The latest FDA report card on the quality of drugs being sold in the U.S. is nothing to brag about.
On a grading scale where 90% to 100% is an “A” and anything below 60% is failing, the average manufacturing site inspection score for drugs marketed in the U.S. in fiscal 2019 would be a solid “C” – or 7.4 on the FDA’s 10-point grading scale. But at least 10 sites had failing marks with scores of 5.
Inspection scores are a foundational measure of drug quality, which the FDA defines as being “safe and effective with every dose, free of contamination and defects.” Those sites with the lowest inspection scores also had the highest number of overall recalls. In general, the inspection grade varied depending on where a manufacturing facility is located or whether it produces biologics, branded small molecules or generics. Sites based in India and Latin America averaged the lowest score, a “D+” or 6.8, according to the FDA’s recently released Report on the State of Pharmaceutical Quality.
EU sites manufacturing drugs for the U.S. market earned a C. But with a 7.7, they had the highest score when broken down by location. U.S. drug manufacturing sites were right behind at 7.6. Sites in China earned a “C-” with a score of 7. (See Site inspection scores, below.)
Factoring into the lower scores in India was an assessment of site and process risks related to the formation of N-nitrosodimethylamine (NDMA) and other nitrosamines. Excessive levels of the probable carcinogen has led to the recall of several cardiovascular, heartburn and, now, diabetes drugs.
When grouped by the type of drugs they produce, facilities that manufacture drugs with biologic license applications (BLAs) had the top average grade – a “B,” or 8.2. Facilities that produce only branded small molecules with a new drug application (NDA) averaged a “B-,” or an 8. Facilities manufacturing generics, or drugs with abbreviated new drug applications (ANDAs), had a “C” average – those that produce both NDAs and ANDAs scored a little higher than those that only produce generics.
Nearly one-fourth of the sites inspected were cited for data integrity problems; one in five had issues with lab controls; and about 15% were cited for equipment problems, according to the FDA report.
The site inspection scores, which indicate compliance with current good manufacturing practices, are based on quality inspections conducted over the past 10 years, even though much has changed in how the FDA inspects drug facilities over that time frame. Since 2015, the agency has been conducting more foreign inspections than domestic ones, whereas in the first half of the decade, domestic inspections far outnumbered foreign ones.
While the total number of foreign inspections continue to outpace domestic ones, the FDA is still conducting more inspections in the U.S. than it does in any other individual country. In fiscal 2019, 42% of the sites the FDA inspected were in the U.S., followed by 17% in the EU, 15% in India and 9% in China. (See FDA drug manufacturing site inspections and Change in percentage of annual drug manufacturing site inspections performed by FDA, below.)
For the most part, those percentages reflect the proportion of manufacturing facilities in each country. But as was pointed out during a Senate Finance Committee hearing a few weeks ago, the number of facilities don’t reflect the volume or numbers of active pharmaceutical ingredients and finished dosage forms being produced in each country for the U.S. market.
Also, inequities remain with how the FDA inspects foreign facilities vs. domestics ones, according to a Government Accountability Office (GAO) report released earlier this month. All domestic inspections, except pre-approvals, are unannounced, but foreign facilities are usually given up to 12 weeks’ advance notice of an FDA inspection, the GAO said.
While important, inspection reports aren’t the only determiner of drug quality. The FDA also considers the quality defect reports it receives about individual drugs from industry, health care providers and consumers. Those reports, which include Medwatch reports and field alert reports (FARs), vary by therapeutic space. For instance, although immunological products account for just 2.1% of all approved prescription drugs in the U.S., they account for 19% of all product quality defect reports, according to the FDA. Many of those complaints are related to the devices used to administer the drugs.
Last year, 145 products had more than eight Medwatch reports with identifiable trends but no FARs, the FDA said. Of those, 69% were generic drugs, which make up 90% of U.S. prescriptions, and 31% were NDAs. (Whereas manufacturers are required to issue a FAR within three days of receiving information about significant quality problems with a distributed drug, the Medwatch program collects data from health care providers and patients.)
In addition to inspections and its reporting programs, the FDA routinely samples and tests marketed drugs for conformance to manufacturing specifications. Noncompliance has followed trends over the years, due in part to what the FDA is testing for at the time. Recent concerns about NDMA levels led to more FDA testing of cardiovascular drugs over the past two years. (See Noncompliant testing results of sampled products, below.)
As a result, cardiovascular drugs were the most recalled drug class in fiscal 2019. Of the recalls in that class, 52% were related to nitrosamine impurities, the FDA said.