After years of discussion and work, FDA has made the structural changes that will make the new regulatory and manufacturing concepts an everyday reality.
The concepts for a new FDA framework for regulating manufacturing—the framework that now supports quality-by-design, risk-based regulation, process analytical technology (PAT), and their kin—began to emerge around 2002. The agency was looking for ways to loosen some of the regulatory bonds that, officials felt, constrained manufacturing progress in the United States—while finding a way to cope with the combined pressures of a growing number of products, fewer FDA inspections, diminishing financial resources, advances in technology, an emphasis on risk-based regulation, and international harmonization (1, 2).
The industry press has written a lot about those planned changes in the years since, but generally in the future tense (3, 4). The word "paradigm" was used; for once, it might have been appropriate. But, there were also raised eyebrows and an implied, "if it happens."
Or, as one observer put it, "It is not a dream anymore. It is not a PowerPoint presentation. The business case has been made."
"I don't blame the industry for not believing," says FDA Deputy Commissioner Janet Woodcock, MD, acknowledging that those outside the agency can sometimes have trouble distinguishing fundamental change from mere rhetorical flourish. "But we really are going to do it."
How can you bring shape and make fundamental conceptual changes in an organization this large, this diverse? "The most important thing," says Woodcock, "is to have a consistent core set of messages, and to be able to adapt them to different people's situations or different programs around the agency."
FDA continues to develop its site-risk model, already being used to guide inspection activities.
The agency's manufacturing regulators, says Woodcock, "have really embraced the new principles. Now, that doesn't mean 100% of the people are apostles of the new way of thinking, but we've seen very, very concrete changes."
Has quality-by-design permeated the industry as deeply as it has the agency? "No," says Woodcock. "The industry is very conservative. I do believe that many of the leaders of manufacturing in industry are convinced. And more important, maybe they believe FDA is sincere and believe we are changing."
Restructuring for quality
FDA is changing. During the past nine months, FDA has made a series of structural and procedural changes that commit it to its new course. The agency has, for example, restructured the Office of Regulatory Affairs with the explicit intent of supporting risk-based inspection (5). And, the agency has realigned many operations throughout the Center for Drug Evaluation and Research (CDER), reorganizing the Office of Compliance (OC), and the Office of Pharmaceutical Science (OPS), among others.
Because of resource constraints, FDA seeks to focus its inspection activities at the top end of the curve, on sites most likely to merit monitoring.
At OPS, Director Helen Winkle has assigned more staff to implementing quality-by-design guidances and the associated work in all of the groups' component offices. OPS has completely rebuilt the Office of New Drug Chemistry into the Office of New Drug Quality Assessment (ONDQA), specifically to accommodate the new vision of the chemistry, manufacturing, and control (CMC) review process, dubbed the "Pharmaceutical Quality Assessment System."
"That new review process could not have been achieved without restructuring our office," says ONDQA Director Moheb Nasr, PhD. "We changed review assignments. We changed our division structure. We separated premarketing from postmarketing review. We changed everything."
OPS has integrated the Office of Biotechnology Products (OBP)—imported from the Center for Biologics Evaluation and Review (CBER)—and set it to work adapting quality-by-design to large molecules. These initiatives "challenge OBP to think how regulating biotech product quality can benefit from the initiatives shaping the treatment of small molecules," says OBP director Steven Kozlowski, MD. The group has reached the point where "our overall organizational structure can support this. We have a strong science base in our organization, and they're very attuned to the biological impact of structural changes."
The Office of Generic Drugs has instituted question-based review—a template or a list of questions that industry can follow, questions designed to give as much information as possible. Like ONDQA, the Office of Generic Drugs has adopted the International Conference on Harmonization (ICH) Quality Overall Summary, and "we are also changing our format in submitting the CMC sections of our applications," says OGD director Gary Buehler, RPh. "We're doing this to be able to use the Common Technical Document Format specified in the ICH guidances. We are transitioning to the Common Technical Document Format, and we are encouraging the electronic format (eCTD)."
OPS's Office of Testing and Research (OTR) is devoting increasing resources to understanding what PAT and quality-by-design look like in a practical setting. As analytical methods move onto the manufacturing floor in industry, OTR has established its first manufacturing science group and installed first pilot-scale equipment, mirroring the mingling of lab and line. "Maybe," says Lucinda F. Buhse, PhD, director of OTR's Division of Pharmaceutical Analysis, "you can't have manufacturing and quality control any more. Maybe you need to just have one group interested in product quality and that's their job."
Amid all of these changes, it is difficult to pick out the watershed. For some, it was last November's creation of ONDQA. For other's, it was this June's mass revocation of seven CMC and stability guidances, replacing them, if temporarily, with ICH guidance documents.
The quality-by-design cycle.
"All seven of those guidances had a lot of elements of the old system in them," Winkle says. "This put us in a difficult situation, because we were getting asked a lot of questions, and our reviewers followed these guidances to the T." Sponsors who follow the superseded guidances will not be penalized, Winkle says. The problem was that applicants who tried to adopt the new methods outlined in the ICH guidelines were in technical violation of the outdated guidances, so they were being penalized.
ONDQA pilots quality-by-design review
In July 2005, what is now the Office of New Drug Quality Assessment asked for 12 companies to volunteer to take part in a pilot program designed to develop guidance for the new quality assessment system (6, 7). ONDQA asked participating companies to submit CMC, and control information, demonstrating their "quality-by-design, product knowledge, and process understanding of the drug substance and drug product in a new drug application." The pilot submissions were to focus on critical pharmaceutical quality attributes (related to chemistry, formulation, manufacturing process design, and product performance) and their relevance to safety and effectiveness, following the ICH draft guidance, "Q8-Pharmaceutical Development."
"As part of this program, we are requesting participants to provide two pieces of information that are currently not submitted," Nasr explains. "The first is an expanded pharmaceutical development section, applying Q8 and putting the quality-by-design concept into practice. Second, we are also requesting a comprehensive Quality Overall Summary. We are not telling them how to submit it or what to submit; we want them to submit what they think is appropriate, giving them flexibility, so we can start up a dialogue. And, I think that will be a challenge."
In the past, industry has complained that FDA guidelines are too prescriptive and not truly science-based. "But now we are telling them, 'Submit what you think is relevant to that particular product or that particular application.'"
ONDQA does not automatically accept all CMC pilot applicants. The sponsors needed to "provide a convincing case of what additional CMC information will be included in the submission: What are the quality-by-design approaches? What are the risk-assessment and risk-control strategies?"
Once the proposal is accepted, a rigorous—and unprecedented—interaction begins. "Traditionally, that dialogue does not take place," says Nasr. "We get the application. We review it. We interact with the regulatory affairs folks. But now we have the agency scientists sitting down with the industry scientists talking about the science. And, that's the only way you can have a science-based review."
"I have to admit," says Nasr, "that I underestimated the resources needed to facilitate this scientific dialogue. It's very intensive. You have to prepare, you have to discuss, you have to evaluate the issues, you have to provide written responses to the questions. So I think that, during the transition from the traditional approach to quality-by-design, there will be an increase in resources as we run the two programs in parallel."
"But, when the dust is settled" and all of the guidances and annexes are in place, says Nasr, "I would predict that the resource requirements will go down because of the gaining of knowledge and expertise. I expect with our quality-by-design approach and regulatory flexibility, it will result in a reduction in the number of supplements. So the resources that we currently use to review supplements will be available for new applications."
First quality by design approval
On May 10 of this year, FDA approved Pfizer's new "Chantix" (varenicline tartrate) tablet for smoking cessation, after priority review. The product was the first CMC pilot-program enrollee to win approval. Pfizer's Jeffrey Blumenstein described the quality-by-design experience in June, at a presentation at this year's Drug Information Association Annual Meeting (8).
Much of the submission was complete before the CMC pilot was announced, Blumenstein reported, but many of the basic quality-by-design elements were already in place, so the company elected to enter the CMC pilot program. The product's "classical" dosage form and chemical synthesis promised to minimize problems. And, the company had already performed a significant amount of quality-by-design analysis.
The active pharmaceutical ingredient—developed before the quality-by-design discussions began—is well characterized. And, Pfizer developed the drug product under its existing "Right First Time" initiative, performing formal risk assessments and establishing design space through a design of experiments.
No penalties for using, or avoiding, quality by design
"One thing we are emphasizing in the [ICH Q8-Pharmaceutical Development] guideline is we are not changing our regulatory requirements," says Nasr. "The regulatory requirements that we have today are appropriate and are acceptable." Rather, the quality-by-design approach is an option the industry can use to meet those requirements. But if drug makers select the quality-by-design road, "it will be useful in a variety of ways for their internal operations, for the efficiency of manufacturing, to avoid potential compliance difficulty—and it will result in regulatory flexibility" proportional to the amount and quality of the developmental information produced, and "the amount and kind of information and relevant knowledge they share with the agency."
The agency is determined not to penalize applicants that opt to make the extra effort to make a quality-by-design submission. The review process must simultaneously focus on the new elements in submission but without pouncing on any deficiencies in the new elements to prevent approval. "We are not penalizing them for sharing or providing additional information," says Nasr. "We are not going to delay the review process, which was another fear: 'The more information I give you, the more questions you raise, the longer it will take to approve my drug.'"
Embracing quality systems
Joseph Famulare, Acting Deputy Director of CDER's Office of Compliance, leads the group preparing FDA's forthcoming Quality Systems guidance, expected as early as September. He also is deeply involved in the ICH Q10 Quality Systems working group. In this case, the FDA guidance will appear well before the ICH document. "That doesn't in any way mitigate our commitment to harmonize ICH quality systems under Q10," he says. "We felt it important enough to put it out there now, and we'll be flexible once ICH completes their work on it."
Industry, he says, is looking for a quality system to maintain the state of control that it can to ensure realization of a quality drug product and facilitate continuing improvement over the product life cycle. Being able to establish workable quality systems is the essential control to successfully implement a quality-by-design or continuous improvement system.
To take that benefit to the full extent, we see there being a need for a quality system that can handle that change control, understand the effects on the product, and to be able to move forward as industry being the innovator and not have to, for example, file many supplements to FDA. Have FDA be industry's, for lack of a better term, quality control mechanism.
The forthcoming Quality Systems Guidance, says Famulare, will pull together all of the principles—quality-by-design, risk management, and an overarching quality system—that will define pharmaceutical manufacturing in the 21st century.
New approaches to inspection
Overworked and understaffed, the agency has not met its statutorily mandated inspection targets for a number of years. In its available inspectional effort where it will do the most good, the agency has revamped its inspection processes. Two major changes are the risk-assessment model it uses to channel inspections to facilities most likely to need monitoring and the creation of an elite "Pharmaceutical Inspectorate," trained to evaluate the high-technology quality-by-design processes of the future.
The agency has been using—and refining—its risk-assessment model over the past years to "make sure we target our resources the best," Woodcock says.
"We're enhancing that model," adds Famulare, "and we're going to start to study more on our inspections, process capability, volume, and other factors that will even better focus what we cover when we get there for the inspection," adding additional data, such as recall statistics, as time goes on.
Under a 2003 memorandum of understanding with ORA, members of the Pharmaceutical Inspectorate work for ORA under the traditional district office structure, but work with the office of compliance for their assignments and training. ORA provides the basic structure through ORAU, the ORA University.
The Pharmaceutical Inspectorate's first class of 45 "Level 3-certified" inspectors has graduated. "They're going out now and starting to inspect," says Famulare, and a new class is being enrolled to follow them next year. Their training included classroom work on risk analysis, quality-by-design, new approaches to validation, new science, and new technologies.
FDA is looking at expanding elements of the Pharmaceutical Inspectorate training to the whole field force. Then, he says, many of these concepts will start to trickle more broadly across the agency.
PAT is here to stay
"I do want to make it perfectly clear," begins OPS director Winkle, "PAT is not going away," she says firmly. To underscore the point, OPS is making PAT a routine part of the review process, "where the industry can deal more closely with the people who are responsible for making the review decisions on their applications."
Winkle emphasizes that PAT is a necessary tool for implementing quality-by-design. "Unless companies can embrace this approach and feel comfortable that we're going to support them, we're not going to move into our quality-by-design quite as rapidly," she says.
Another key to succeeding with PAT is standards development, Winkle says. Activities such as those of ASTM's E55 Committee (on Pharmaceutical Application of Process Analytical Technology) are essential to fill in the gap between FDA's high-level guidance and practical, validatable implementations in the factory. And bridging that gap is important, Winkle says, because "PAT is really the driver" of continuous improvement, quality-by-design, and the other foundations of science-based manufacturing.
Through direct discussions and contracted surveys, Winkle has tracked industry's understanding and acceptance of such key concepts as quality-by-design, PAT, and design space.
"The results have been very, very positive on quality-by-design," Winkle says. "The respondents seem to have a good concept of where we're trying to go and what they need to do . . . With PAT, there's a little bit more hesitance on industry's part because PAT hasn't been run out of the review area. I think industry tends to feel that if the review requires it, then obviously it's necessary and something they can work with." That will change.
There is still resistance, of course. Winkle reports this exchange at an industry meeting: "We were talking about quality-by-design and the whole new system. A regulatory affairs officer from industry told me, 'Now, just look at this from my standpoint: If I go to my CEO and say I want to do this under quality-by-design and I don't know exactly what I'm going to do, how long it's going to take, or when our product is going to make it on the market, he's going to say, Use the old system.'"
How long will it take for the new system to become standard practice? "When Ajaz Hussain [the former Office of Testing and Research acting director and PAT evangelist who is now at Sandoz] used to give talks on PAT, he'd say, 'In 2020,' and I'd give him a hard time," Winkle says. "But now I look at it and I think 2020 is probably pretty realistic," for bringing in the last of the small companies in and getting everybody feeling comfortable.
1. J. Wechsler, "FDA Launches Major Review of CGMPs," Pharm. Technol. 26 (10), 16–26 (2002).
2. J. Wechsler, "Modernizing Pharmaceutical Manufacturing," Pharm. Technol. 26 (2), 16–24 (2002).
3. L. Bush, "The End of Process Validation as We Know It?" Pharm. Technol. 29 (8), 36–42 (2005).
4. L. Bush, "FDA Lowers Barriers to Process Improvement," Pharm. Technol. 29 (10), 54–64 (2005).
5. M. Rios, "ORA Restructured," ePT—the Electronic Newsletter of Pharmaceutical Technology, June 29, 2006, www.pharmtech.com/pharmtech/article/articleDetail.jsp?id=352885, accessed July 21, 2006.
6. "FDA Pilots New Quality Assessment System," Pharm. Technol. 29 (8), 20 (2005).
7. FDA, "Submission of Chemistry, Manufacturing, and Controls Information in a New Drug Application Under the New Pharmaceutical Quality Assessment System; Notice of Pilot Program," Federal Register 70 (134), 40719–40720 (July 14, 2005).
8. Jeffrey Blumenstein, PhD, "QbD Pilot Experience," paper presented at the 42nd Drug Information Association Annual Meeting, Philadelphia, PA June 18–22, 2006.