Part 2: An Analysis of FDA FY2018 Drug GMP Warning Letters

In the first part of this series, we provided an overview of findings along with a general look at drug GMP warning letters over the last six years.  If you missed part one, you can find it here.

Here we cover the spread of warning letters outside of the U.S. and review enforcement of OTC manufacturers and contract manufacturers/laboratories. We also look at import alerts associated with warning letters and data integrity deficiencies.

The data presented here for FY2018, ending Sept. 31, 2018, is based on drug GMP warning letters posted by the FDA no later than Jan. 1, 2019.

Following are brief highlights of noteworthy findings and trends, followed by a more detailed analysis:

  • Manufacturers in China received the most warning letters issued to sites in a single country.  Firms in China received 24 warning letters, firms in the U.S. received 22 (see Figure 1).
  • The breakaway category of manufacturers in FY2018 that received warning letters are manufacturers of over the counter (OTC), non-prescription drugs.  Fifty-three percent of warning letters to drug product manufacturers were issued to OTC manufacturers.  This is similar to the seemingly disproportionate enforcement focus that FDA placed on compounding pharmacies and outsourcing facilities several years ago (see Figures 3 and 4).
  • The number of warning letters issued to OTC manufacturers more than doubled between CY2017 and CY2018 from 17 to 39 respectively.  More countries, ten vs seven, were associated with these warning letters in CY2018 (see Figures 3 and 4).
  • At least 20 warning letters were issued to firms who 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.
  • Import alerts were associated with 48 of the 73 warning letters issued to sites outside the U.S. 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 who 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 U.S. in FY2018.  Those issued to U.S. 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 (see Figures 5 and 6).

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Figure 1 shows the geographic distribution of warning letters issued outside the U.S.  China received the largest number of warning letters issued to a single country in FY2018 and over the six-year period.


India received the next highest number of warning letters, followed at a distance by Europe.  Over the past four years the number of warning letters to sites in China has steadily increased, while warning letters issued to sites in India have increased then held steady.

Sites in ‘Asia’ (Japan, China, India, Taiwan and Hong Kong) account for approximately 71% of drug GMP warning letters issued outside the U.S., the same as the percentage over the six year period FY2013 – FY2018.

European countries include the U.K. and are counted together.  European-area countries with sites that have received warning letters over the six fiscal years include:

  • Ireland
  • Spain
  • Czech Republic
  • Italy
  • Portugal
  • Denmark
  • Austria
  • Netherlands
  • Germany
  • Hungary
  • the U.K.
  • Switzerland

Figures 2 and 3 show that sites in ‘Asia’ (Japan, China, India, Taiwan and Hong Kong) account for approximately 71% of drug GMP warning letters issued outside the U.S., the same as the percentage over the six year period FY2013 – FY2018.


In FY2018 and the six year period FY2013- FY2018 sites in Europe received 12% and 16% of warning letters, respectively.  With the Mutual Recognition Agreement between the U.S. and the EU, it will be interesting to see if the number of warning letters to European sites begins to decrease in FY2019.  This agreement includes twenty health authorities in the EU effective November 28, 2018 with the remaining EU authorities expected to be added by July 2019.

OTC Manufacturers

CY2018 included a dramatic focus on OTC manufacturers worldwide reminiscent of the focus on compounding pharmacies and outsourcing facilities that began in 2014.

Figures 4 and 5 show the warning letter enforcement data on this group of manufacturers for the last eleven years.  The dramatic changes began in CY2017 and increased again in CY2018. The numbers for CY2018 will likely increase beyond those reported here as additional warning letters issued in 2018 are posted in early 2019.

Sites in China and the U.S. each received ten warning letters, sites in South Korea received five and sites in Europe received four.  Six additional countries had sites that received either one, two or three warning letters. Both China and South Korea saw more than two-fold increases between CY2017 and 2018.  The number of countries increased from seven in CY2017 to ten in CY2018.




Contract Manufacturers and Laboratories

FY2018 warning letters continued to focus on contracted activities, an area of focus that in my opinion will continue into the foreseeable future.  At least 20 warning letters mention contracted activities compared to at least 11 last year.  Thus, 21% of warning letters issued to firms that were not compounding pharmacies were directly associated with contract manufacturing or testing.  Five sites were located each in South Korea, China and the US; Europe had three sites and Australia had two.

Import Alerts Associated with Warning Letters

Seventy-three warning letters were issued regarding sites outside the U.S., and 47 of these had associated import alerts for failure to comply with drug GMPs or refusal of an inspection. So not only did 64% of firms that received warning letters have the expense associated with remediation of the warning letter itself, they are prevented from selling product from these sites in the U.S., excluding FDA-identified medically necessary products.

In many cases this likely provides an economic hardship.  Firms in China received 24 warning letters and 21 of these also were placed on import alert. China, India, and Korea taken together, account for 68% of the import alerts associated with warning letters.  Each country likely had additional sites that were the subject of import alerts, but these were not associated with warning letters.

Data Integrity Deficiencies in Warning Letters

Figure 6 shows the number of warning letters issued both inside and outside the U.S. that included references to data management and data integrity.  This group and analysis excludes those warning letters issued to compounding pharmacies.

Data integrity deficiencies in warning letters continue to identify the predicate rule(s) to which firms did not adhere.

Figure 7 provides a graphic representation of the data.  The percentages for both U.S. and OUS warning letters have consistently decreased between FY2016 and FY2018; perhaps we’ve turned the corner here but we still have a long way to go to eliminate this problem.





Contract manufacturers and their sponsors were a focus again this year, and I would expect that to continue and expand in FY2019. Some sponsors will only take their responsibilities for selection and oversight of contract manufacturers seriously if they suffer an economic impact, such as a contract manufacturer that is subject to a serious enforcement action that results in a delay to product approval or a cessation of manufacture to undertake necessary facility and equipment remediation.  

The breakaway category for warning letters in FY2018 was manufacturers of OTC drug products.  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.  

China continues to lead in the country receiving warning letters, as it did in FY2017.  This year saw the addition of the Republic of (South) Korea to the countries whose companies received an increasing number of warning letters.  I would expect this to continue into FY2019 also.

Where are we heading in 2019?  Overall, look for the following trends in warning letter enforcement actions:

  • Continued focus on data integrity and data governance.
  • Continued focus on OTC manufacturers because of the number of individuals using these products and the seemingly poor understanding and compliance with GMPs as shown in this year’s warning letter collection.
  • Contract manufacturers and laboratories and those that contract for their services will see continued attention by the FDA.

In the last post of this series, we will review the interval between inspection and issuance of warning letters, and the interval between inspection and issuance of import alerts.  Continue reading here.

[NOTE: We do all the work so you don’t have to. Start your free trial of the GMP Regulatory Intelligence Newsletter and let industry expert Barbara W. Unger do the scanning, filtering, analysis, and synthesis for you.]



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About the Author

Barbara W. Unger is Govzilla’s Quality Expert and Editor-in-Chief of GMP Regulatory Intelligence. She formed Unger Consulting, Inc. in December 2014 to provide GMP Quality consulting services to the pharmaceutical and biopharmaceutical industry. At Amgen, she led the segment of the Corporate GMP Audit group at Amgen focused on API manufacturers, Quality Systems and Computers. She developed, implemented and maintained the GMP Regulatory Intelligence program for 8 years at Amgen Inc. This included surveillance, analysis and communication of GMP related legislation, regulations, guidance and industry compliance enforcement trends. This was an essential service and tool within the Corporate Audit function.

Unger Consulting Inc. | | 805.217.9360

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