FDA Warning Letter: Testing into Compliance using Unvalidated Test Methods

In April 2022, the U.S. Food and Drug Administration (FDA) published a Warning Letter dated March 14, 2022, to an American drug manufacturer. The Warning Letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) the FDA found when inspecting three of the company's drug manufacturing facilities.

The inspections took place between August and November 2021. The Warning Letter, which was preceded by several FDA 483s, also includes repeat observations from previous FDA inspections.

The list of deficiencies listed in the Warning Letter is quite extensive and covers the following topics:

  • Cleaning procedures and cleaning validation: The company manufactures numerous over-the-counter (OTC) drug products in various dosage forms on non-dedicated equipment, but was not able "to provide adequate justification that current cleaning procedures adequately remove drug residues and prevent cross-contamination". Furthermore, the "cleaning procedures lacked adequate specificity and detail to be performed consistently and be validated."
  • Method validation: Numerous test methods used for in-process testing, for the release and stability testing were not adequately validated. Multiple test methods were reported as deficient, and a lot of validation or verification reports were missing.
  • Excel sheets: Excel workbooks used for calculations did not produce reliable results.
  • Contract Testing Lab: One of the facilities also conducts testing for other drug manufacturers. The FDA is concerned that CGMP violations may also affect the quality, safety, and efficacy of the drugs the company tested for the clients.
  • Quality Unit Oversight: The Quality Unit (QU) did not provide adequate oversight of the manufacture of the company's drug products manufactured at the multiple facilities.

Three further observations are particularly notable:

Out-of-specification (OOS) laboratory results and investigation into cross-contamination

In the Warning Letter, the FDA summarizes the company's investigation into cross-contamination of 22 lots. The company simply compiled all 22 cases into a single investigation, modified the analytical method, and retested new sample preparations.

As this retests also produced failing test results, the company then used a new and unvalidated test method to test the failed samples again. This finally led to passing results. For the company, this was sufficient, without further investigation, to release the drug product lots for distribution. In another case, based just on assumptions, lots were retested using unvalidated test methods until passing results were obtained.

The FDA summarizes the procedure as follows: "In both instances of cross-contamination, you disregarded all previous failing test results without providing adequate scientific justification to invalidate the original OOS or identify a root cause. Instead, your firm resampled and retested failing lots with invalidated and unverified test methods until passing results were obtained."

Stability Testing

In another case, the company has also made things very easy for itself: During stability testing, OOS test results in the 25 °C ± 2 °C, 60% ± 5% relative humidity stability program for numerous batches were obtained. The laboratory then tested reserve samples stored under less-stressed conditions and without controlled relative humidity. Now passing results were obtained.

According to the FDA, the company has simply drawn the following conclusion: "After obtaining passing results, you concluded that 60% ± 5% humidity storage condition was the cause for the aspirin sub-potency and [the] impurities without scientific justification, maintaining that the OOS results `may not represent condition of typical lot 18J024 consumer goods in the marketplace.´ At the time, your firm took no market action."

HPLC Data Integrity

Numerous data integrity violations were observed in the HPLC laboratory:

  • Analysts ran single injections without justification.
  • In the audit trails, multiple actions such as "Deleted Methods," "Aborted Runs," "Deleted Manual Integrations," and "Stop Data Acquisition" were found, but without a documented purpose.
  • Analysts had the privileges to modify approved test methods in HPLC equipment.

The company now has a lot of work to do, as the list of measures and investigations required by the FDA and the documents to be prepared are very extensive. Until further notice, the production and testing of drugs at the facilities are suspended. The firm has to notify the FDA before resuming the operations.

The complete Warning Letter to Ultra Seal Corporation is available on the FDA's website.

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