Part 1: An Analysis Of FDA FY2018 Drug GMP Warning Letters

This article, the first in a series of three, presents a detailed summary of the drug GMP warning letters issued in FY2018, as well as a comparison of trends since fiscal year 2013.  

A comprehensive GMP intelligence program includes evaluation of health authority enforcement actions, including:

  • FDA Forms 483
  • Warning letters
  • Seizures
  • Recalls
  • Consent decree agreements

This allows manufacturers and sponsors to identify new trends in the focus of FDA inspectors and act to address or justify similar situations at their own firms.

Section 4.2 of ICH Q10, Pharmaceutical Quality System, specifies the “Monitoring of Internal and External Factors Impacting the Pharmaceutical Quality System” including “Emerging regulations, guidance and quality issues…”.  Enforcement actions should be monitored as a component of quality issues mentioned in the Q10 guidance.

Although the FDA is more transparent than other health authorities regarding enforcement actions, readers are encouraged to follow information published by:

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.  The data for over-the-counter (OTC) products represent CY2018 effective also January 1, 2019.

The number will likely increase as FDA resumed publication of warning letters after the partial government shutdown.  Thus, the OTC numbers we present here are likely an underestimate.

[RELATED: You can access a list of the most recent FDA warning letters, FDA drug recalls, FDA import alerts for drugs and selected devices and more each week with a subscription to the GMP Regulatory Intelligence Newsletter. Start your FREE trial today.]


NOTE: The term “compounding pharmacy” used here includes outsourcing facilities and is considered as a category separate from drug manufacturers based on their legal foundation.  These sites are all located in the United States, but they are not combined with data from U.S. drug manufacturing sites in this article.

Outsourcing facilities were established by the FDA as entities under an amendment to the Food Drug & Cosmetic Act in November of 2013.  FDA published draft guidance describing how outsourcing facilities might comply with GMP regulations in December 2018.  These firms are not considered in the data for import alerts, data integrity and OTC manufacture.

The narrative, tables, and figures address three broad areas:  

  1. Type of manufacture (API, dosage form, API and dosage form, compounding pharmacy/outsourcing facility), and country associated with the warning letter.
  2. Particular targets of warning letters issued this year, including over-the-counter (OTC) drug products, drug product manufacturers, data integrity and contracted operations.
  3. Interval between the inspection and enforcement actions, including issuance of a warning letter or import alert.

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

  • The number of drug GMP warning letters continues to increase over the previous years from 42 in FY2015, to 102 in FY2016, to 114 in FY2017, and 127 in FY2018 (Figures 1 and 2).
  • Excluding the compounding pharmacies and outsourcing facilities, the FDA continues to focus its enforcement actions outside the U.S.  Over three times as many warning letters were issued to firms outside the U.S. compared with those issued to domestic firms (see Figure 1).
  • The compounding pharmacy/outsourcing facility segment continues to receive enforcement attention from the FDA.  We have, however, turned the corner on these warning letters and they have decreased for two consecutive years in both absolute number and percentage of the total (see Figures 1 and 2).
  • Continuing a pattern from last year, drug product manufacturing sites more than doubled the number of warning letters received from the previous year.  This is likely associated with the dramatic increase in OTC drug product manufacturers who received warning letters (see Figures 1 and 3).

Warning Letter Data

Figure 1 shows that drug GMP warning letters more than doubled from FY2015 to FY2016 and increased again in 2017 and 2018 though not by as large a percentage.

Figure 1 also shows that while the FDA continues an intense focus on compounding pharmacies, the warning letters to these entities have decreased significantly for two years in a row.  I doubt this is because they have become more GMP compliant, but likely because many have decided to cease the compounding of sterile injectable drugs.

The number of warning letters issued to drug product sites increased over 50% from 47 in FY2017 to 73 in 2018.  This is likely associated with the increase in warning letters issued to OTC manufacturers from 17 in CY2017 to 39 in CY2018.


FY2018 warning letters issued to API sites decreased slightly compared to FY2017.  The number of warning letters issued to drug product sites increased over 50% from 47 in FY2017 to 73 in 2018.  This is likely associated with the increase in warning letters issued to OTC manufacturers from 17 in CY2017 to 39 in CY2018.

FDA has continued a focus on homeopathic drug manufacturers and manufacturers of human cell and tissue products with three and four warning letters respectively in 2018.  FDA continues to exercise enforcement discretion here and will intervene with enforcement actions when public health is at risk. I expect letters to human cell and tissue firms to increase in FY2019 and beyond.

And finally, the FDA continued to cite deficiencies in process validation.  Specifically, the FDA cited the failure to implement an ongoing process monitoring program to ensure that the manufacturing process remains in a state of control. This is applicable to all types of drug manufacture, oral and topical dosage forms, as well as sterile injectables (see Figures 2 and 3).




Compounding pharmacies and outsourcing facilities continue to receive enforcement attention though we seem to have officially turned the corner here with decreasing number and percentages of warning letters issued to this group in two consecutive years.  We will continue to monitor this metric and see whether FY2019 shows a similar decline.

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

  • A diminishing focus on compounding pharmacies and outsourcing facilities though warning letters and recalls will continue in significant number.
  • There likely will be 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 see increasing enforcement actions based on their overall potential impact on public health and the FDA’s stated focus to improve risk-based enforcement in those areas. FDA is exercising enforcement discretion until 2020 at which time they expect these firms to be operating under Investigational New Drug (IND) applications for therapies that are not approved under a BLA or NDA.

In the next post, we review warning letters outside of the U.S., enforcement of OTC manufacturers and contract manufacturers/laboratories, import alerts associated with warning letters and data integrity deficiencies.  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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