Ursachenanalyse: Was findet sich in FDA Warning Letter?

Vor kurzem haben wir über zwei Warning Letter der FDA berichtet, eines an ein Unternehmen in Italien und eines an ein Unternehmen in den USA, in denen eine unzureichende Ursachenanalyse (Root Cause Analysis - RCA) kritisiert wurde.
Auch in anderen Warning Letter, die im FDA-Finanzjahr 2024 herausgegeben wurden, wird eine unzureichende Ursachenanalyse angeführt. Dies zeigt sich als eine häufige Feststellung bei FDA-Inspektionen.

Untersuchungen und Ursachenanalysen sind die Grundlage für ein konformes pharmazeutisches Qualitätssystem. Nicht wenige GMP-Verstöße, die zu FDA Warning Lettern (und auch EU Non-GMP Compliance Reports) führen, sind auf unzureichende Untersuchungen zurückzuführen. In einem Warning Letter der FDA heißt es, dass unzureichende Untersuchungen zu nicht identifizierten Grundursachen, unwirksamen CAPA und wiederkehrenden Problemen führen können ("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, Mexiko, Januar 2024).

Lokale GMP-Vorschriften auf der ganzen Welt verlangen ausreichende Untersuchungen im Falle von Abweichungen. In den USA sind die Anforderungen hierzu zum Beispiel in folgenden Paragrafen des Code of Federal Regulations (CFR) festgelegt:

• § 211.180 General Requirements:
  "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 (...).

Die Einhaltung dieser Vorschriften wird bei Inspektionen der FDA überwacht. Dies zeigt sich häufig in Beobachtungen, die in Warning Lettern niedergeschrieben werden. Im Folgenden sind die in Warning Lettern aufgeführten Beobachtungen in der ersten Hälfte des FDA-Finanzjahres 2024 aufgeführt:

Colonial Dames Company, USA (Dezember 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 (Januar 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 (Februar 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 (Februar 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 (Februar 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 (März 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."

Diese und andere Warning Letter können auf der Webseite der FDA eingesehen werden.