So far, in 2017, the Food and Drug Administration’s Office of Manufacturing Quality in the Center for Drug Evaluation and Research has released fourteen Warning Letters. Of these, 100% involved manufacturing facilities outside the United States; seven to Chinese sites, one to a British firm, one to an Italian facility, three to Indian companies, and two to Japanese locations. While it is too early in the year to assess whether this reflects an increased FDA focus on foreign inspections, companies should take note if they have manufacturing sites outside of the U.S. or utilize contract manufacturers in other countries.
We will not review in detail all fourteen Warning Letters publicly released by CDER’s Office of Manufacturing Quality. We will note that, while the agency issued the letters in 2017, most of the non-compliance activities occurred in 2016. All of the Warning Letters involved violations of current Good Manufacturing Practices and adulteration of drug products. More than half of the actions related to manufacturing of active pharmaceutical ingredients; the others related to finished pharmaceuticals. It’s almost like double vision.
- Companies must audit all facilities they use for compliance with FDA requirements. This involves all sites, whether an API or finished pharmaceutical facility, whether domestic or foreign, or whether it is its own company plant or a third-party firm.
- Regular auditing and monitoring of foreign firms, in addition to the execution of quality agreements, may help maximize regulatory compliance and minimize commercial disruptions. No one wants a blue morning or a blue day.
- A foreign site’s non-compliance can result in a Warning Letter, as we have noted here. There can be other consequences, which could have other significant commercial impact. For example, FDA could issue an Import Alert, whereby products are held at the U.S. border until FDA is comfortable with the company’s compliance. In addition, the agency can delay approval of pending marketing applications for violations relating to quality concerns. These actions require urgent attention and can lead to a financial emergency (if you are following the underlying musical theme in this Bulletin).
- Many countries have different regulatory and quality standards from those required by FDA. Companies cannot merely rely on a foreign firm’s assertion that it passed its most recent local or country governmental inspection. While it is a positive development, a good report card in one case does not guarantee a passing grade from FDA.
- FDA’s Office of International Programs has foreign posts in China, Europe, India, and Latin America. These posts, and their specific locations, reflect the agency’s awareness that many products intended for the U.S. are manufactured outside of this country. It also allows FDA to expend more time and resources at ex-U.S. facilities to ensure compliance. FDA isn’t playing head games with industry; its intentions are clear.
- A GMP problem at a foreign establishment may lead to increased scrutiny at the U.S. manufacturing facilities of the same company.
- It may feel like the first time that FDA has increased its enforcement activity against manufacturing sites outside of the U.S. It is not. The number of publicly-released Warning Letters issued in 2017 is, indeed, noteworthy. However, FDA has stated over the years that, resources permitting, it intends to continue its inspectional scrutiny of sites located outside the country, particularly as companies rely more on those facilities to manufacture their products.