Day Two of the open GPhA Annual Meeting featured a panel on FDA and industry perspectives on a quality culture. Janet Woodcock, M.D., Center Director, Center for Drug Evaluation and Research (CDER) provided the agency’s new vision for quality, turning over 50 years of FDA regulatory inspections on its heels. Woodcock explained that FDA has been taking a closer look at quality and how it is achieved in consumer products. At the core, Woodcock observed, quality is about meeting or exceeding customer needs, so it is customer driven. For pharmaceutical products, this means that the product delivers what is described in the product label and is not contaminated. And the public wants pharmaceutical products to do what they expect them to do and they want the products available and affordable without extra surprises, such as unknown possible adverse effects or quality issues, she added.
Quality issues reflect poorly on FDA and industry, Woodcock said. CDER’s goal is, therefore, to develop a nimble and agile center that can reliably measure quality without extensive oversight, she said. But manufacturers have to own quality from making their products.
Woodcock noted that FDA’s own regulation of quality over time has not been following this truth and instead has been providing “tickets” for quality issues by issuing 483 inspection reports, snapshots of specific quality issues without identifying the real underlying problem. Manufacturers then incorrectly believed their goal was FDA compliance, when the goal should have been to make quality products that are fit for their purpose and reliable.
As a result, FDA is planning to “radically change” to better meet the quality objectives and pull the “right behavioral levers” to drive the industry to where it needs to be. Woodcock acknowledged, however, that some manufacturers do have a quality culture, sent from the CEO down the chain and sometimes back up again. But FDA needs to figure out better ways to move industry there, she said. To achieve the objective, FDA needs to explain the changes and where the agency is going with quality regulation, while at the same time attending to the huge backlog of ANDA applications. Woodcock believes that changes in FDA’s quality reviews will have an impact on the backlog.
FDA’s overall objective is to incentivize fit for purpose drugs without extensive regulatory oversight. Some means to those objectives, Woodcock explained, are: 1) an automation process to add IT support, 2) the Program Alignment Group (PAG) process, and 3) the new Office of Pharmaceutical Quality (OPQ)—all of different time frames. OGD is running on a new IT platform that will be applied to CDER for all new drugs with quality as a big part of it. From GDUFA, FDA has been able to collect information about all manufacturing facilities and has integrated inspections of those facilities to create great visibility in field reports. For example, FDA can look at all reports of broken glass or the inspectional history of a firm. FDA did not have this before, which led to a more random inspection process rather then one driven by certain quality metrics. This IT platform has more analytical capabilities that will be similarly applied to FDA’s ANDA and later NDA reviews, which will take about a year to be fully operational, and is an extensive rehaul that will be enhanced by electronic submissions.
PAG is a process to redesign how ORA operates with CDER, Woodcock described. ORA will specialize its compliance officers and inspectors to particular products, which will magnify their ability to function efficiently and reduce delays between reviews and inspections. CDER is rewriting inspection templates that have been utilized for the past fifty years to move away from merely fixing specific deficiencies to fixing the quality problem driving those deficiencies. FDA now recognizes that its deficiency-citing process played into the continuing problems observed, because it created a culture to merely fix the specific deficiencies observed as a compliance issue. Woodcock said that the initial tests of the new templates and potential for better coordinated reviews and inspections “look pretty good,” but will take a lot of hard work to change, given the fifty-plus-year mindset.
OPQ was established in January 2015 with 1,000 people. OPQ contains all OGD and Office of New Drug (OND) product reviews of quality. Prior to OPQ, CDER had no way to determine the state of quality for the industry, Woodcock described, only snapshots from inspections or 483 reports–and nothing by region, firm, or products. Using GDUFA money and taking over nine months, FDA established an inventory of the manufacturing sites making drugs for distribution in the United States, available right now in 2015. Woodcock said that it took lots of IT and data individuals to reconcile data bases that were “admittedly wrong” and create for the first time a quality baseline by which future manufacturing can be measured. “Most industries trying to achieve quality will have dashboards—critical attributes for quality—that focus on measuring some things,” Woodcock observed. While FDA’s current dashboard is “artisanal”, i.e., done by hand, it will be done by a computer system soon, which FDA hopes all manufacturers will follow on a more granular level internally. FDA plans to put out a guidance to explain this process and provide an opportunity for comment.
Based on this dashboard of relevant quality measures, FDA will gather intelligence to determine which facilities to inspect and how often. In addition, OND will start looking at innovator products from the investigational stage, tracking to post-marketing for a while to help generate critical quality attributes. FDA will then be moving this away from narrowing specifications to identifying clinically-relevant specifications for each product to know what is important to be controlled, including identifying crucial quality attributes for patients’ needs. CDER’s Office of Life Cycle Products will move innovator products to life cycle products, so when it comes to generics, they will understand the product and figure out important parameters for generic products as well. And preapproval OGD inspections will include more input from product review teams with the goal to have the patient experience the same for both generic and the counterpart innovator product.
Woodcock said that quality starts with design of the product, design of process to make the product, and the control strategy to mitigate risks that harms quality. CDER has been looking at failure mode analysis to figure out how to mitigate predictable problems. A quality culture accepts that there will be mistakes and does not blame individuals for identifying weak points but rather seeks means to fix the weaknesses. CDER is taking these quality measures to heart by adopting its own quality culture and identifying a risk-based approach to learn its own quality attributes and how to improve its activities. Without knowing the current state of industry quality, FDA does not know if what is it doing will help or hurt the industry for quality and hopes that its new metrics will enable FDA to determine that.
Woodcock concluded her presentation with a final observation that FDA’s quality initiatives are a journey of several years, with a contemporaneous goal to meet and exceed GDUFA goals. She believes these initiatives ultimately will make industry happy.
In a dialog with the industry panel, it was revealed that GPhA is working on a white paper to provide a unified voice for quality in the industry. As some foreshadowing of the paper, topics that will be addressed include making quality critical for patient safety and product success that is championed by management. Some key elements of the topics include values, ethics, philosophical engagement, senior leadership engagement, employee engagement, governance, and communication.
The panel also discussed continuous manufacturing, asking whether generic companies can do this or only innovators. In a continuous manufacturing system, chemicals are pumped continuously 24/7, into a small channel or tube, typically a few millimeters in diameter, where the chemistry is precisely controlled, so that by the time it leaves the tube, the product is made, so no time is lost to heating, cooling, and discharging. In contrast, batch manufacturing involves discrete processing steps in large quantities at specific times, where the actual manufacture of the product is only a small part of the cycle time and the rest of the time is lost adding ingredients, heating them up, and getting them out to be used in other processing steps, sometimes at other facilities. Woodcock thought that the generic industry has a general lack of knowledge of continuous manufacturing, where there may be many opportunities to utilize such systems. Woodcock said that while continuous manufacturing involves an initial investment including human capital to understand the process, it does not require a lot of equipment, and FDA has advanced manufacturing team that can help manufacturers to understand such processes.
The Meeting closed with its every-popular CEOs unplugged session. Topics in this final session included price competition, company consolidation, potential for self-branding of generics and particularly biosimilars, more vertical integration with active pharmaceutical ingredients, an increasing interest in niche and specialty markets, the need for FDA to deliver on its GDUFA commitments for more timely review not just infrastructure enhancements leading to more rigorous inspections and quality initiatives, a request for more communication with FDA during product reviews, hesitation for FDA’s labeling initiative that could cause be disruptive, more interest in biosimilars, and uncertainty regarding how the biosimilar patent challenges will or will not proceed.
