No one can say for sure what the ultimate impact of the U.S. FDA’s pharmaceutical quality metrics initiative will be on both pharmaceutical manufacturers and the Agency’s enforcement practices. A vision of what the future holds, however, materialized during the 2014 PDA Pharmaceutical Quality Metrics Conference in Washington, D.C., Dec. 2–3.

The very first talk of the meeting offered a glimpse into a possible future state, and the final panel discussion with FDA and EU regulators helped further flesh out a possible vision. In between, conference attendees participated in breakout groups to offer feedback on predefined quality metrics selected by FDA for consideration and also helped PDA further its effort to hone in on what constitutes a strong and reliable quality culture. Yet, the meeting concluded with many questions still needing answers and much more work to be done by the Agency, manufacturers and organizations like PDA if this vision is ever going to materialize.

Guy Villax, CEO, Hovione kicked off the meeting by introducing the idea of FDA Commissioner Margaret Hamburg’s “Dean’s List.”

Villax noted a substantial discrepancy between the volume of product sold, dominated by generics, or “small pharma” companies, and the dominance of innovators, or “big” pharma companies, over total sales revenue. But at this and other conferences on quality metrics, employees of large companies compose most of the audiences. In addition, there is discrepancy in the role of manufacturing. Large pharma relies on innovation and patents to drive profits, whereas small pharma and generics companies rely on efficiency in manufacturing and other business elements.

Nevertheless, he asserted, patients and regulators demand the same quality product no matter what the source.

In discussing the current regulatory system which requires compliance with cGMPs, Villax asked, “What is more important to a patient, paperwork or a team that wants to do the right thing?” The quality culture, is important because it is what makes quality “sacred.”

Villax used driving as an analogy to compare quality systems to quality culture. Quality systems are no greater than the roads upon which people drive, he said. There are well-defined rules about speeding, etc. Quality culture, on the other hand, is like the driver. It is the driver that anticipates when other cars are doing something wrong or if there is rain, etc.

Quality systems provide the evidence of compliance and are easy to regulate, legislate and enforce. They are useful to identify bad behavior, which is the “cornerstone of regulatory oversight.” Quality systems can be established in the same way companies build a plant: easy to fake, but unable to drive good behavior.

Quality culture, Villax went on, addresses the unexpected. Quality culture is not definable but easy to spot. It is not explicitly assessed in inspections and virtually absent from regulations. It takes a long time to build, as it mirrors people’s values and ethics. Finally, it is impossible to game or fake and is the central driver of good behavior or innovation.

When FDA issued the Federal Register notice in 2013 calling for industry input into its quality metrics proposal, Villax noted that only one company response—from Pfizer—mentioned quality culture. Villax quoted the company’s submission: “Without the quality culture, product quality and business continuity are not assured.”

While it might be difficult to define a strong quality culture, Villax noted that it is easy to see the lack of one. “Data integrity problems should raise flags,” Villax said. “What’s the point of a quality system if a culture of fraud dwarfs culture of quality?”

FDA’s Dean’s List is the Carrot

FDA must offer some incentives to effect change (1). But right now, “FDA does not drive good behavior, just good compliance,” Villax explained. The Agency “excels in use of the stick, but the toolkit has no carrot.”

A quality Dean’s List is one way FDA can reward good behavior. Villax compared his idea of this Dean’s List with the U.S. Occupational Safety and Health Administration’s Voluntary Protection Program. Companies that do an outstanding job receive a VPP star. Villax stated that this star “clarifies what is a role model, rewards the role model, gets everyone proud, and is uncomplicated and inexpensive.” The FDA quality Dean’s List would be similar to the VPP.

Villax cautioned that whatever system is put in place, it cannot “reward just the firms who pay exorbitant amounts for flashy manufacturing technology, etc. Rather it must recognize those who make high quality product at an affordable price with reliable technology and strong systems.”

Villax concluded that it is “time to give more weight to people and their values than to paperwork. FDA needs to reward good behavior; it needs the Dean’s List.”

He showed an image of a bell curve on which the left side represented firms that routinely run afoul of regulatory agencies (the one’s the authorities regulate well), while the middle consists of the vast majority of firms that meet the expectations but do no more, and the exceptional firms that have strong quality cultures on the right side of the curve (see Figure 1). The firms on the right would comprise the Dean’s List.

Figure 1 Villax’s Quality Curve: Firms on the right would comprise FDA’s quality “Dean’s List”

As part of his talk, Villax suggested that inspections can play a huge role in the assessment of quality culture at pharmaceutical companies. FDA’s Office of Surveillance in CDER’s new Office of Pharmaceutical Quality is looking to do just that.

Following Villax’s presentation, the Acting Director of the Office of Surveillance Theresa Mullin provided insight into how FDA intends to build a new surveillance program.

“FDA is not going to become some kind of super quality management board for industry,” she first cautioned. Rather, the aim is to use “limited oversight resources to maximize public health protection.”

The Office of Surveillance was created to strengthen FDA’s knowledge of:

• Who manufactures drugs for patients
• Where are these drugs made
• How well are the drugs produced

The oversight strategy is global across all sites and local at given sites, so FDA needs reliable, high quality information to prioritize its inspections. “You need to have good documentation of those states of reality. You have to know what is going on enough to feel confident that you don’t have to go someplace or that you can rely on the information you have that a facility is fine,” said Mullin.
To do this, FDA needs high quality data. Current sources of information for the Agency are “fragmented, disparate and incompatible.” In many cases it is “paper” and “entered into different systems.” She listed several examples of compliance information, including field alerts, recall alerts, CMC supplements, annual reports and EIRs/483s. Putting this information together currently is a slow, clunky process for the Agency, and the current system actually hampers the Agency’s ability to be strategic.

The Food and Drug Administration Safety and Innovation Act (FDASIA), under Titles VII 706 and 705, gives the Agency specific tools to establish a risk-based inspection schedule. Mullin explained that FDA needs to:

• Gather analyzable data for ongoing quality assessments
• Develop an effective and efficient process for quality surveillance inspection
• Create standards for consistently gauging and grading state of quality observed by investigators; specify positive range to build and expand on current structure of observations focused on failures and deviations.

The envisioned inspections will still be built around the system of rankings introduced over a decade ago, which uses a notional scale: extreme failure/critical GMP deviations; substantial failure/major; and unacceptable/minor. The thought is, Mullin said, to add new rankings to the notional scale to recognize firms along Villax’s entire compliance curve: acceptable, enhanced, and well done.

FDA also will look at not just risk-based inspections, but tailoring them so that they are “rule-based, incorporating expert knowledge” and allow investigators to identify “signs and symptoms of quality culture.” The inspections will be set up to “support consistent recording of observations by investigators.” This will include electronic tools along with structured and streamlined inspection reports ensuring that investigators can readily produce accessible analyzable information of maximum downstream value for future decisions on a facility.

EMA Joins the Discussion

Head of International Affairs, EMA, Emer Cooke provided the EMA’s first public thoughts on FDA’s metrics initiative.

She noted that European regulators have been discussing the program, but “haven’t got to the stage where we thought we had a product we needed to engage with at the European level collectively.”

Cooke expressed her “key signs” of constituted quality culture:

• clear and effective leadership from the top (ICH Q10)
• strategic planning for quality and supply chain security and resilience
• patient focus
• utilization of measurement analysis and knowledge management
• a clear workforce focus (“workforce is seen as an enabler of quality”)
• manufacturing and quality seen to create a strategic advantage
• results are gathered, analyzed and fed back to facilitate continuous improvement

On a more tangible level, firms can be evaluated by staff levels, training, staff knowledge of tasks and quality system documentation, response to inspector queries, and ongoing interactions between manufacturer and authority.

Specifically regarding quality metrics and Europe, Cooke stated that there is “no formal European position.” Nevertheless, “quality-metrics-like data is collected and reviewed during inspections,” she said.

“We are very interested in learning more, starting a healthy international debate, and discussing the consequences in a more global context,” she concluded.

The regulatory experience on quality culture was addressed by Gerald Heddell, Director, Inspection Enforcement and Standards, MHRA, Heddell talked about his Agency’s compliance management process. This process attempts to proactively address problems at firms before they escalate to serious compliance actions and plant shutdowns. He discussed three recent cases where the process helped firms correct serious problems without severe regulatory action.

The compliance management process is an example of how regulatory authorities can “influence behaviors in companies without going down the route of formal action, which is enormously time consuming for the company and the regulator and doesn’t benefit the patient,” said Heddell.

Regulators and firms must strive to forestall a “cycle of despair,” in which those making the products:

• Don’t know what to do
• Don’t care
• Cannot cope
• Do only what is expected of them
• Give only what is measured
• Don’t think the rules apply to them
• Feel the procedures are too complicated

Hallmarks of a good culture, Heddell went on, include a strong shadow of the leader. In other words, quality values are made clear from the CEO and the Board, that “walk the talk.”

Tangible indicators of quality culture are:

• Robust quality systems
• A relevant organization
• Continuous improvement processes

Speaking for CBER, Mary Malarkey, Director, Office of Compliance and Biologics Quality, said the adoption of robust quality systems has had an “extremely positive impact” and quality metrics “has a place in terms of measuring those programs.” CBER is engaged with CDER in the initiative. “We are working with them, and we [are] thinking it is extremely important.”

New Office to Own QS Data

Russell Wesdyk, Scientific Coordinator, CDER, said that the Office of Pharmaceutical Quality symbolizes FDA’s effort to transform itself into an organization that equally focuses on both compliance and quality. Enforcement will continue to be of highest enforcement, “but at the same time, we want to focus on quality and part of that is focusing on surveillance: looking at all products, all sites and how they are performing over the lifecycle,” he explained.

The Office of Surveillance will serve as business owner of quality data systems and the pharmaceutical quality platform, developing and managing analytic and predictive programs and a new inspection paradigm and assessment program focusing on surveillance of quality.

Wesdyk touched on the metrics in which FDA currently is interested in receiving data:

• Lot acceptance rate
• Right first time rate
• Product quality complaint rate
• Invalidated OOS rate

He also reviewed many of the quality culture metrics that PDA’s own Quality Metrics Task Force has helped identify. The remainder of the meeting was spent with participants breaking into smaller groups to interactively discuss the quality culture metrics.

The final sessions included summaries of the breakout group discussions and a panel discussion led by FDA and EU regulatory representatives. [Editor’s Note: For a partial transcript of the regulatory panel, see “Metrics Conference Regulatory Panel” Sparks Lengthy Discussions,” p. 31.]

The breakout discussion readouts were presented by the lead discussion facilitators: Gabriele Gori, Global Head of GMP Compliance and Auditing, Novartis Vaccines, Anil Sawant, PhD, Vice President, Enterprise Regulatory Compliance, Johnson & Johnson, and Glenn Wright, Senior Director, Project Management, Eli Lilly and Company. The PDA Quality Metrics Task Force is currently preparing a paper to discuss the conclusions derived by the conference discussions for publication in an upcoming issue of the PDA Letter. They are also working on the an analysis of the PDA Quality Metrics Survey conducted last fall (see p. 36 of the September 2014 PDA Letter), which also will be published later this year.

A lengthy Q&A session followed the readouts. The lead facilitators were joined with the following industry experts to broaden its scope of experience: Deborah Autor, Sr. Vice President, Strategic Global Quality and Regulatory Policy, Mylan, Eric Drape, Group Executive Vice President, Global Head of Quality, Teva, Guy Villax, Jacqueline Elbonne, PhD, Sr. Vice President, Global Quality, Merck, Erwin Vanhaecke, PhD, Head, Novartis Group Quality, Novartis, Martin VanTrieste, Sr. Vice President of Quality, Amgen, Anders Vinther, PhD, Chief Quality Officer, Sanofi Pasteur, and Zena Kaufman, Sr. Vice President, Global Quality, Hospira.

An interesting question was posed early in the panel discussion. One audience member noted that according to the readouts, more than 90% of conference participants viewed the traditional quality system is not suitable enough to create a quality culture at a site or within a company. While the result is not surprising, he said, it is a “staggering result when you think that we’ve had all these years of regulation designed to ensure that companies focus on quality product.” He asked the panel, “Where did we go wrong and what should we do about it?”

Mylan’s Autor, who recently joined industry from FDA, stated, “If there’s any flaw there, I think it’s in thinking that the regulations form the ceiling of what we need to do, rather than the floor. I think, as an industry, we often lapse into doing what the regulator says because we’re closely regulated, and not getting beyond that. GMPs, to me, lay out basic paperwork and processes that need to be followed, but certainly not enough to ensure high quality.”

Sanofi’s Vinther added, “I think that we could ask ourselves how good a job have we done to integrate quality into the general business of the company, and a good example is the quality system itself. Is the quality system written to the minimum standards or is it written in a way that actually makes good sense in the company?”

Teva’s Drape stated, “Looking into the evolution of the pharma industry, the pharma industry has been, for many years, an industry of fat cats, and, therefore, the focus on the efficiency was not as important as in other industries that have lower margins. And our main focus has been on ability to pass inspections and not so much on efficiency in everything that we do. So we had QA organizations that [put] quality systems in place, and then as soon as the quality system was able to demonstrate that it was good enough to pass inspections, they were just pouring a huge layer of concrete on top of that to prevent any change of the system.”

Merck’s Elbonne expanded on Drape’s remarks. “My experience has been, for companies that get into trouble, they start to figure out the cultural piece and how they need to really invent themselves to be successful and sustainable. I think companies that typically have been successful traditionally, passing inspections and getting products out of the door with a good quality, probably haven’t had that incentive to really start to match the how piece—of how you engage people in those systems and processes, how they understand how the business processes relates to what they do on the shop floor.”

Furthermore, Elbonne said, “We’re starting to see, or hope to see, I think, a shift to more of a consistent view of how we engage people in the quality management system, which really is the way to build quality at this point.”

Manufacturing/Ops. a Key Stakeholder

Another audience member noted to the panel the conspicuous absence of employees from operations and manufacturing at the conference. He asked the panel if they thought it was important to get those folks active in this process and, if so, how.

Villax recommended that PDA offer a discount at next year’s meeting to “every quality person that brought in a manufacturing person.”

VanTrieste said, “Clearly, a quality culture is not effective if it’s only in the quality unit. It has to be across the company. And I think part of the reason that we don’t get a lot of manufacturing people at this kind of event is because we say it’s quality culture, and they naturally think quality means the organizational unit or quality means compliance, and not really product quality, efficiency and operational excellence. So I think quality culture is a good brand, but maybe the brand has to change a little bit. Maybe we need to think about what that branding is, not only to get people to come to conferences, but to be more effective in rolling it out in people, in organizations.”

Drape added, “maybe also just a general question. How many manufacturing people, engineer people ever attend any PDA meeting? We must have those statistics, and is this meeting any different from those? My gut feeling is it probably isn’t, which is different from when you go to an ISPE meeting. They have way more engineering and tech ops people. So I’m not sure it’s only how we title it. I think it’s also the audience that we target.”

PDA’s Chair, Harold Baseman stated from the floor: “That’s a very good point. We do have statistics on that, and, actually, depending on what the subject matter is, we do have a different mix. I will say that at the ISPE meetings we’re seeing more engineering people, design engineering, and so forth, but I’m still not exactly certain that we’re grabbing that other group, that manufacturing group.”

Vinther said it is “very important is make sure you bring somebody. So next time when you come, bring somebody from operations. I’ve done that several times.”

Autor agreed that inviting someone from manufacturing or operations is a great idea, but, “I think it’s like anything else, we have to make a business case.” If you can make a business case to bring colleagues from manufacturing and operations, you will be successful, she added.

It would be impossible to cover all the fantastic dialogue that took place at the 2014 PDA Pharmaceutical Quality Metrics Conference, but from beginning to end, the audience was engaged in helping to flesh out a vision for a new regulatory paradigm based on quality culture.

Reference

1. Villax, G. “FDA Needs to Step it Up.”Chemical & Engineering News 91 (2013): 3 tinyurl.com/kug3q6h