Today, drug manufacturers make many medicines for the U.S. market—including both brand-name and generics—in other countries. To protect patients and consumers, the FDA has programs to address the challenges to drug quality posed by globalization.
Donald D. Ashley, J.D., director of CDER’s Office of Compliance, and Michael Kopcha, Ph.D., R.Ph., director of CDER’s Office of Pharmaceutical Quality, explain the FDA’s work to assure the safety and quality of medicines through strong oversight on a global scale.
What tools does the FDA use to assure that only safe, effective, quality medicines reach patients and consumers?
Kopcha: All drugs must consistently and safely provide their intended benefit. To do this, drug manufacturers must meet quality standards that ensure every dose of a drug is of the appropriate strength and free of contamination and defects. We have a number of tools to ensure drug manufacturers meet quality standards.
Our experts thoroughly assess a drug – and its manufacturing process – before approving it for the market to ensure manufacturers can meet quality standards. But we don’t just look at paper, we audit the production line. In fact, we require an evaluation of the manufacturing facilities prior to drug approval.
Our tools don’t stop at drug approval. We also regularly test products on the market in our state-of-the-art laboratories to confirm they meet quality standards. Our surveillance programs help identify possible problems so manufacturers can address them before they cause potential harm to patients. We conduct regular inspections of drug manufacturing facilities to ensure compliance with our requirements, with a particular focus on the facilities and drugs that have the potential to be the most problematic, based on our scientific expertise. We also conduct inspections specifically to evaluate complaints and allegations made against a manufacturer. If there are reports of defects or recalls, we monitor the manufacturers to ensure they fix the problem in a timely manner.
None of these tools are sufficient on their own, but when used collectively, we have high confidence in the quality of the U.S. drug supply.
How does the FDA know that drugs legally marketed in the United States but made outside of the United States are not of lower quality than drugs made domestically?
Kopcha: The quality of our drug supply is better than ever before. There is no difference in the quality of drugs based only on where they are made. We use the same tools to assure quality whether a drug is manufactured in the United States or abroad. We apply the same quality standards and conduct the same inspections of manufacturing facilities regardless of where they are located – and we inspect all over the globe.
Some regions of the globe do have somewhat higher levels of violations found during inspections, but this is because facilities without a history of regular FDA inspections are likely to be less familiar with our requirements. It is very important to keep in mind that our requirements for these facilities are designed to prevent problems. If an inspection uncovers an issue at a facility, it does not mean there is a defect with the marketed product. Rather, the inspection is meant to assure that there will not be a problem with the quality of a marketed product.
We conducted a major test on marketed products. We bought 323 different drugs sold in the United States but made around the world – including more than 100 generic drugs from India. All samples we tested met the market quality standards regardless of where they were made.
How many manufacturers have quality issues?
Ashley: As Mike mentioned, we prioritize inspections based on the facilities and medicines that have the potential to be the most problematic. We inspect drug manufacturing facilities around the world, and 80 to 90 percent of them – regardless of location – are substantially compliant with our requirements. When we do identify manufacturing issues, we see similar issues in the United States and around the world. We take swift action to protect patients when we find problems that pose a significant risk to patient health.
Some manufacturers are still working on improving their processes. We have been inspecting manufacturing facilities for many decades, but not all types of facilities have been inspected with the same frequency, particularly those making lower risk over-the-counter (OTC) medicines. In the past several years, we have been working to inspect all facilities that had not been previously inspected. This is one of the reasons we have recently seen an uptick in problems identified in facilities making lower-risk OTC medicines.
Generic drugs are more likely to be made outside of the United States. How do you make sure that they are not of lower quality than brand-name drugs?
Kopcha: First, I’d note that it is common for companies to manufacture products for brand and generic drugs in the same facility. Much of the U.S. drug supply originates beyond our borders, and yet the generic drugs on the market today are better than ever before. Generic drugs are as safe and effective as their brand counterparts and have the same quality as brand-name drugs.
Since the start of the Generic Drug User Fee Program in 2012, FDA has hired more than 1,000 additional experts to work specifically on generic drugs. We conduct a more sophisticated and rigorous assessment of generic drug applications than ever before. FDA created the office I lead specifically so that the same people that assess the quality of brand-name drugs also assess the quality of generic drugs. The expectations for quality are the same in both cases.
The FDA conducts inspections of generic drug manufacturing facilities to ensure good manufacturing practices. We monitor brand-name and generic drugs to make sure manufacturers produce safe, effective, quality medicines for patients.
Don’t forget we are patients, too. I trust generic drugs and I take generic drugs.
What happens when the FDA suspects a quality problem?
Ashley: We have several tools available when we suspect quality issues at a drug manufacturing facility. Often, we will conduct an inspection of the facility. Our highly-trained investigators conduct domestic and foreign inspections with the same depth and rigor. We have even conducted unannounced inspections at manufacturing facilities in India and China with FDA investigators based in those countries. For example, if we receive information from a credible informant or a complaint involving allegations of data destruction or manipulation, or our own reviewers identify concerns, we will conduct an unannounced inspection of the facility to investigate the allegations. If we find problems, regardless of whether the facility is domestic or foreign, we immediately take action to address potentially harmful medicine, such as recommending the company recall its medicine if it is already on the U.S. market. If it is a foreign manufacturer, we may put companies on import alert to block potentially unsafe medicines from entering the U.S. market. Import alerts are one of our most effective tools for preventing substandard medicines from reaching U.S. patients.
We also seize medicines from warehouses or manufacturing facilities, issue warning letters to advise a company of their violations of the legal requirements, and test imported medicines at the border to ensure the medicines are what they claim to be. These are just a few of the tools we may use.
All companies are held to the same requirements, and we will continue to take action as necessary and appropriate when manufacturing practices do not meet our requirements.
Does the FDA mainly find problems with the safety or quality of marketed drugs through inspections?
Kopcha: We do not rely solely on inspections to uncover quality issues. We also capture feedback from industry, health care professionals and consumers through reports submitted to MedWatch or the FDA Adverse Event Reporting System (FAERS). After reviewing these reports, we may contact the manufacturer to request additional information about possible safety or quality issues. Our scientists will test samples to see if there is a quality issue with the drug in question. We take all this information seriously, and our scientists routinely review this information to help inform our decisions.
Does FDA work with drug manufacturers to make sure they are aware of FDA requirements for their facilities?
Ashley: As Mike mentioned, prevention is key. Our goal is to identify possible problems so manufacturers can address them before they cause potential harm to patients. This is why we proactively promote compliance through clear communication and collaboration with the pharmaceutical industry. We strive to define clear policies and expectations and deliver impactful outreach and educational trainings for industry personnel on how to comply with the requirements. This collaboration is important in our efforts to shield patients from harm and we want to be certain manufacturers are aware of our requirements and they comply with them. For example, we have conducted trainings for industry in the United States, Europe, India, China, and other parts of the world. We regularly participate in national and international pharmaceutical conferences to provide key insights to improve quality and compliance with FDA requirements.
What should you do if you suspect a problem with the quality of your medicine?
Ashley: If you suspect an issue with the quality of a medicine, please contact us directly via the agency’s MedWatch program. Also contact your health care professional immediately if you have a question about your medicine.