Root Cause Analysis: What can be found in FDA Warning Letters?

We recently reported on the issuance of two FDA Warning Letters, one to a company in Italy and one to a company in the US, which included observations on inadequate root cause analysis (RCA). However, also in other Warning Letters issued in FDA's fiscal year 2024, insufficient root cause analysis is cited and seems to be a frequent finding in FDA inspections.

Investigations and Root Cause Analysis are the basis of a compliant pharmaceutical quality system. Quite some GMP violations that lead to FDA Warning Letters (and also EU Non-GMP Compliance Reports) are caused by inadequate investigations. As stated in an FDA Warning Letter, "Inadequate investigations can lead to unidentified root causes, ineffective CAPA, and recurring problems that compromise the ability to manufacture safe and effective drug products" (Glicerinas Industriales, Mexico, January 2024).

Local GMP regulations around the world require sufficient investigations in the case of deviations. In the US, requirements for investigations are for example laid down in the Code of Federal Regulations (CFR):

• § 211.180 General Requiremnets:
  "Written procedures shall be established and followed for such evaluations and shall include provisions for (...) (2) A review of complaints, recalls, returned or salvaged drug products, and investigations (...) (f) Procedures shall be established to assure that the responsible officials of the firm, if they are not personally involved in or immediately aware of such actions, are notified in writing of any investigations conducted" [reg.complaints].
• § 211.192 Production record review
  "Any unexplained discrepancy (...) or the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated, (...). The investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy. A written record of the investigation shall be made and shall include the conclusions and followup."
• § 211.198 Complaint files
  (2) "Where an investigation under §211.192 is conducted, the written record shall include the findings of the investigation and followup. (...). (3) Where an investigation under §211.192 is not conducted, the written record shall include the reason that an investigation was found not to be necessary (...).

Compliance with these regulations is investigated during FDA inspections. This can often be seen in observations written down in Warning Letters. In the following, findings cited in Warning Letters in the first half of the FDA fiscal year 2024 are listed:

Colonial Dames Company, USA (December 2023)

• "you did not provide a detailed investigation identifying the root cause for the evaporation, nor
  supporting data to assure your CAPA is adequate."

Glicerinas Industriales, Mexico (January 2024)

• "Failure to document, explain, and investigate any deviation from established procedures"
• "you did not reject the lots and failed to fully identify a clear root cause for the contamination source. Your firm also failed to implement a corrective action and preventive action (CAPA) according to your procedure until after FDA cited your firm.

Bell International Laboratories, USA (February 2024)

• "Your quality unit (QU) lacked adequate control over your over-the-counter (OTC) drug manufacturing operations and failed to ensure that you had adequate procedures. For example, your QU failed to ensure:
  - Adequate investigations into non-conformances (21 CFR 211.192).
  - Adequate investigations into complaints (21 CFR 211.198(a))."
• "Your response is inadequate because you did not address how you will ensure that investigations contain adequate root cause determinations, corrective action and preventive action (CAPA), and effectiveness checks".

Sichuan Deebio Pharmaceutical, China (February 2024)

• "Your firm's quality unit (QU) failed to (...) extend product quality complaint investigations to other batches or APIs potentially associated with the root cause, failure, or deviation".

Cosmetic Specialty Labs, USA (February 2024)

• "For example, your QU failed to ensure: (...) Thorough investigations into out-of-specifications (OOS) results, deviations, and other discrepant results are performed per an adequate written and approved procedure".

Antaria Pty. Ltd., Australia (March 2024)

• "The root causes were not clearly defined nor adequately documented"
• "you failed to describe a holistic review of all investigations, root cause analyses and corrective actions for adequacy"
• "ensure that all other laboratory methods vulnerable to the same or similar root cause are identified for remediation".

Cohere Beauty, USA (April 2024)

• "Your investigation only focused on reviewing formulation and customer complaints but did not adequately investigate the root cause".

Natco Pharma, India (April 2024)

• "Your firm's investigations into unexplained discrepancies were inadequate. Your quality unit (QU) failed to thoroughly investigate all finished product batches and components associated with unexplained discrepancies."
• "You concluded your investigations without a root cause determination supported by evidence or initiating CAPA."

All the Warning Letters can be found on the FDA Website.