Current good manufacturing practices (CGMPs) are the cornerstone of drug safety. However, it’s an area where many pharma manufacturers still struggle. In fact, 30 percent of FDA pharmaceutical warning letters issued in the first half of 2022 cite CGMP violations (Source:

FDA warning letters include many violations noted during inspections, including filthy production areas, illegible records, and rusty equipment. While those violations represent serious deficiencies, they can be relatively easy to identify and resolve.

However, other CGMP violations can be more difficult for organizations to resolve to the FDA’s satisfaction. These include inadequate root cause analysis, incomplete written procedures for production and process control, and lack of appropriate supplier controls. These issues are unacceptable to the FDA and pose consumer safety risks that could damage both profitability and reputation.

In this article, we look at some of the most common failures cited in recent pharmaceutical warning letters and the role of the quality management system (QMS) as an essential means of minimizing the risk of quality issues and warning letters.

Document Management Procedures

Failure to establish and maintain written procedures is a top violation cited in recent pharmaceutical warning letters. The warning letters identify both written procedures as missing or insufficient for critical areas such as:

  • Stability testing programs
  • Sanitation and equipment maintenance procedures
  • Production and process control
  • Prevention of microbiological contamination
  • Preparing master production and control records

Quality Management Perspective: A modern quality management system (QMS) can help pharmaceutical manufacturers avoid these citations by centralizing documentation and process controls. An enterprise QMS (EQMS) makes it easy to perform queries to find where documentation gaps exist. Furthermore, companies can link document updates to employee training requirements as proof that employees have appropriate knowledge required for their roles.

Inadequate Investigations

Lack of appropriate investigations was another key source of FDA pharmaceutical warning letters in the first half of 2022. The FDA specifically calls out investigations into out-of-specification (OOS) test results.

For example, problems noted include:

  • Failure to investigate all potential sources of problems, such as attributing OOS results (deviations) to analyst error without further question
  • Attributing OOS results to equipment issues without implementing new controls to prevent the problem in the future
  • Failure to conduct a timely investigation into OOS results, allowing potentially dangerous products to continue to be released
  • Failure to investigate and control all batches that are potentially affected

The FDA has provided detailed guidance on investigating OOS results, which manufacturers may find helpful for avoiding these problems. Unfortunately, failing to do so increases the likelihood that problems will continue, some of which can be high risk.

Quality Management Perspective: An EQMS uses best practice workflows to enable investigation of any quality events and issues in a controlled process. Problem-solving tools within the QMS can include decision trees, 8D, failure mode and effects analysis (FMEA), and the 5 Why method. In addition, an EQMS integrates root cause analysis and CAPA processes to close the loop on quality issues. Furthermore, the system has controls in place to facilitate analysis of preventive measures to reduce future risk.

Maintaining and Protecting Records

Compliance with record maintenance requirements is a common issue in recent warning letters. The FDA requires documentation be attributable, legible, contemporaneous, original, accurate, complete, consistent, enduring, and available (ALCOA+ principles of data integrity). Generally, it is assumed that inadequate documentation practices directly impact data integrity.

For example, specific citations in FDA pharmaceutical warning letters include:

  • Missing or incomplete batch production records
  • Manufacturing production logbooks with pages torn out
  • Destroying batch records, including while the product was still in distribution
  • Incomplete records
  • Records without a stamp indicating they are controlled and current copies
  • Maintaining written records of calibration checks and equipment inspections

Quality Management Perspective: Paper records and logbooks are notoriously difficult to control, making them a key target of FDA observations and warning letters. A digital QMS, by comparison, provides a centralized, controlled repository for maintaining production records in accordance with FDA requirements. In addition, document control helps maintain a state of audit readiness—a key concern as regulators resume in-person inspections.

Data Integrity

Multiple warning letters in 2022 have called out manufacturers for serious questions over data integrity.

As examples, specific citations in FDA pharmaceutical warning letters include:

  • Not accurately recording or verifying all experimental data, resulting in incorrect calculations
  • Lack of appropriate controls for access to computer systems, allowing deletion and modification of data
  • Lack of QA review of original laboratory records
  • Releasing product without reviewing audit trails
  • Electronic security issues such as having a master computer login and password
  • Outright falsification of data by an analyst for several years, wherein the individual entered completely arbitrary values to avoid sample reprocessing
  • Not documenting sample reprocessing
  • Using non-validated spreadsheets to calculate finished assay results

Quality Management Perspective: While digital recordkeeping is on the rise, maintaining records consistent with ALCOA+ principles of data integrity remains a key challenge. An EQMS provides an advantage over spreadsheets with permission-based access to records. Further, an EQMS provides a complete audit trail of access, changes, and approvals as evidence of FDA compliance.

Supplier Quality Management

Contract manufacturing organizations (CMOs) require a high level of oversight by any manufacturer in any industry. However, the pharmaceutical supply chain is one that, if poorly managed, can have serious consequences. Therefore, it’s no surprise that the FDA is focused on finding high-risk practices in supplier quality. In several cases, the pharmaceutical warning letters noted poor practices in verifying the identity of drug components. The rush to market must be tempered with a consistent supplier quality protocol.

For example, specific citations in FDA pharmaceutical warning letters include:

  • Testing glycerin for diethylene glycol a toxic chemical associated with fatal poisoning incidents worldwide
  • Testing ethyl alcohol for methanol, a toxic chemical associated with fatal poisoning incidents worldwide
  • Failing to validate and establish the reliability of supplier test analyses
  • Failure to test each incoming material lot
  • Accepting supplier test results without verification
  • Not qualifying the contract laboratories

Quality Management Perspective: Supplier quality management within the QMS can help manufacturers ensure incoming product quality and safety of end-products. Well-engineered supplier quality management processes can automate the process of testing incoming lots and tracking key metrics. In addition, tools like supplier scorecards provide a standardized method for supplier qualification and maintain those records to demonstrate compliance. Finally, an automated document management solution within the QMS provides controls for supplier quality agreements and digital evidence to support certified supplier programs.


Perhaps the most troubling aspect of recent crop of warning letters is that many of the citations represent repeat violations. This highlights how imperative it is to automate and connect quality processes to minimize risk. Inevitably, controlled processes within a centralized quality platform can better manage FDA compliance and result in fewer pharmaceutical warning letters.

Amidst regulations and market competition, companies using an enterprise QMS have a key advantage in avoiding FDA warning letters. Only by improving methods for maintaining data integrity, fast-tracking investigations, validating supplier quality, and centralizing record management can manufacturers bring products to market faster with fewer recalls, patient safety issues, and lower quality costs.

About the Author

Stephanie Ojeda is Director of Product Management for the Life Sciences industry at AssurX. Stephanie brings more than 15 years of leading quality assurance functions in a variety of industries, including pharmaceutical, biotech, medical device, food & beverage, and manufacturing.