The number of drug GMP warning letters issued by the FDA saw yet another year of increase in FY2018. The escalation though, is not as dramatic a difference as in some previous years. Barbara Unger has presented her breakdown and analysis of the warning letters making up those issued in FY2018, as well as a comparison of trends since FY2013 and informed predictions of potential FY2019 trends.
Unger's analysis considered the evaluation of health authority enforcement actions, including FDA Forms 483, warning letters, seizures, recalls, and consent decree agreements. This allows manufacturers and sponsors to identify new trends in the focus of FDA inspectors and to act to address or justify similar situations at their own firms.
Noteworthy themes
- Type of manufacture (API, dosage form, API and dosage form, compounding pharmacy/outsourcing facility) and country associated with warning letters.
- Particular targets of warning letters issued this year, including OTC drug products, drug product manufacturers, data integrity, and contracted operations.
- Intervals between the inspection and enforcement actions, including the issuance of a warning letter or import alert.
The FY2018 trends
- The number of drug GMP warning letters continues to increase over the previous years, from 42 in FY2015 to 127 in FY2018.
- Manufacturers in China received the most warning letters issued to sites in a single country. China received 24, while the US received 22.
- The breakaway category of manufacturers that received warning letters in FY2018 is manufacturers of OTC nonprescription drugs. 53% of warning letters to drug product manufacturers were issued to OTC manufacturers, more than doubling between CY2017 and CY2018, from 17 to 39. More countries, 10 vs. seven, were also associated with these warning letters.
- This group, on the whole, appears to have failures in fundamental aspects of GMP, including the need for an effective quality unit, testing of incoming materials and components rather than simple reliance on the supplier’s certificate of analysis, testing of product prior to release to the market, and failure to have real-time data to support expiry labeling.
- The data for over-the-counter (OTC) products represent CY2018, also effective 1 January 2019. The number will likely increase as the FDA resumes publication of warning letters after resolution of the partial government shutdown. Thus, the OTC numbers presented here are likely an underestimate.
- Continuing a pattern from last year, the number of drug product manufacturing sites that received warning letters more than doubled from the previous year. This is likely associated with the dramatic increase in OTC drug product manufacturers that received warning letters.
- The compounding pharmacy/outsourcing facility segment continues to receive enforcement attention from the FDA. However, the corner seems to have been turned on these warning letters and they have decreased for two consecutive years in both absolute number and percentage of the total.
- Still, this trend needs to be reviewed in FY2019.
- Excluding the compounding pharmacies and outsourcing facilities, the FDA continues to focus its enforcement actions outside the US. More than three times as many warning letters were issued to firms outside the US compared with those issued to domestic firms.
- At least 20 warning letters were issued to firms that were contract manufacturers/laboratories or to firms that did not exercise appropriate controls over their contracted operations. This continues a focus that began last year.
- The issue seems to be that some sponsors will only take their responsibilities for selection and oversight of contract manufacturers seriously if they suffer an economic impact.
- Import alerts were associated with 48 of the 73 warning letters issued to sites outside the US in FY2018. Firms in China, India, and Korea that received warning letters were the subject of 32 of the 48 import alerts associated with warning letters. China was also in first place here, with 21 of the 24 firms that received warning letters being subject to import alerts.
- The percentage of warning letters that cite deficiencies in data governance/data integrity decreased from the high point of 81% in FY2016 to 60% for firms outside the US Those issued to US firms decreased from 73% in FY2016 to 45% in FY2018. Data integrity deficiencies are cited in 57% of all warning letters, excluding those issued to compounding pharmacies, down from a high of 79% in FY2016.
- The interval between inspection and issuance of warning letters continues to decrease for all categories, though the most dramatic decrease has been for warning letters issued to sites outside the US Warning letters issued to compounding pharmacies and outsourcing facilities continue to take the longest time to issue after inspections are completed. The interval between inspection and issuance of import alerts continues to be just under 50% of the time between inspection and warning letter issuance.
Predicted FY2019 trends
Overall Unger warns what to look out for in FY2019:
Diminishing trends
A diminishing focus on compounding pharmacies and outsourcing facilities, though warning letters and recalls will continue in significant numbers.
Continued focus
Continued focus on data integrity, data governance and OTC manufacturers. Those that contract for their services will also see continued attention.
Increased attention
Ongoing and increased attention in process validation, particularly ongoing process monitoring, as required in both the FDA and EMA validation guidance. Stem cell product manufacturers and manufacturers of human tissues and cellular products will most likely also see increasing enforcement actions. This is based on their overall potential impact on public health and the FDA’s stated focus to improve risk-based enforcement in those areas. The FDA is exercising enforcement discretion until 2020, at which time it expects these firms to be operating under IND applications for therapies that are not approved under a BLA or NDA.
Editor's note: Barbara Unger granted permission to publish this excerpt from her article originally published in Life Science Leader.
