FDA Warning Letter: No Quality Unit, No Thorough Investigations and No Stability Program

Recommendation

13/14 September 2023

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Dealing with different compendial methods

The U.S. Food and Drug Administration (FDA) has published a Warning Letter dated March 28, 2022, to NDAL Mfg Inc., a Californian drug manufacturer.

The firm utilizes Contract Manufacturing Organizations (CMOs) to manufacture nasal spray products. An agreement with one of the contractors stipulated that NDAL Mfg Inc. is responsible for drug product release to the market.

During an inspection from September 8 to 20, 2021, the FDA investigators found significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. The FDA criticises the lack of a quality unit (QU), an insufficient investigation into microbial contamination and an inadequate stability program. Despite the fact that the company had hired a quality manager in the meantime and used the services of an external consultant, the Warning Letter could not be prevented.

The company has committed to temporarily suspend the production of drugs for the U.S. market.

Quality Unit

According to the FDA, the firm "did not have a quality unit (QU) and failed to have adequate procedures to ensure that all drug products produced [...] possessed appropriate quality attributes."

For example, no procedures for the approval of components provided to the CMOs, for investigating out of specification (OOS) results, and for evaluation of customer complaints were established. Specifications being used by the CMOs to release the drug products commercially could not be provided.

In the overall picture, the FDA considers the firm’s quality system to be inadequate. The FDA has asked for a whole range of measures to be taken. Thus include:

• "A complete and final review of each batch and its related information before the QU disposition decision.
• Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all drug products.
• A detailed description of [...] procedures and processes for conducting audits of [...] CMOs to ensure that they operate in compliance with CGMP."

Investigation into Microbial Contamination

The Warning Letter states that the firm failed to perform a thorough investigation into the microbial contamination that occurred with a specific lot of a nasal spray manufactured by one of the CMOs. It is particularly serious that the company was unable to provide an investigation that the microbial contamination was limited to only one lot.

Stability Program

There were also surprising deficiencies in the stability programme. The company could only provide a report from an outside laboratory for one lot manufactured of the nasal spray products under accelerated conditions. "Full shelf life studies were not conducted. Furthermore, the report does not contain predefined acceptance criteria, or a description of the container-closure system utilized, and the lot involved was not manufactured by [the] current CMO." The company also could not provide assurance that the test methods are stability indicating. It, therefore, seems questionable on what basis the company could establish the three-year product shelf life.

In addition to the CGMP violations, the FDA also accuses the firm of unapproved new drugs violations. To view the complete list of violations and the conclusion given by the FDA, please see the warning letter to NDAL Mfg Inc.