FDA Warning Letter for Canadian Drugmaker - HPLC and Data Integrity in the Focus

The U.S. Food and Drug Administration (FDA) has recently published a Warning Letter dated May 29, 2020, to Cosmaceutical Research Lab Inc., a Canadian over-the-counter (OTC) drug producer. During an inspection from November 18 to 22, 2019, the FDA found significant violations of current good manufacturing practice (CGMP), including data integrity issues related to HPLC analysis.

Extra Injections without a clearly identified Purpose

According to the FDA, the company "injected samples with the intention of obtaining an “unofficial” result and/or failed to clearly indicate if the single injections were standards to determine whether high-performance liquid chromatography (HPLC) instruments were fit for use." Furthermore, the company performed extra HPLC injections without a clearly identified purpose and using ambiguous nomenclature. In addition, the FDA inspectors found torn documents in the trash related to quality and production.

This procedure is obviously not in accordance with GMP. "Unofficial sample injections are not acceptable. All analytical data must be retained and reviewed as part of the official record." For this reason, the FDA requires "an update on the unofficial injection assessment and other data integrity assessments" as well as "a complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient." 

Lack of Impurity Testing and Use of deficient Testing Methods

According to the FDA, the company lacked impurity testing for one of the products. Of particular importance is that the product may contain a potentially carcinogenic impurity, which Cosmaceutical Research Lab Inc did not test for. Thus, the amount of the impurity in the final product to which a user might be exposed to is not known.

The FDA now expects a detailed response which should include, amongst others, "an action plan and timelines for conducting full chemical and microbiological testing of retain samples to determine the quality of all batches of drug product distributed to the United States that are within expiry as of the date of this letter."

Lack of Stability-Indicating Methods for Testing of finished Drug Products

Another point mentioned in the Warning Letter is that Cosmaceutical Research Lab Inc lacked stability-indicating methods for testing the finished drug products. The company also lacked forced degradation studies.

In response to the Warning Letter, the FDA asked the company for a comprehensive, independent assessment and CAPA plan to ensure the adequacy of the stability program.

Inadequate OOS Investigations

Finally, the FDA criticized the investigations into out-of-specification (OOS) results. As an example, the FDA mentioned the following observation:
For a specific API, OOS results were obtained. Although the coworkers recognized that an original sample had been damaged during testing, the original sample was not retested. Furthermore, the OOS investigation did not involve hypothesis testing to scientifically show dilution error was the root cause of the OOS results.

In this context, the FDA is requesting a retrospective, independent review of all invalidated OOS results for U.S. products and a comprehensive review and remediation plan for the OOS result investigation systems.


Based upon the nature of the violations, the FDA strongly recommends engaging a consultant to assist the firm in meeting CGMP requirements. As the quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs manufactured, the FDA also recommends retaining a qualified consultant to assist in the companies' remediation. Regardless of this, the FDA expects

  • a comprehensive investigation into the extent of the inaccuracies in data records and reporting,
  • a risk assessment of the potential effects of the observed failures on the quality of the drug products,
  • a management strategy that includes the details of the global CAPA plan to ensure the reliability and completeness of all data generated.

For further details, please see the original FDA Warning Letter to Cosmaceutical Research Lab Inc.

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