meaningful design space.

Reduction of CMC supplements. Reduction of CMC supplements was considered a good area to apply QbD principles in the short term via expanded use of comparability protocols. For changes to unit operation design space, session participants thought that examination of quality attributes specific to that unit operation plus linkage to downstream unit operations was an adequate approach. Discussants appreciated that some aspects of design space are specific to facilities and equipment.

Process validation breakout report

Pharmaceutical process validation requires a comprehensive understanding of a manufacturing process and a demonstration of adequate control throughout its life cycle. Product life cycle begins with pharmaceutical development. As introduced in ICH Q8, quality can be designed into the manufacturing process from process understanding through establishment of a design space and using a risk-based control strategy. The life cycle begins with product and process development and continues through validation activities to confirm that the developed process works as intended and reproducibly produces the desired product at commercial scale. Because the product is manufactured commercially, the process design is verified with ongoing assessments of process performance. Variability is identified and controlled using existing and emerging tools such as process analytical technology (PAT) applications and risk mitigation strategies. The result is confidence in quality and advances in process understanding so that effective improvements may be implemented.

The decisions that must be made throughout a product's life cycle such as the considerations in establishing design space and the approach to validation, can be based on a risk assessment that considers the degree of confidence required with respect to potential patient impact and supply. The level of confidence or assurance that should be obtained from various studies and evaluations should correspond to the level of risk identified.

Validation consists of process development, process confirmation and continual verification. The traditional three- batch approach to validation is not meaningful—sometimes it provides too much, sometimes too little. Although approaches to process validation may be changing, the principles of process validation have not changed. Participants in this breakout session identified these core principles as:

  • Identifying and controlling what is critical

  • Using in-process measurements as part of evaluation

  • Demonstrating a state of control

  • Demonstrating reproducibility over time

  • Justifying and documenting changes in controls

Process validation confirms the design space and control strategy. The validation approach should be flexible and risk- based dependent upon level of process knowledge and understanding. The challenge often is how to demonstrate knowledge gained at a smaller scale through limited full-scale batches. Consequently, full-scale confirmation should focus on scale-dependent aspects that impact CPQAs.

Session participants felt that risk assessment is valuable to establishing a validation strategy. By using risk assessment, one will be able to identify critical attributes and predict effect of changes, use prior knowledge, and reduce "over validation" for a well-understood process. Risk assessment should be used to determine impact of changes on CPQAs. It is critical that changes are documented and tracked.

Implementation of quality systems: opportunities and challenges breakout report

The concept of a quality system has been described in FDA's Guidance for Industry: Industry Quality Systems Approach to Pharmaceutical CGMP Regulations and will be further articulated in ICH Q10. The combination of QbD, use of risk- management principles, and an appropriate quality system should lead to "a maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high-quality drug products without extensive regulatory oversight" (1). This breakout session explored the understanding and implementation of the quality system concept along with relevant challenges and successes. Aspects of the quality system that were discussed included change management, and integration of risk management and knowledge management.

There is increased understanding of the role the quality system plays in achieving a science- and risk-based approach to pharmaceutical manufacturing over the product life cycle. As a result, the design and effectiveness of the quality system is an emerging area of discussion and effort. There was shared understanding among participants on the significance of management's role in a quality system's effectiveness. In addition, they identified the crucial role of the change management system and the use of the principles and tools of knowledge and risk management. As the pharmaceutical business moves to a global platform, discussants reinforced the need for and the value of global harmonization of a regulatory guidance for quality systems.

ICH and international activities breakout report

International cooperation has been one of the guiding principles of FDA's CGMPs for the 21st Century quality initiative. The agency's global strategy to improve the quality of pharmaceutical products includes enhancement of relevant international harmonization activities and increased sharing of regulatory information with counterpart authorities in other countries. Because it is crucial that pharmaceutical quality standards and requirements be harmonized to the fullest extent possible, collaboration with industry and other regulatory authorities through the International Conference on Harmonization has been an important aspect of FDA's overall international strategy. ICH Guidelines Q8, Q9, and Q10 are the cornerstones of the new ICH quality vision of creating a regulatory framework that enhances public health promotion and protection.

At a Fall 2006 ICH meeting in Chicago, representatives discussed the future vision for ICH quality topics. The objective of the meeting was to identify those areas in pharmaceutical quality which need to be addressed at the ICH level to further advance the goal of achieving the same global submission. ICH's industry representatives and obervers from Europe, Japan, and the US came with an aspirational view to achieve a transparent, science- and risk-assessment based approach to product development, dossier submission, review, consistent implementation of Q8, Q9, and Q10 across the ICH regions, as well as some future opportunities for new ICH quality topics that could be addressed to help achieve the objective cited above.

Question-based review (QbR) initiative: Office of Generic Drugs breakout report

FDA's Office of Generic Drugs (OGD) publicized its question-based review (QbR) approach in 2005. Over the course of 2006, some sponsors began to address QbR questions in their abbreviated new drug applications (ANDAs). OGD began to fully implement the QbR approach in 2007. This Pharmaceutical Quality Initiatives Workshop session discussed the effect of QbR on the generic drug-development process and explored the use of directed questions to guide sponsors in preparing quality overall summaries that lead to efficient application review.

Based on early experiences and initial feedback, participants found that QbR has encouraged generic sponsors to use QbD elements and principles, changed the paradigm of the generic pharmaceutical development process, and changed the quality assessment within OGD with positive comments from the reviewers.

Generic industry is interested in knowing how much more information on development activities is needed for filing ANDAs. They would like OGD to provide more clarity on expectations for the quality overall summary and pharmaceutical development report. In addition to the current proposal for supplement reduction, industry representatives would like additional metrics that go beyond the preliminary risk-assessment strategy proposed by OGD. ANDA sponsors also would like OGD to use postapproval data to evaluate and grant regulatory relief. For some firms, additional development work (e.g., process) will be needed to fully address QbR before submission.

Postmarketing regulatory process breakout report

Preparation and review of supplements for routine postmarketing changes are generally recognized as burdensome, and both FDA and industry are seeking a better utilization of limited resources. Manufacturers continue to express difficulty in determining what status a change should fall into: prior approval supplements (PAS), changes being effected (CBE), or annual reports. FDA does not always concur with the strategy as proposed by the manufacturer. Additionally, the requirements for filing supplements for routine changes can hinder a firm's willingness to invest in continual improvement.

Participants in this breakout session felt that revisions to the current postmarketing regulatory process should be considered to use a risk-based approach for review and approval of process or control changes. Where manufacturers can demonstrate process understanding and product knowledge within a QbD environment, a streamlined or more flexible approach to regulatory strategy should be available. This should encourage the regulated industry to embrace new and improved technologies and/or regulatory agreements in support of improvements to product quality and efficiency.

Discussants also explored the impact to the inspection process as a result of managing certain types of changes through the quality system. They proposed:

  • Current postapproval regulatory process warrants revision based on risk assessment

  • Current process acts as an impediment to improvement in processes of a firm

  • All CBE supplements possibly be eliminated and that postmarketing approval process options be reduced to PAS and annual reports

  • Both critical and noncritical changes can be managed through a firm's quality system

  • Multi-site companies should have a single robust global change management system

  • Change management system should include multi-disciplinary review

  • Change management system should be supported by knowledge management system

  • Annual reports should be limited to a summary or index of changes

  • Supporting data should be maintained by the manufacturer

  • GMP inspection process should remain an audit of the effectiveness of a firm's quality system.

Implementation of quality risk-management breakout report

The ICH Q9 document on risk management has been issued by FDA as a guidance and is at Step 5 (implementation) in the ICH process. In addition, there is an official ICH Q9 briefing pack available online at www.ich.org, that provides valuable training presentations. However, there is still concern from industry and regulators in developing a shared understanding of the implementation of quality risk-management tools. Exploring the concerns, analyzing the more difficult issues, and sharing case studies can achieve a common understanding. This breakout session explored some of the controversial and difficult aspects of implementing quality risk management, including the importance of a clearly defined risk question, implementation of risk management over the product life cycle as part of an overall quality strategy, and a sharing of training successes.

Quality risk-management principles are used over the life cycle of the product and as part of decision-making for pharmaceutical quality systems. The most common tools appear to be Failure Mode Effect Analysis (FMEA) and Fishbone analysis. Quality risk management has shown to be an effective tool in the design of new facilities and in the classification of quality attributes and processing parameters as critical and noncritical.

The characteristics of a good quality risk-management process include integration into the pharmaceutical quality system rather than residing in a separate department. A multi-disciplinary group within a firm brings the strength of varied experiences and knowledge. Employing a trained, independent yet knowledgeable facilitator can help ensure the team maintains a focus on the process while still being open to new ideas. By bringing an objective analysis to subjective issues, vested interests (e.g., "silos") can begin to diminish. Quality risk management works best when it is used proactively and should not be used to justify a bad decision. When new information becomes available that can impact a prior quality risk assessment, iterative processes can ensure the quality assessment is not static. Moreover, at the end of the risk assessment, additional risk factors arising as the result of accepting, mitigating, or reducing a risk factor should also be evaluated. Participants in this workshop session noted that the pharmaceutical industry can effectively learn from the device industry, which has mandatory requirements for conducting risk assessments.

An effective pharmaceutical quality system requires quality risk management as an enabler integrated into processes and decisions. For example, using quality risk management in evaluating a change to a validated process can help identify any ramifications of making a change. With this knowledge, a site can determine the appropriate level of testing to ensure the change does not negatively impact the ability to meet predetermined quality attributes.

The path ahead

The Pharmaceutical Quality Initiatives Workshop planning committee recommended that FDA consider several proposals and next steps. Five overarching focus areas emerged from the three-day workshop as key to addressing remaining challenges and moving toward the "desired state:"

  • Formalizing a regulatory agreement

  • Defining risk management, quality by design, and design space

  • Carrying out education, training, and future workshops

  • International harmonization with other regions

  • Maintaining momentum at FDA.

Regulatory agreement. By definition, this is an agreement envisioned (at the time of product approval) between FDA and the applicant on the management of postapproval CMC changes. More specifically, it is a customized, product-specific regulatory framework proposed by the applicant to manage and/or implement postapproval changes based on demonstrated product and/or process understanding and controls. The agreement could facilitate continual improvement and product life cycle management while providing a scientific basis for applicants to manage postapproval changes, thereby reducing the number of postapproval supplements. Regulatory flexibility is predicated on meaningful improvements to pharmaceutical development and scientific information submitted in an application.

Key recommendations:

  • An FDA and industry team needs to work together to develop a mock agreement in 2008

  • The mock agreement should demonstrate the regulatory flexibility that can be obtained by using QbD during pharmaceutical development and increase the role of a firm's internal quality system to manage change over a product's life cycle

  • The framework should be the same for biotechnology products, but details will differ.

Definitions and terminology. Workshop participants felt that common understanding of key terms associated with risk management and QbD must be cultivated collaboratively by industry and FDA. This terminology serves as a fundamental foundation for implementing quality initiatives and must be usable in all regions around the globe. Discussants proposed the following:

  • Risk-management relates to life-cycle management. A subsequent FDA-ISPE Workshop, "Product Quality Life Cycle Implementation: Practical Approach to Quality by Design," was held in June 2007, covering design space, quality control strategy, and critical quality parameters.

  • Terminology must be shaped in concert with the progress of ICH quality topics: pharmaceutical development (Q8), quality risk management (Q9), and quality systems (Q10).

  • FDA and the Pharmaceutical Research and Manufacturers of America (PhRMA) should cosponsor an ICH roundtable discussion on active pharmaceutical ingredients (API) to determine how to incorporate ICH Q8, Q9, and Q10 into API development

  • A 3–5 member FDA and industry team should be formed to draft, finalize, and publish definitions and examples in a suitable journal in 2008.

Education and training. As experience with new approaches is gained, more specific and highly technical discussions and real-world training opportunities, to be headed by industry, are needed by 2009, according to workshop participants. Technical guidance needs to be developed in collaboration with stakeholders such as ISPE. FDA will facilitate future educational conferences and workshops managed by industry to promote understanding of specific technical issues with examples and case studies encompassing QbD, process validation, and pharmaceutical development (ICH Q8), quality risk-management in defining the control strategy (ICH Q9), pharmaceutical quality systems (ICH Q10), and work being done with generic stakeholders to develop a model example for design space.

International harmonization. FDA's 21st Century initiatives have placed the agency in a favorable position in the emerging regulatory global environment. To fully realize the benefits of FDA's initiatives and promote the global upgrade of pharmaceutical manufacturing, careful planning and coordination of implementation will have to occur in each international region. To facilitate this, the Pharmaceutical Quality Initiatives Workshop participants suggested that:

  • Future technical workshops be held in Europe and Asia as well as in the US

  • A process validation guidance for industry be harmonized by 2009

  • Regulatory requirements and interpretations of the harmonization of quality systems be finalized in 2008

  • Collaboration to determine the right information and format for submissions that facilitate science and risk-based regulatory decision-making be completed in 2008

  • Develop a long-term ICH quality vision which ensures consistent implementation and includes drug substance be completed by the end of 2007.

Maintaining momentum. Both FDA and industry agreed at the workshop that the following should receive high priority going forward:

  • Publish a process validation guidance in 2008 that includes what process validation would look like under QbD

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

  • Determine how to achieve 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 pilot program and establish additional pilot programs for both postapproval and biotechnology to highlight successes and identify areas for improvement

  • In 2009, hold a workshop on the holistic impact of ICH Guidelines Q8, Q9, and Q10, and the pilot programs to review status, highlight successes, and identify areas for improvement.

Industry and FDA have a common purpose to make safe and effective new therapies available to patients as quickly as possible while improving quality, reducing manufacturing time, and eliminating waste. The pharmaceutical industry has long recognized the need for improvement in these areas but has lagged with buy-in for the new approaches to pharmaceutical development and manufacturing. FDA will continue to seek industry input and collaboration as it focuses on building upon the concepts explored at this workshop. The introduction of new technologies and innovations into pharmaceutical manufacturing must be guided, as always, by rigorous science. Tremendous benefits to the public, industry, and regulators are foreseen.


The authors would like to acknowledge the contributions of Diana Amador (FDA), Ferdinando Aspesi (Wyeth), Gregory Blank (Genetech), Richard Bowles, III (Schering-Plough), Susan Cady (Intervet), Monica Caphart (FDA), Barry Cherney (FDA), Gregory Claycamp (FDA), Emer Cooke (EU), Roman Drews (FDA), Eric Duffy (FDA), Douglas Ellsworth (FDA), Raafat Fahmy (FDA), Gurpreet Gill-Sangha (FDA), Brian Hasselbalch (FDA), John Hennessey (Merck), Charles P. Hoiberg (ISPE), Patricia Hughes (FDA), Robert Iser (FDA), Gordon Johnston (GPhA), Susanne Keitel (EU), Thomas Lynch (Talecris), Karen Main (AstraZeneca), Christine Mundkur (Barr Pharmaceuticals), Gordon Munro (Watson Pharmaceuticals), Joseph Phillips (ISPE), Carol Rehkopf (FDA), Edwin Rivera-Martinez (FDA), Nancy Rolli (FDA), Raymond Scherzer (GlaxoSmithKline), Susan Setterberg (FDA), Brenda Uratani (FDA), Timothy Wozniak (Eli Lilly and Company), Lawrence Yu (FDA), and Diane Zezza (Schering-Plough) for their valuable assistance by serving on the workshop planning committee and/or moderating some of the workshop breakouts. In addition, the editorial contributions of Kathleen Jordan (FDA), David Morley (FDA), and Frederick A. Golec (Wyeth) are very much appreciated.


1. J.W. Woodcock, "Pharmaceutical Quality in the 21st Century—An Integrated System Approach," presented at AAPS Workshop on Pharmaceutical Quality Assessment—A Science- and Risk-Based CMC Approach in the 21st Century (Bethesda, MD), Oct. 5, 2005.

There is no copyright in US Government work (per 17 USC 105), and the work the authors are providing is a US Government work.

Representatives of the US Food and Drug Administration and Industry*

*Authors of this report include:

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).

All correspondence should be addressed to Dr. Moheb Nasr, FDA, Office of New Drug Quality Assessment, 10903 New Hampshire Ave., Bldg 21, Rm #2630, Silver Spring, MD 20993-0002.

Progress and updates* on FDA's pharmaceutical quality initiatives

A Q&A with workshop participants by Angie Drakulich

Q: "Regulatory flexibility" continues to be a hot topic, especially with regard to design space. Companies want to know what type of flexibility they may actually see if they submit quality-by-design (QbD) based documents. Will there be any near-term clarification of such flexibility from the US Food and Drug Administration?

A: The types of "regulatory flexibility," better known as "flexible regulatory approaches," are described in the International Conference on Harmonization's Q8 Guideline, Section 2. They include: risk-based regulatory decisions (reviews and inspections); manufacturing process improvements, within the approved design space described in the dossier, without further regulatory review; reduction of postapproval submissions; and real-time quality control, leading to a reduction of end-product release testing. FDA developed and implemented a few regulatory pathways of the agreed-upon flexible regulatory approaches, including, if appropriate, movement within design space, reduction of postapproval submissions without prior approval or changes-being-effected supplements, real-time release, etc.—Answered by Dr. Moheb Nasr, director of the Office of New Drug Quality Assessment, Center for Drug Evaluation and Research, FDA

Q: With regard to design space and other QbD-based documents, many of these are considered "living" documents that will continuously change and be updated. How will these constant changes impact the inspection process, postapprovals, etc.?

A: According to ICH Q8, movement within the design space is not considered a change. Thus, verifying and updating the design space can be accomplished under the applicant's quality system. But, redefining or expanding the design space postapproval will require a supplement. It is possible that the design space management can be captured as part of the CMC Postapproval Management Plan (PMP), formerly known as 'regulatory agreement' '....FDA is considering...the issuance of a guidance to implement a PMP. The PMP policy, when implemented, would be on a voluntary basis. However, if a PMP is submitted by the applicant and reviewed and approved by FDA, it will be binding on the applicant and FDA.—Answered by Dr. Nasr

Q: One of the primary action items proposed during the 2007 Pharmaceutical Quality Initiatives Workshop was the publication of a process validation guidance in 2008 to focus on what process validation would look like under QbD. What is the status of this guidance? Will industry see a draft in 2008? And will manufacturers be allowed the typical comment period?

A: Yes to all questions posed. The draft guidance will be in line with the ICH Q10 document on pharmaceutical quality systems which is currently at Step 3, the public comment period.—Answered by Joe Famulare, deputy director of CDER's Office of Compliance

Q: The CMC Pilot Program breakout session recommended an end-of-Phase 2 or a mid-Phase 3 meeting between firms and FDA to discuss QbD implementation programs. Might this happen? If so, what type of preliminary information will be required from manufacturers to engage discussion about QbD implementation?

A: This is already happening. Based on FDA's experience in the past year, several sponsors have voluntarily submitted QbD-related questions for discussion in an end-of-Phase-2 meeting. The type of preliminary information needed depends on the type of questions raised by the sponsor.—Answered by Dr. Nasr

Q: The Pharmaceutical CGMPs for the 21st Century—A Risk-Based Approach initiative set out to develop "a product quality regulatory system for the future." As pointed out during the 2007 workshop, international cooperation is a guiding principle to this approach. However, given the exponential growth of pharmaceutical manufacturing abroad and the recent series of negative events tied to products made overseas, especially in China, do you feel that the initiative has enough of an international approach? In your opinion, is there more that can be done? Are there plans to extend the CMC Pilot Program globally?

A: ICH guidelines Q8, Q9, and Q10 are based on the same concepts and principles as the Pharmaceutical CGMPs for the 21st Century (i.e., a science- and risk-based approach to drug development and product life cycle management). Recognizing the importance of globally harmonized approaches to these new concepts, the ICH expert working group will convene this June to develop a plan for implementing Q8, Q9, and Q10. The outcome of that meeting will be made public as soon as possible. In addition to ICH, FDA is committed to collaborating with our international partners to facilitate the implementation of modern science and risk-based approaches to pharmaceutical development and manufacturing throughout the entire product life cycle. FDA is unaware of any plans to extend the pilot program globally.—Answered by Dr. Nasr

Q: Can you address the fifth goal that came out of the 2007 workshop for the path ahead: maintaining momentum within FDA? For example, Commissioner Andrew von Eschenbach recently gave a speech about FDA's need to "re-create" itself to meet the regulatory needs and challenges of today's food and drug market. How are FDA investigators preparing to take a new approach? How will the objectives of the these goals affect inspections?

A:All of the initiatives referenced here involve training coordination and communication between CDER and investigators. This continues to advance on a steady pace with the CMC Pilot Program involving close collaboration between review, compliance, and inspection and details of Pharmaceutical Inspectorate candidates to the Center. There will be more to come with regard to what the Commissioner reported as FDA's Office of Regulatory Affairs completes its revitalization plan and work plans are developed for FY 2009.—Answered by Mr. Famulare

*This Q&A interview took place in March 2008, one year after the Pharmaceutical Quality Initiatives Workshop.