It is widely agreed that pharmaceuticals should be manufactured to a high standard of quality, because they are frequently critical to human health, and because the consequences of quality problems such as sub-potency, lack of sterility, or product mix-ups can be so devastating. Nevertheless, the U.S. Food and Drug Administration (FDA) continues to see major problems in pharmaceutical manufacturing. And these are not limited to one industry sector. We have recently encountered problems at multiple domestic facilities, as well as ex-U.S. sites; we find manufacturing problems affecting over-the-counter as well as branded and generic prescription drugs; large multi-nationals as well as small firms are implicated, and biologics as well as traditional drugs have been involved.
In many of these recent cases, the consequences for the manufacturer have been serious. In addition to the costs of recalls and lost sales, lines or whole facilities often must be shut down for remediation, prolonging the gap in production. Some firms may lose the ability to access the U.S. market. There also can be serious reputational consequences for companies that must recall their products and then are unable to supply their customers for an extended period.
Manufacturing problems also may have serious consequences for patients, prescribers, and consumers. The recent drug shortage crisis exemplifies one set of consequences. For decades, the health care community and patients have taken the traditionally high-quality, reliable U.S. drug supply for granted. Currently, some essential drugs needed to treat life-threatening conditions are unavailable or in very short supply. The clinical community has been shocked by this situation. Congress, the Administration, and the media have expressed a tremendous amount of anxiety and concern about drug shortages. Many of these shortages have been driven by drug manufacturing quality failures, bringing this issue into the spotlight. Shortages of essential drugs can result in serious health consequences, as patients' treatments may be delayed, or physicians may be forced to use a less desirable alternative, for example, as cancer therapy. Less commonly, drug quality problems may directly lead to adverse health consequences, for example, when a patient receives the wrong drug due to a mix-up in packaging.
The FDA continues to respond to poor manufacturing practices via compliance and enforcement actions, but clearly the responsibility for maintaining quality rests squarely with the manufacturers themselves. In response to this ongoing cluster of problems, it may be time to step back and try to uncover the root causes of this seemingly intractable issue. The widespread and successful adoption of six sigma and related quality management techniques in other manufacturing sectors would imply that reliable, high-quality manufacturing is also attainable in the pharmaceutical sector. We must ask ourselves, in an area where the stakes are so high, why is this not being achieved?
In the mid-late 1990s, the U.S. experienced a striking cluster of manufacturing failures and related enforcement actions, including government legal interventions such as injunctions and consent decrees. Subsequently, in the early 2000s, the FDA undertook an evaluation of the situation. It was obvious that, despite significant FDA inspectional and compliance activities, the quality of pharmaceutical manufacturing was uneven and substandard practices were not uncommon. After much deliberation and consultation, the FDA concluded that the state of manufacturing science in the pharmaceutical sector needed to be improved. It was also clear that the extensive regulatory oversight of the sector had impeded innovation. On the other hand, it was obvious that, for the innovator side of the industry, manufacturing was not a management priority compared to the research and development enterprise. Senior manufacturing executives told us that manufacturing had “second class” status in the firms. More surprisingly, we learned that manufacturing excellence was not viewed as a competitive advantage in the generic drug sector.
As a result of these findings, we initiated the Pharmaceutical Quality for the 21st Century Initiative. This project stressed adoption of new science and technology in pharmaceutical manufacturing, and also focused on the adoption of comprehensive quality management systems with the capacity to fully oversee quality without regulatory interventions. The initiative eventually led to a number of changes, including:
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New harmonized ICH guidances related to pharmaceutical development, quality risk management, and pharmaceutical quality systems (ICH Q8, 9, and 10)
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Formation of a Pharmaceutical Inspectorate in the Office of Regulatory Affairs (the FDA's field organization)
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Changes to FDA's chemistry, manufacturing and controls (CMC) review process
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A focus on manufacturing science
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○ FDA's Quality by Design (QbD) Initiative
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○ Increasing academic participation in scientific projects
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○ Greater industry uptake (e.g., adoption of QbD)
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While it is clear that these steps were successful in both in launching a new emphasis on the science of drug manufacturing, and a new emphasis on quality management, they clearly were not sufficient and the needed improvements were not uniformly adopted by the industry. A new evaluation will need to focus not only on science, but also on the role of regulation and any other factors that could provide the impetus for adherence to a needed level of quality management.
That said, scientific advances in pharmaceutical manufacturing, which hold so much promise, should continue to move forward. For example, during the initial discussions of process analytical technology over a decade ago, there was great concern that the FDA would not accept use of such technology. In fact, some industry scientists flatly stated their view that it would not be allowed by the regulators. Additionally, there was worry that no vendors could be found, as such equipment was rarely used in the sector. The recent International Forum on Process Analytical Technology meeting on January 22–26, 2012, which drew many hundreds of attendees, including FDA staff, and vendors, all eager to discuss the latest science and applications of the technology, is evidence that these fears were needless.
Despite the profound changes that have occurred, I believe it is likely that manufacturers are continuing to perform many activities that are unnecessary for maintaining product quality. These are performed because of lack of knowledge about critical quality attributes and the impact of the manufacturing process on these attributes, and also because of regulatory requirements that are implicated when a knowledge gap exists. I also believe that, conversely, many activities that would achieve optimum results are not performed, often because of the investment of time and resources that would be required. Therefore, there is a lot of room for improvement. A more thorough scientific understanding of factors affecting drug product quality could significantly boost manufacturing efficiency and reliability.
What about the regulators? What is the purpose of various activities performed by FDA staff, and how might they be optimized?
New and generic drugs undergo a CMC review during the initial application stage and for certain manufacturing changes. The purpose of this review is twofold. First, reviewers are assessing if the product performance is acceptable. For example, is it stable over the dating period? Are impurities acceptably controlled? Does it have acceptable content uniformity? If performance is acceptable, the second question is, does the manufacturer have a control strategy that will keep it acceptable? This includes acceptance procedures, process controls, and end-product testing. For manufacturers filing a QbD submission, is the design space scientifically supported? In general, I believe that regulators should not have preconceptions about the types of control strategies implemented by manufacturers, but rather should evaluate the scientific data that support them.
Subsequent to the CMC review, the FDA may perform a pre-approval inspection of the manufacturing site(s). The purpose of this inspection is to evaluate if the control strategy outlined in the application has actually been implemented, and if so, whether it is successful, and also to evaluate the physical state of the facility and its ability to support the control strategy. This inspection, and subsequent surveillance inspections, will also assess the site's quality management system, to determine if it is properly detecting and dealing with deviations.
A large number of recent manufacturing failures can be traced to failures of the firm's quality management system. In some cases, the quality management system ignored or failed to follow up on customer complaints. In other cases, multiple repeated deviations were treated as separate incidents rather than an obvious trend. Another recurring theme has been investigations “to nowhere”—investigations that end with no additional understanding or insight into why the problem may have occurred, and thus no hope for prevention. All of these failures suggest a QMS that is insufficiently empowered or resourced to adequately carry out its essential functions. This issue will need to be a focus for the FDA in evaluating additional steps it might take in response to the recent spate of manufacturing problems.
The FDA must continue to evaluate its review, inspectional, and enforcement practices to make sure they are maximally effective and not unnecessarily burdensome. Over the last year, the Center for Drug Evaluation and Research has re-constituted the Council for Pharmaceutical Quality. One task of the council will be to evaluate the effectiveness of drug quality regulation. The FDA is also keenly aware that it must work in concert with the international drug regulatory community, as pharmaceutical manufacturing is a global activity.
Another area of concern for both regulators and pharmaceutical manufacturers worldwide is the growing threat to both supply and distribution chains. Criminal incursions in these chains pose an ever-increasing threat to the quality of the drug supply. Ongoing discussion of ways to better manage these chains is expected. While management and tracking strategies are very important, scientific advances can also contribute significantly, especially on the supply side, and should not be neglected.
In summary, while much progress in the science of pharmaceutical quality has been made in the last decade, significant challenges remain. It is likely that some manufacturers will continue to aggressively adopt modern manufacturing science and quality management, and will be able to maintain a reliable level of high quality without regulatory interventions. Others will continue to “skate close to the edge,” risking catastrophic quality failures. Regulators must learn how to incentivize and reward the former, while devising new strategies deal with the latter, to ensure that all drugs entering the health care system have acceptable quality.
- © PDA, Inc. 2012
