OPQ Reports on State of Drug Quality in FY2018

In a report released Monday, the US Food and Drug Administration’s (FDA) Office of Pharmaceutical Quality (OPQ) provides a look at the pharmaceutical quality landscape for drugs and biologics intended for the US market.
 
The report itself breaks down different metrics related to product quality and manufacturer compliance with current good manufacturing practice (cGMP) to paint a picture of the overall pharmaceutical quality landscape.
 
While FDA reports an overall positive impression of pharmaceutical quality in the US, the report comes as the agency faces criticism over the quality of generic drugs made in China and India.
 
Manufacturer Demographics
 
According to FDA, there were 4,676 registered drug manufacturing sites in its catalogue, excluding medical gas suppliers, compounders and outsourcing facilities.
 
Fifty-eight percent of those facilities manufacture one or more approved drug or biologic intended for the US market.
 
“Of the sites manufacturing application products, a large percentage (46%) manufactures products of both new drug applications (NDAs) and abbreviated new drug applications (ANDAs),” FDA writes.
 
The remaining 42% are considered “no application” sites, meaning they manufacture products that do not require premarket approval such as over-the-counter (OTC) monograph, unapproved or homeopathic products.
 
FDA says it observed a 29.7% increase in the number of registered no application sites in FY2018, which “highlights the importance of postmarket surveillance of these sites as the products and sites do not receive premarket review.”
 
Seventy percent of drug manufacturers registered with FDA in FY2018 were based in the US, India, China, South Korea and Germany.
 
The report notes that FDA de-registered a large number of manufacturing sites in Asia in FY2018 as those sites did not manufacture any products intended for the US market, including 110 sites in South Korea alone.
 
FDA also says it observed a 32.8% jump in the number of registered packaging and labeling sites in FY2018, which it says may indicate an increase in outsourcing operations.
 
Another finding in the report is that the top three registered manufacturing sites by number of individual listed products in the US, China and India in FY2008 accounted for 9.5%, 11.2% and 12% of all listed products manufactured in those countries, respectively.
 
While the report specifies that two of the three US sites manufacture homeopathic products, it does not specify what type of products are made at the top sites in China and India. However, the report does note that on average, Indian manufacturing sites produce 2.5 times more individual products than Chinese facilities.
 
“This does not indicate the volume of production at the sites, nor the active status, only the variety of products registered to be manufactured for the US market. Ultimately, these data convey insight into how a small number of sites are responsible for a large number of listed products,” FDA writes, noting that the number of products made at a site is considered when prioritizing inspection resources.
 
Inspections
 
In FY2018, FDA says its investigators carried out 1,346 drug quality inspections, covering 29% of registered sites, with most of those inspections taking place outside the US.
 
“We use a site inspection score, on a scale of 1 to 10, as a measure of a site’s compliance to cGMP regulations based on the classification of FDA drug quality inspections conducted over the last 10 years,” FDA explains, noting that the scores are only meant for comparison and to help the agency allocate resources.
 
The average inspection site score in FY2018 was 7.5 out of 10, which FDA says does not indicate any significant trends from the previous year, when the average score was 7.7.
However, FDA says it does see differences in scores based on geographical region, application type and manufacturing sector, with sites in the US and Europe scoring 0.7 to 0.9 points higher on average than sites in China and India, which both had an average site score of 7.0.

FDA says these scores “indicate an acceptable level of compliance” but adds that it sees “opportunities for increased outreach to, surveillance of, and enforcement of certain markets.”
 
FDA also points out that the average score for sites that manufacture application products is “statistically higher than for no application sites,” at 7.8 compared to 6.6. “Further statistical analysis shows that no application sites consistently and significantly underperform regardless of geographic region,” FDA writes.
 
Drug Quality
 
The report attempts to estimate drug product quality by analyzing reports from industry, healthcare providers, patients and consumers, including consumer complaints, field alert reports (FARs), MedWatch reports and biotechnology product deviation reports (BPDRs), as well as drug shortage and recall data.
 
According to the report, the number of defects reported to FDA were statistically higher for NDA products compared to ANDA products, with an average 5.8 quality related MedWatch reports and 4.1 FARS per NDA compared to 3.4 quality related MedWatch reports and 1.8 FARS per ANDA.
 
“Recall rates have generally held steady over the past five years and appear specific to incidents,” FDA says, citing the high rate of recalls for angiotensin II receptor blockers (ARBs) linked to nitrosamine impurities in FY2018 and FY2019. FDA points out that while the average inspection score for ARB manufacturing sites was 7.4 in FY2018, that figure does not include more recent inspections prompted by the discovery of the impurities.
 
Manufacturers associated with recalls also had lower than average inspection scores, with an average score of 5.9.
 
However, FDA notes that a significant proportion of recalls over the last five years involved sites that were “historically not subject to routine surveillance inspections such as re-packers,” with 1,002 recalls linked to just two re-packers during that period.
 
When it comes to drug shortages, FDA says it has seen a decline in the overall number of shortages since 2011 but notes that nearly two-thirds of products in shortage are sterile injectables (64%) and/or generic drugs (63%).
 
FDA