Prelude to an FDA Warning Letter


Undeniably, there are a lot of things in life that we prefer to avoid — traffic lights, sharp edges on coffee tables and FDA warning letters — to name a few. Warning letters tend to be a little more distressing as they are often accompanied by other things we would like to avoid. Warning letters usually follow a standard motif, beginning with an enumeration of specific findings, follow-up instructions, a deadline for completing the follow-up instructions, and potential consequences for not following through with the follow-up instructions. In a nutshell, dealing with warning letters from the U.S. Food and Drug Administration (FDA) typically involves crafting a highly detailed course of action for correcting the infractions, including how many bottles of pain reliever will be needed before it’s over.

What Warning Letters Are All About

All companies developing regulated products are capable of receiving a warning letter when one or more things are out of conformance. It’s not simply a matter of lacking experience or resources. Typically, warning letters address violations of the Quality System Regulations (QSRs) more than actual product concerns.

On the surface, common scenarios that lead to receiving a warning letter involve at least one of the following:

  • Not having written procedures that conform to FDA regulations.
  • Having written procedures that conform to FDA regulations, but not actually following them.
  • Having written procedures that conform to FDA regulations, following them, but not having adequate (or any) documentation to serve as proof that they are indeed being followed.

At a more industry-specific level, the following sections discuss some common circumstances that could lead to medical device, pharmaceutical and blood and biologics companies receiving a warning letter.

Medical Device

Anyone in medical device manufacturing knows that compliance is a colossal and complex effort beset by numerous processes and variables that are often as cooperative as screaming kids in a grocery store. Any number of things can slip through the cracks and fall right into the lap of a regulatory inspector.

Medical Device Reporting (MDR) is one of the more popular violations that show up on FDA warning letters. Regulation 21 CFR Part 803 mandates that manufacturers, importers and device user facilities report certain device-related adverse events and product problems to the FDA. The following guidelines clarify when MDR events should be reported:

  • Upon learning that a device may have caused or contributed to a death or serious injury.
  • After becoming aware that a device has malfunctioned and would likely cause or contribute to a death or serious injury if the malfunction recurred.

In December 2018, a biomedical company received a warning letter citing inadequate handling of a device malfunction that was revealed in a complaint. Specifically, the company was called out for having no documentation proving that the malfunction would not likely cause or contribute to a death or serious injury if the malfunction were to recur. “Your firm became aware of the event on April 2, 2015, but failed to submit an MDR for the referenced event.”(1)

Other medical device compliance violations that become the subject of warning letters include:

  • Inadequate complaint handling procedures.
  • Inadequate process validation procedures.

Complaint Handling

Complaint handling guidelines are spelled out in 21 CFR 820.198, which states that a medical device manufacturer must establish and maintain procedures for receiving, reviewing and evaluating complaints.

The following questions are helpful for determining the proper action for a complaint:

  • Is it a reportable event that needs to be submitted to a regulatory agency based on the requirements of 21 CFR 820.803?
  • Does the complaint require a failure investigation and/or an MDR based on the requirements of 21 CFR 820.198(d)?
  • Is additional corrective action required based on the requirements of 21 CFR 820.100?

As with MDR, the FDA has high expectations for the documentation that accompanies complaint handling. Essentially, all complaints, as well as the actions, decisions and situations surrounding the complaints, must be clearly explained and justified. Warning letters for complaint handling often address the company’s effort (or lack of) to investigate malfunctions. Inspectors rely heavily on the documentation to make their assessment of how the company is complying with the QSR.

Process Validation

According to 21 CFR Part 820, medical device manufacturers must establish by objective evidence that a process consistently produces a specific result or product according to its predetermined specifications—with virtually no errors. Process validation provides assurance that when a process operates correctly, the output — product — is correct.

The QSR outlines Current Good Manufacturing Practice (CGMP) regulations that govern the design, manufacture, packaging, labeling, storage, installation, and servicing of all finished devices intended for human use. There is no specific requirement regarding when to perform process validation, but the recommendation is the earlier the better. The Global Harmonization Task Force (GHTF) Guidance provides useful guidelines for understanding how to perform process validation.(2)


It goes without saying that companies developing pharmaceutical products can quickly become engulfed in documentation. Documents can number into the thousands even before the preclinical phase is complete. That said, it’s no coincidence that documentation has earned a spot on the FDA’s list of top warning-letter-worthy compliance violations in the pharmaceutical industry.

For a drug manufacturer to operate safely and within the bounds of compliance, the FDA requires a pharmaceutical researcher’s and/or manufacturer’s standard operating procedures (SOPs) to be clearly written, maintained in a consistent and timely manner, and readily available.

Errors and nonconformances in pharmaceutical product development are inevitable if:

  1.  Employees do not have clear, up-to-date written instructions for every task.
  2.  Employees do not follow No. 1 to the letter.

Documentation was the focal point of an FDA CGMP violation discovered at a pharmaceutical outsourcing company in September 2018. The FDA’s warning letter cited that the firm failed to establish and follow appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile, which includes validation of all aseptic and sterilization processes (21 CFR 211.113(b)).”(3)

Other common compliance violations in pharmaceutical development include:

  • Laboratory controls are not scientifically sound.
  • Discrepancies and/or failures in investigations.

Laboratory Controls Not Scientifically Sound

21 CFR 211.160(b) mandates that pharmaceutical companies ensure that the specifications, standards, sampling plans and test procedures for assuring that drug products are scientifically sound and conform to appropriate standards of identity, strength, quality and purity. It further states that the laboratory control requirements are followed and documented at the time of performance.

Maintaining laboratory controls involves effectively integrating various quality processes such as for change control, document control, employee training, audits and corrective and preventive actions (CAPAs). Nonconformance to this regulation can have a deep-rooted impact on product quality and consistency that would be difficult and time-consuming to recover from.

Discrepancies and/or Failures in Investigations

Investigation discrepancies or failure to adequately complete an investigation are violations the FDA frequently sees. According to 21 CFR 211.192, all procedural deviations must be thoroughly investigated and documented. If your pharmaceutical company is unable to identify potential root causes of discrepancies and make a sufficient and accurate record of them, their internal investigations will be viewed by the FDA as incomplete.

This was the case with a generic drug manufacturer, that actually received two warning letters for the same violation. The facility was cited for “incomplete investigations of out-of-specification results and manufacturing deviations.” The warning also stated that the company lacked scientifically-supported conclusions and prompt CAPA.(4)

Blood and Biologics

Given the intricate techniques and wide range of variables in biologics products, corrective and preventive action (CAPA) is critical to honing and refining manufacturing processes and products. Apparently, it’s not a particularly enjoyable task as it tends to be a common issue in FDA warning letters.

A biologics product manufacturing firm was the recipient of a warning letter for CAPA violations in September 2015. One CAPA event was opened when a laboratory employee mixed up steps when using the “Instructions for Use” document. Another CAPA was opened after an employee made a packaging error. When reviewing the reports and forms, the inspector observed that the firm failed to fully record and verify all of the corrective and preventive actions for both errors.(5)

The FDA also frequently cites biologics companies for these violations:

  • Records are not concurrently maintained.
  • Deviations procedures are inadequate.

Records Are Not Concurrently Maintained

Continually maintaining records requires a lot of time and effort, but it’s a necessary process to ensure that records are updated concurrently with each step in the collection, processing, compatibility testing, storage and distribution of each unit of blood and blood components. The records need to be detailed, provide a complete history of the work performed, and be easily traceable.

Deviations Procedures Are Inadequate

The parts that suppliers produce are not always perfect, so deviations are inevitable. The FDA understands this, but it still expects all blood companies to establish procedures, including supplier management processes, that will identify and mitigate deviations as quickly as possible in order to reduce or eliminate errors.

How to Get Taken Off the FDA's Warning-Letter Mailing List

Many of the violations cited in warning letters tend to be connected to documentation. Maintaining production timelines while ensuring quality, safety and efficacy is extremely difficult if you’re carting stacks of paper documents through the production areas. A good way to avoid receiving undesired correspondence from the FDA is to digitize documentation management.

The FDA is a proponent of modernizing health care product manufacturing as revealed in its draft guidance on quality considerations for continuous manufacturing, “The FDA supports the adoption of modern manufacturing technology as a foundation for improving the overall quality of products and availability to patients.” In essence, digital technologies are enabling regulated companies to move away from paper, eliminate production bottlenecks, and prevent warning letters from showing up in their mailboxes.(6)


  1. FDA warning letter to OriGen Biomedical Inc., Dec. 20, 2018,
  2. Quality Management Systems – Process Validation Guidance, Edition 2, January 2004
  3. FDA warning letter to Atlas Pharmaceuticals, LLC, Sept. 10, 2018,
  4. “Akorn Receives Second Warning Letter This Year.” FDAnews Drug Daily Bulletin, July 19, 2019,
  5. FDA warning letter to Bio-Rad Laboratories GmbH, Sept. 3, 2015,
  6. “Quality Considerations for Continuous Manufacturing Guidance for Industry,” U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), Feb. 2019,

2019-bl-author-david-jensenDavid Jensen  is a content marketing specialist at MasterControl, where he is responsible for researching and writing content for web pages, white papers, brochures, emails, blog posts, presentation materials and social media. David has over 25 years of experience producing instructional, marketing and public relations content for various technology-related industries and audiences. He writes extensively about cybersecurity, data integrity, cloud computing and medical device manufacturing. He has published articles in various industry publications such as Medical Product Outsourcing (MPO) and Bio Utah. David holds a bachelor’s degree in communications from Weber State University and a master’s degree in professional communication from Westminster College. 

Ultimate Guide

The Ultimate Guide to Connected Quality Data

Enjoying this blog? Learn more.

The Ultimate Guide to Connected Quality Data

Get the Guide
[ { "key": "fid#1", "value": ["GxP Lifeline Blog"] } ]