Helen N. Winkle

To understand the challenges and opportunities associated with implementing quality by design (QbD), FDA contracted an independent consultant to evaluate current industry adoption of QbD. This article summarizes those findings and proposes actions FDA can take to encourage full-scale QbD implementation.

In 2004, FDA released its final report on "Pharmaceutical Quality for the 21st Century: A Risk-Based Approach." The purpose of the initiative, which was launched in 2002, was to encourage innovation and implementation of new manufacturing technologies, focus the agency's resources on those areas of pharmaceutical manufacturing considered to pose the most risk, and improve on the consistency and predictability of  the agency's work in ensuring drug quality and safety. In the 2004 report, FDA outlined its initiation of quality by design (QbD)—a science- and risk-based approach that begins with predefined objectives for meeting the desired clinical performance and emphasizes product and process understanding and process control.  

Working with regulators in the European Union (the European Medicines Agency and European Competent Authorities) and Japan, FDA has been instrumental in furthering QbD objectives through the International Conference on Harmonization (ICH), and industry has made progress in implementing QbD in terms of its corporate culture, operations, and quality systems. But, as is the case with many new endeavors, challenges still exist that inhibit full-scale implementation. 

In an effort to understand these challenges and identify opportunities for adoption, FDA contracted an independent consultant to objectively evaluate and develop a fact-based consensus view on the state of QbD adoption. The team got input from several sources—literature research, database searches, and interviews with industry leaders—to gauge industry's current perspectives on QbD and its level of adoption. This article summarizes the consultant's findings, to include key adoption challenges and implementation issues, as well as actions that FDA can take to encourage full-scale implementation and ultimately ensure the production of high-quality products. 

QbD has continued to gain momentum during the past several years. One of the most striking factors has been an increase in the codification and practice of QbD in a standardized basis. More and more companies are experimenting with and using the concept, as well as developing mechanisms to support it. That being said, companies are at very different levels of maturity in terms of QbD adoption. Four levels of maturity were identified in the report.  

, is defined as a company that is skeptical about the value of QbD. The company uses conventional development practices and has no QbD platforming. The second level, 

, defines a company that is trying QbD, but is still uncertain about the initiative's potential value. This company tends to apply QbD to a small subset of projects and processes and has implemented limited or no QbD platforming. The third level, 

, is a company that is convinced about QbD's impact and is beginning to see some of the benefits. This company uses QbD techniques regularly, but not universally, and may engage in some life-cycle management with integrated QbD platform and network strategy. Finally, the fourth level, categorized as

, defines a company that is completely convinced about QbD's positive impact and has seen the benefits. This company uses QbD in almost all development programs. It also has a systematic, comprehensive review and redesign of in-line products. Table I illustrates, by drug type, the level of maturity of those companies that were examined. 

Table I: Level of maturity and drug type of examined companies. 			

There are still many challenges as FDA promotes the concepts of QbD. Industry, academia, and FDA need to work together to pursue the opportunities, overcome the challenges, and realize the benefits that QbD implementation has to offer. This is necessary to ensure that QbD concepts are incorporated not only when the first activities are initiated around a product's development, but also during the design of the process that is used to make the product and other activities associated with a product's life cycle. In conducting its research, the team discovered 10 key challenges related to QbD adoption.  

The first four, noted below, are challenges industry faces internally as it attempts to implement QbD: 

 One of the most important factors in successful implementation is the application of QbD across the entire operating model. The research, however, showed that several companies experienced misalignment horizontally across the organization, a disconnect between leadership and middle management, a culture of conservatism, an unwillingness to redesign certain aspects of their operating model, and the belief that QbD was low on the company's priority list because the initiative was not required and the benefits were not guaranteed. 

The majority of companies believed that QbD has a strong business case, but skeptics felt that QbD would slow time to file (generic products) or that the amount of clinical trials necessary to implement QbD for drug substance production steps (e.g., upstream) made the business case negative until there were further advances in the actual science (biologic products). 

Specific challenges that were identified included the belief that QbD was an insufficient solution for controlling variability of raw materials, it would require companies to develop new skill sets and obtain new technology that are viewed as out of reach, and it would be difficult to gather, manage, and analyze all of the product data generated during development. 

 Industry was concerned about how to bring QbD to fruition while managing a complex supply chain that includes both suppliers and contract manufacturers. 

Based on interviews with industry, six challenges to QbD implementation specific to FDA and other regulatory bodies emerged. These include: 

5.  Inconsistent treatment of QbD across FDA. 

 Companies felt that FDA understood QbD requirements differently both within and between offices. This inconsistency leads to the belief that FDA may not review filings in a consistent manner. 

6. Lack of tangible guidance for industry. 

The majority of companies, especially those in the novice and pilot categories, felt the need for a more tangible guidance on how to actually implement QbD. Companies wanted clarification from FDA on matters such as acceptable methods, criteria to select and deselect critical quality attributes, standards by which to judge adequacy of controls, and criteria for analytical method substitution. 

7. Regulators not prepared to handle QbD applications. 

While FDA continues to take steps to remedy this, interviewees were still concerned about matters such as new reviewers' level of experience and a perceived high turnover rate. 

8. The way promised regulatory benefits are currently being shared does not inspire confidence. 

This challenge is primarily the result of the lack of codification of real regulatory benefits from FDA. Without clear benefits, proponents of QbD in industry have expressed difficulty in promoting the idea within their companies.  

9. Misalignment of international regulatory bodies. 

A concern consistently raised by companies at the rollout and fully implemented levels of adoption was whether QbD applications would be accepted by other regulatory bodies. Although no interviewees had experienced rejection by these groups, they did comment on the increased time and effort required in other markets.  

10. Current interaction with companies is not conducive to QbD. 

 Companies felt that, historically, there was not a lot of comfort talking with FDA; however, companies are eager to open and improve on this communication. 

Table II: Key challenges according to industry segment. 			

Table II provides an analysis of what challenges are most relevant for the different drug types, while Table III identifies what challenges are most apparent by stage of adoption. 

Table III: Different challenges highlighted by different stages of adoption. 			

The team's analysis shows a strong preliminary business case for QbD. Interviews proved false two commonly held beliefs that QbD is very expensive and will drive costs up and that QbD will take a long time and require much more analysis. Interviews provided evidence that the cost to implement QbD is in fact minimal and the increase in time, if at all, is negligible (see Figure 1). 

Figure 1:  Conceptual timeline showing quality-by-design (QbD) versus traditional development. 			

Analysis also identified many potential benefits from QbD. In terms of quantifiable benefits, value comes from four main areas: a reduction of cost of goods sold and capital expense, increased technical development productivity, improved quality (and lower risk), and increased sales.  

Ultimately, for companies to experience the most business benefits possible, two things must be in place: (1) companies must be aligned across the entire operating model to capture the full benefits that QbD enables in manufacturing and quality control, and (2) FDA must ensure a high quality and consistency of review and compliance (e.g., train reviewers, provide stronger guidance and ground rules for QbD filings) and deliver on the regulatory benefits many companies feel were promised. 

As previously noted, the team's research highlighted many challenges to QbD implementation. In response, several options were provided to encourage and accelerate QbD adoption.  

 Three options were provided under this category: 									

 Many companies felt this was a powerful way to encourage QbD adoption. As such, FDA may want to consider whether to do this and, if so, what those incentives should be and what benefits could come from introducing these incentives.

Develop tangible guidance for QbD execution.

 Companies—especially those in the early stages of adoption—were confused by what QbD means and how to execute such a huge endeavor. They strongly believed that they could benefit from more tangible guidance.

Determine whether to mandate implementation of QbD.

 If, within certain segments, there is a possible public health risk due to lack of scientific understanding by industry and the incentive to increase that understanding is limited, mandating QbD could be considered.

Two options were provided under this category: 									

Ensure consistency of review process in terms of scientific knowledge and quality of review. 

The desire for a consistent review process and well-trained reviewers is unanimous throughout industry. FDA is aware of this need and continues to train and prepare reviewers to adequately assess QbD applications.

Harmonize how QbD is approached across FDA.

 FDA should present a unified approach to QbD to ensure that the momentum around QbD adoption in industry is strong. 

Three options were provided under this category: 									

 Industry almost universally asked for more frequent dialogs with FDA. The companies who participated in the Office of New Drug Quality Assessment's chemistry, manufacturing, and controls (CMC) pilot programs felt they benefited from the increased, and often less formal, communications. While increased levels of communication may pose constraints on FDA as they relate to resources, a system should be crafted that allows for a level of communication that is acceptable and manageable for both FDA and industry.

Create more buy-in by disseminating case examples.

 Industry asked for real, tangible examples of what applications FDA has approved or denied and why those decisions were made. FDA can work with companies whose applications have been approved to develop examples that are sensitive to proprietary information, as well as disseminate findings and tips on successfully navigating challenges.

 Companies felt that a lack of international harmonization was one of the consistent challenges. FDA should continue to seek opportunities to work with other regulatory bodies and ensure alignment on what QbD means, what QbD requires, and how regulatory flexibility can be granted.

The independent report served as an excellent assessment of QbD implementation by the pharmaceutical industry and of FDA policies and practices from industry's perspective. We were extremely encouraged to see from the report that the understanding and practice of QbD is evolving, gaining momentum, and generating passion throughout industry. As a result of the report, we have accelerated our internal drive toward the implementation and adoption of QbD and are in a better position to determine what we need to support the process for the next 5 years.  

Looking back, the first 5 years of the QbD initiative were spent developing the concept of QbD. This included setting the aspiration and getting stakeholders on board—something we accomplished by initiating a number of outreach efforts; working with international regulators and industry to  develop the ICH Q8, Q9, and Q10 guidelines on pharmaceutical development, risk management, and quality systems; and increasing our own internal knowledge and capability.  

Looking forward, we plan to spend the next 5 years focusing on putting QbD into consistent practice, including ensuring the clarity of our vision, message, and aspirational targets and timelines; clarifying expectations and benefits of QbD within FDA and industry; and ensuring a broad codification and guidances. As such, we are working toward consistency of concepts within FDA, including: (1) ensuring that other organizations involved in supporting QbD (e.g., inspectional components) are completely aware of the principles of QbD and how they need to be applied, and (2) enhancing collaboration among the organizational components that are responsible for the overall quality of drugs. We are in the process of developing and implementing our internal quality system to ensure the quality and consistency of all CMC reviews, including the review of QbD submissions.  

We believe that the implementation of QbD has been significant in advancing FDA's desired state for pharmaceutical manufacturing: "A maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high quality drug products without extensive regulatory oversight" (1). We look forward to continuing to work with industry and other stakeholders to ensure this desired state is reached. 

is director of the Office of Pharmaceutical Science (OPS) at the Center for Drug Evaluation and Research (CDER) within FDA. 

is director of the Office of New Drug Quality Assessment in OPS, CDER, at FDA, 10903 New Hampshire Ave., Silver Spring, MD, 20993, tel. 301.796.1900, 

*To whom all correspondence should be addressed. 

 1.  J. Woodcock, "The Desired State: A Mutual Goal of Industry, Society, and the Regulators" (October 2005). 

Articles

Directors from FDA's Center for Drug Evaluation and Research summarize findings in an FDA-commissioned report on QbD and propose actions the agency can take to encourage full-scale QbD implementation.