The FDA continues to receive questions from the public about the ongoing investigation into the nitrosamine impurities found in the ARB class of medicines, particularly around the complex nature of the root cause of the impurities and their detection. In the interest of transparency and to advance the public understanding of this scientific and public health issue, we are sharing the below frequently asked questions. More information can be found here.
Q: When did FDA first find out about this issue?
A: As shared in a statement issued last summer, a U.S. manufacturer of valsartan products, Prinston Pharmaceuticals Inc., contacted the FDA on June 19, 2018 about its products containing valsartan active pharmaceutical ingredient (API) manufactured by Zhejiang Huahai Pharmaceutical Co. (ZHP). Prinston informed CDER that they had stopped making valsartan products because ZHP had detected an impurity in the API – a chemical known as N-nitrosodimethylamine (NDMA). NDMA is a probable cancer-causing chemical found in trace amounts in water and some foods. However, the levels of NDMA in ZHP’s valsartan API – while still trace amounts – were unacceptable.
Shortly after initiating our investigation, we learned that a foreign regulator was also reviewing medications containing valsartan API manufactured by ZHP and considering a recall. We have closely coordinated with the European Medicines Agency, European Directorate for the Quality of Medicines, Swissmedic, Regulatory Operations and Regions Branch and Therapeutic Products Directorate of Health Canada, and the Pharmaceuticals and Medical Devices Agency in Japan since that time, sharing information about our investigation with them and other regulatory bodies and learning about their findings.
We recognized that we had to find answers to several important questions: How many U.S. valsartan products are affected? Where did the impurity come from? What are the potential health consequences of the impurity? How many patients are affected? How long have patients been exposed to NDMA or other nitrosamine impurities? How do we ensure that patients and providers are informed so that health care is minimally disrupted? How do we prevent drug shortages? And could other ARBs contain nitrosamine impurities?
Our first priority was to inform patients and health care providers.
Updates on this issue are available on our website.
Q: The FDA inspected Zhejiang Huahai Pharmaceutical's facility that manufactures valsartan API in 2017, and again in 2018 after the agency learned of the NDMA impurity in ARBs. The 2018 inspection resulted in the agency placing the facility on import alert and issuing a warning letter. What was different between the 2017 and 2018 inspections? Why didn’t FDA find the nitrosamine impurities earlier?
A: The FDA inspects facilities for a variety of reasons, including during the drug approval process, for surveillance purposes and when we learn of a potential issue in a facility (for cause). There are also many factors that inform the FDA’s decisions at a given time regarding what action to take following an inspection. We make those decisions in the interest of patient safety based on all information available to us, including evidence collected during an FDA inspection and a manufacturer’s proposed corrective actions. The 2017 inspection uncovered some quality control issues, including a failure to adequately investigate unidentified impurities, but FDA’s inspectional observations during the 2017 inspection related to analytical tests performed by ZHP where nitrosamine impurities would not normally have been detected.
As we do after all inspections, the FDA reviewed the inspectional observations, and considered the company’s proposed corrective actions when deciding what action to take to ensure the proposed corrective steps were adequate to protect the public health.
When the agency learned that NDMA was present in valsartan APIs produced by ZHP, as well as other manufacturers, the FDA initiated a for-cause inspection to investigate the root cause of the NDMA in the valsartan API produced by ZHP and other manufacturers. As a result of one of the for-cause inspections, the FDA placed ZHP on import alert and issued them a warning letter outlining several manufacturing violations, including a lack of impurity controls, change controls and cross contamination from one manufacturing process line to another.
While we are still investigating the root cause of the nitrosamine impurities, based upon evidence gathered thus far, we believe these impurities present in angiotensin II receptor blockers (ARB)-containing products, including valsartan, losartan and irbesartan, are likely generated when specific chemicals and reaction conditions are present in the manufacturing process of the API. These impurities may also result from the reuse of materials, such as solvents, during the API manufacturing process.
The chemical properties of nitrosamine impurities in these active pharmaceutical ingredients make them difficult to detect. During an inspection, the FDA reviews the manufacturers’ impurity test records and depends on manufacturers conducting appropriate tests that are capable of identifying a particular impurity. It is the manufacturer’s responsibility to understand and assess their manufacturing process, assess any changes to that process and, based on that assessment and understanding, ensure test methods utilized can detect impurities expected to develop during the manufacturing process. When the issue was discovered in 2018, the FDA developed and posted tests that were capable of identifying nitrosamine impurities in ARBs.
Before this investigation, it was unclear that nitrosamine impurities could be formed during the specific ARB API manufacturing process. The FDA has since been working with ARB API manufacturers to put strategies in place to minimize or eliminate the process risk for the formation of nitrosamine impurities, in addition to the long-standing requirement to test their drugs for impurities to assure medications are safe for patients.
Q: Is FDA increasing its inspections in China and India to avoid these issues in the future given the issues found at Zhejiang Huahai and other ARB manufacturers?
A: FDA surveillance inspections are always prioritized according to a risk-based assessment that includes consideration of the facilities, the products manufactured and the potential risk to patients they pose.
As part of our response to the impurities found in ARBs, we have launched a comprehensive and thorough investigation into the ARB class, including inspections of facilities that manufacture these drug products and their components. The shift you’d expect to see as a result would not necessarily be of facilities in China and India, but of those facilities that make ARBs and their components. We remain confident in the use of the FDA’s current risk-based approach, which does not include geographic location as a risk factor and in our continuing ability to protect patients from products that have the potential to cause harm.
Q: How does the FDA use inspections to ensure product quality for drugs with such a large scope of manufacturing worldwide?
A: First, it may be helpful to share how we look at our surveillance program in the context of our oversight of product quality generally. Here is how our risk-based inspection program works:
The Food and Drug Administration Safety and Innovation Act (FDASIA) signed into law in 2012 replaced the fixed minimum inspection interval for domestic establishments with the requirement that the FDA inspect domestic and foreign drug establishments “in accordance with a risk-based schedule” that considers establishments’ “known safety risks.”
This defined a risk-based inspection frequency for all sites, regardless of location, to promote parity in inspectional coverage and the effective and efficient use of FDA resources to address the most significant public health risks.
One goal of the site selection model is to achieve parity in inspection frequency, meaning equal frequency for sites with equivalent risk, regardless of geography (foreign versus domestic), or product type (e.g., whether originator, generic, or OTC monograph).
Risk factors used in the site selection model are consistent with section 510 of the Federal Food, Drug & Cosmetic Act. This provision identifies specific risk factors and allows the FDA to determine additional ones. The risk factors considered in the model are as follows:
- The compliance history of the establishment.
- The record, history, and nature of recalls linked to the establishment.
- The inherent risk of the drug manufactured, prepared, propagated, compounded, or processed at the establishment.
- he inspection frequency and history of the establishment, including whether the establishment has been inspected pursuant to section 704 within the last 4 years.
- Whether the establishment has been inspected by a foreign government or an agency of a foreign government recognized under section 809.
- Any other criteria deemed necessary and appropriate by the Secretary for purposes of allocating inspection resources.
The number of sites assigned for routine surveillance inspection in a given year varies depending on FDA capacity as determined by multiyear resource planning with FDA’s Office of Regulatory Affairs, the primary inspectorate of the FDA.
Goals of the surveillance inspection program, as defined in Compliance Program 7356.002, are to ensure that sites consistently manufacture drug products of acceptable quality and minimize consumers’ exposure to adulterated drug products. The FDA’s inspection programs also provide guidelines to investigators on the depth and scope of each type of inspection.
Thus, while the site selection model defines relative frequency of inspections based on statutorily identified risk factors, the amount of time and effort FDA investigators expend on a given surveillance inspection depends on other risk factors considered during inspection planning and performance as guided by our inspection programs (i.e., Compliance Programs).
Additionally, the FDA’s efforts to ensure product quality are broader than just who we inspect and how:
- The agency offers resources to assist applicants and sponsors ensure drug quality across the product lifecycle. This includes providing 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. Guidance is available that describes how to meet with the FDA, communicate and submit applications and revisions, and provides many ways to engage with the agency to ensure their manufacturing processes meet the standards.
- The FDA makes Compliance Programs and key procedural documents publicly available to give industry and the public, transparency as to how we operate and to provide confidence in our objectivity and consistency.
- The FDA also conducts a thorough assessment of applications prior to approval, including the process and facility information provided in the submission. FDA reviews and monitors changes to approved applications to ensure products remain as safe and effective as when originally approved.
- The agency also monitors and responds to product quality concerns from a variety of sources, including Field Alert Reports submitted by industry, as well as other reports from healthcare providers and consumers.
- The FDA samples and tests drugs from various sources each year to evaluate aspects of quality that can be analytically measured and verified.
- The agency works with other government agencies, domestic and foreign, so that any drug quality problem can be evaluated as to impact on consumers and properly addressed.
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The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.