Over the past 25 years, globalization of drug manufacturing has prompted the FDA to change its regulatory landscape. The shift to overseas production of U.S. goods, including some drugs and their components, predominantly occurred in the early 2000s. It added new complexities to our supply chain. This required the FDA to take different steps to ensure that our drug manufacturing surveillance program kept pace with the evolving landscape and make sure consumers continued to receive safe and effective drug products.
We’ve established a framework to help assure that drug products all meet the same high-quality standards, regardless of where they’re manufactured; and whether they’re brand name or generic products, or prescription or over-the-counter drugs. Today, we’re announcing several steps that improve on that effort.
Helping assure the quality and safety of globally produced products requires a variety of efforts at different times throughout the lifecycle of a drug’s manufacturing and finishing. Our inspections and surveillance of manufacturing facilities are an integral part of this oversight. We need to make sure that our inspections are prioritized based on potential risks to patients, and that we’re using our resources efficiently.
Today, to add greater transparency around our site selection model, we’re publishing our internal policy for how manufacturing facilities are prioritized and scheduled for surveillance inspections. Our policy explains how a facility’s compliance history, recall trends, time since last inspection, inherent risk of the drug being manufactured, processing complexity and other factors are all weighed and considered.
The FDA prioritizes inspections of sites regardless of their location. For manufacturing facilities in other countries, inspections may be conducted by staff in foreign offices, those on temporary duty assignments, or staff that travel internationally to conduct the inspection. In addition, to maximize resources and efficiency, we’ve also pursued opportunities to collaborate with other countries. With our announcement last year concerning the Mutual Recognition Agreement with the EU, we’ve ensured that we can recognize the drug inspections conducted by foreign regulatory authorities that meet U.S. requirements. In doing so, we’re able to dedicate more of our investigators’ time to those sites that pose the greatest risk.
The FDA’s inspections program is a large-scale endeavor. As of Fiscal Year 2017, there were about 5,063 human pharmaceutical sites worldwide subject to routine surveillance inspection – 3,025 of those were foreign-based. For that year, the FDA conducted 1,453 drug surveillance inspections, including 762 on foreign soil, to ensure manufacturers were following Current Good Manufacturing Practice (CGMP) requirements and maintaining high quality standards. To accomplish this critical work, we need to maximize our resources around the globe, which is why the FDA uses a risk-based site selection model to ensure that inspectional resources are allocated in the most efficient and appropriate manner to protect patient health. The risk-based site selection model is structured so that the inspection frequency for all facilities, regardless of where the facility is located, prioritizes our inspections of sites where the drug being produced and the manufacturing processes used pose the greatest potential risk for problems that could harm patients.
In addition to identifying the facilities of greatest risk and prioritizing those inspections, the FDA has also made efforts to ensure our resources are effectively deployed to address inspection demands. Last year, for example, we modernized the structure of our field organization, including inspection operations, to direct our focus and organization around the types of programs we regulate. Previously, we had organized our field activities and resources based on geographic regions. The new structure, which focuses resources based on areas of specialization, allows us to better align the expertise of our staff with our commitments.
But it’s important to note that inspections are not the only way we work to ensure product quality. For example, we provide guidance documents on a range of quality issues, from pharmaceutical development through commercial manufacturing and quality control, on original application submissions and on making changes after approval, addressing active ingredients and finished product. We also obtain drug samples and test drugs from various sources each year to evaluate aspects of quality that can be analytically measured and verified. It’s also important that we’re transparent about inspection outcomes.
Following each inspection, the FDA assesses the significance of the findings leading to a final classification into one of three categories – no action indicated, which means the agency found no objectionable conditions during the inspection; voluntary action indicated, which means the agency found objectionable conditions, but we are not recommending regulatory action at this time; or official action indicated, which means the agency found objectionable conditions and may pursue regulatory action.
The agency recently updated its inspections classifications database, which provides the most recent classifications of inspections of manufacturing facilities conducted for routine CGMP surveillance purposes or inspections of sites conducting bioequivalence/bioavailability studies. The database provides transparency to the industry, the general public, and other regulators into the outcomes of recent observations. The database has also been updated to build on our progress implementing the Mutual Recognition Agreement with the European Union, and now supports inclusion of facility status based on classification of inspection reports from recognized foreign regulatory authorities.
FDA carried out these updates well ahead of our scheduled commitment under the reauthorized Generic Drug User Fee Amendments (GDUFA II) to perform the updates by 2019. The agency went beyond the commitment to provide timely updates regarding generic drug manufacturing facilities – as the database is updated every 30 days with classifications for inspections for all FDA regulated products, not just generic drugs. While we take effort to ensure transparency, it’s important to note that the numbers from our database don’t account for all of the inspections that the FDA conducts at any given time. These are a subset of inspections that have received a final classification. We classify inspections on a rolling basis after taking a thorough look at all the relevant information available. So there’s a lag between the performance of an inspection and the final classification. Communicating information from inspections in a timely way is a priority. We are continually seeking to refine this process.
Ensuring quality standards are met
When objectionable conditions are identified with manufacturing processes or controls, creating a risk of potentially producing an unsafe product, it’s important that the problems are quickly remedied.
What we find is that the majority of firms – both in the U.S. and overseas – are operating within the standards U.S. patients deserve and that meet our standards. When needed though, we exercise our regulatory authority commensurate with the assessed risk, including issuing import alerts, warning letters, and in the most serious cases, working with firms as they recall drugs, seizing drugs in commerce or enjoining manufacturers to prevent further violations. We will continue to remain vigilant in our compliance and enforcement work, and we’ve taken a number of actions already this year.
We’ve enhanced our communications about inspections to facility owners to enable quicker resolution of situations where quality standards are not being met. For example, efficiencies from a Concept of Operations agreement the FDA implemented last year have enabled us to communicate inspection classification information to facility owners within 90 days of the close of a surveillance inspection, a significant improvement from past timelines. We’ve also established procedures to notify applicants when we identify issues during our premarket inspections that could impact approvability of a new drug application by communicating through an information request, discipline review letter or complete response letter. By discovering issues before the production process commences, we’re able to assist companies to circumvent future issues before they occur and help get quality products to patients more efficiently.
Harmonization and fostering technological advancements
In addition to these efforts, cooperation and harmonization with other foreign regulators are critical to ensuring that the drug supply produced outside the U.S. meets our safety and efficacy standards. To advance these goals, we participate in the Pharmaceutical Inspection Co-Operation Scheme (PIC/S), which focuses on harmonizing how inspections are conducted. We also participate in the International Council for Harmonisation (ICH), which is a global body established to facilitate international collaboration that’s been successful in standardizing and elevating drug development practices and quality standards throughout the world. The goal is to ensure companies maintain a level of quality throughout the product lifecycle.
Having the same standards across multiple regulatory agencies makes it easier for manufacturers to ensure compliance with quality standards. This approach reduces the burden from having to implement different sets of requirements. This is also an important role of our foreign offices – to establish relationships with foreign regulators and to build our intelligence regarding these markets so we can target higher risk firms.
We’re also committed to fostering more advanced manufacturing practices, such as continuous manufacturing, that encompass advanced manufacturing technologies, implemented in a way that leads to more innovative, consistent and dependable manufacturing of drug and biological products. These technologies have the potential to help establish more reliable supply of drug and biological products by reducing manufacturing failures that can cause supply disruptions and drug shortages. Just this month, we awarded grants to three research institutions in efforts to adopt this pioneering technology more widely. We’ll continue to advance efforts to support the effective utilization of these new platforms.
We’ll continue to take new steps to address the challenges posed by a globalized drug supply chain. These actions are key parts of our commitment to ensure high-quality manufacturing, and to make sure Americans have confidence in the quality of products sold in the U.S. regardless of where a drug is manufactured.