A main goal for FDA officials in 2014 is to establish a sounder basis for ensuring that drugs and biotech therapies meet high quality standards throughout the product lifecycle. The ongoing crisis in drug shortages has heightened public awareness to the importance of manufacturing operations in maintaining reliable access to needed therapies. Deaths and sickness from substandard products made by less-regulated pharmacy compounders persuaded Congress to bolster FDA authority to prevent such failings, and to require a more effective electronic tracking system to keep unauthorized and counterfeit drugs out of the global supply chain.
Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), has made drug quality a top priority for 2014. To meet legislative requirements to improve systems for preventing drug shortages, CDER has been discussing options for more comprehensive collection of quality data at numerous industry meetings this past year (1). The process for establishing informative drug-quality metrics was a main topic at the Parenteral Drug Association (PDA)/FDA Regulatory Conference in September 2013, the Generic Pharmaceutical Association’s (GPhA) October Technical Conference, and the annual meeting in November 2013 of the International Society for Pharmaceutical Engineers (ISPE). PDA sponsored a Pharmaceutical Quality Metrics conference in December 2013 specifically to reach agreement with FDA officials on a “points to consider” document on the subject.
FDA officials cite the FDA Safety and Innovation Act (FDASIA) of 2012 for providing a firm legal basis for setting clearer standards and for collecting data to assess manufacturing operations. Section 705 of FDASIA requires FDA to establish a risk-based schedule for inspecting drug manufacturing sites, which requires access to more detailed information on facilities and quality controls. Section 706 of the bill authorizes the agency to obtain information on drug production sites and operations in advance of an inspection (2). Together, these provisions support FDA’s strategy for improving how it assesses the ability of a manufacturing site to consistently produce medicines fit for intended use.
CDER officials emphasize that they are not asking industry for new and unknown information, but for access to system performance data already collected by manufacturers for internal use. Routine company metrics include number of lot release tests, out-of-specification results, and lots attempted, rejected, reworked, and reprocessed. Such manufacturing information generally appears in company annual product reviews that are made available to site investigators when requested. But that is too late to support CDER planning for inspections and postmarketing oversight, noted Russell Wesdyk, scientific coordinator in CDER’s Office of Strategic Programs, at the GPhA conference. And each company tends to collect data in its own way, using a range of definitions and sampling plans. FDA anticipates that standard metrics would reduce differences in how firms define “batch,” “lot,” and even “rejection.”
CDER now, consequently, has to assess the risk level of a manufacturing site based primarily on its compliance history, as seen in warning letters and field reports, plus records on recalls and quality problems. But these are not the most informative measures, said Wesdyk. More relevant data provided in advance would better determine the need for an actual site visit, as well as risk factors that might predict future drug shortages and other quality problems. The aim is not to issue “restaurant-style grades,” Wesdyk emphasized, but to provide broad results of industry performance so that companies can see where they stand relative to their peers.
To establish this more informative drug quality data analysis system, FDA has embarked on a broad initiative to define the “right” metrics to collect and audit. Agency officials and industry executives involved with plant management, quality control, and regulatory compliance are examining how to analyze different quality measures and how this information should be provided to regulators to support FDA risk assessment and to help firms improve quality. There is interest in examining how company culture can shape these efforts, plus concerns about the unintended consequences of selecting the wrong metrics. A company might try to speed up lot closeout, for example, if there’s more focus on measuring batch cycle time. Review of complaint trending might lead firms to resolve problems superficially without getting to root causes.
These discussions support FDA efforts to develop guidance on quality metrics, which will be open for comment and feedback and should spur development of further consensus documents. Based on all this input, FDA hopes to define initial metrics by the end of 2014, setting the stage for collecting quality metrics from industry in 2015.
Clear incentives for manufacturers to achieve higher quality production also are part of the discussion. Industry has been disappointed with past FDA quality initiatives partly because the agency granted little regulatory relief to companies that invested in often costly quality improvement efforts. FDA failed to curb requirements for regulating postmarketing changes or to reduce inspections. Now CDER leaders indicate that more complete information on establishments could lead to less frequent field inspections at firms that can document a site’s quality achievement, and there could be reduced supplement-filing requirements for low-risk manufacturing changes.
New quality organization
These initiatives will be supported and managed by a new Office of Product Quality (OPQ) in CDER, which Woodcock expects to become operational this year under her personal direction. It’s “not a done deal,” Woodcock cautioned at the ISPE meeting, but plans are moving forward, and she anticipates that the new organization will “become real” in the coming months.
A goal for OPQ is to establish “one voice for how FDA regulates drug quality”--for new molecules, generic drugs, over-the-counter products, biotech therapies, and small molecules alike. A main theme is to unify review and inspection so they can work together to ensure quality production through a product’s lifecycle. A review and inspection unit, for example, will oversee APIs. Specialists for new drugs may be grouped by clinical indications, while those monitoring generics may be organized according to dosage forms. Microbiologists for all products will be combined to provide a unified approach to microbiology.
An Office of Surveillance in OPQ will manage inspections based on a complete inventory of facilities, plus metrics to assess performance and to identify quality operations--all supported by extensive information systems. And a central Policy Office will issue guidance and regulations and strive for more consistency in CDER actions.
“We have to be predictable and consistent,” Woodcock emphasized at the ISPE meeting. She noted that more modern regulation of manufacturing is crucial for FDA to meet new user-fee goals, to accelerate the development of breakthrough therapies and biosimilars, to prevent drug shortages, and to further harmonize regulatory requirements around the world. At the same time, FDA looks to provide industry with flexibility in achieving standards for review and inspection.
Regulators don’t make drugs, Woodcock observed, but can set the goal posts, encourage improvement, and hold industry accountable. In addition to establishing performance metrics that FDA can use to assess risk, the agency wants to encourage continuous improvement by industry. Manufacturers, Woodcock noted, have to recognize that there is a “cost to poor quality.”