Auswertung der FDA-Warning Letters Fiskal Jahr 2010 hinsichtlich Risikomanagement

Mit Finalisierung der ICH-Leitlinie Q9 "Qualitäts-Risikomanagement" war auch eine Einbindung in die nationalen pharmazeutischen Regelwerke der "Triade" USA, EU und Japan verbunden. Durch diese Einbindung wurde das Thema Qualitäts-Risikomanagement auch inspektionsrelevant.

Was bemängeln aber Inspektoren bzgl. Qualitäts-Risikomanagement?

Vereinzelt gibt es Hinweise, auf was Inspektoren achten. So ist in einem WHO-Papier zum Risikomanagement eine Checkliste zur Inspektion eines solchen Systems enthalten (s. GMP-News vom 27. September 2010). Ein Question and Answer-Dokument der MHRA gibt ebenfalls Hinweise, s. GMP-News vom 20. September 2010. Eine weitere Quelle sind die FDA-Warning Letters. Nachfolgend Beispiele für Zitate aus den Warning Letters des Fiskal-Jahres 2010 (Oktober 2009 - September 2010), s. auch GMP-News vom 27. Januar 2011.

"Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed, nor has your firm extended investigations to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy [21 C.F.R. § 211.192]. For example:
a. Your firm did not thoroughly investigate particulate contamination found in lot […] of […] injection. This particulate contamination ranged in size from less than 0.5 to 5 mm for vials and less than 0.2 to 8 mm for syringes. During a second inspection, particulate contamination was discovered in a syringe sample. Despite this finding, your firm did not re-inspect the remainder of the syringe sub-lot or the vial sub-lot. In addition, your firm did not conduct a formal risk assessment of the particulate contamination found in the drug product and its possible impact on product quality."

"Your firm has not rejected drug products failing to meet established standards or specifications and any other relevant quality control criteria [21 CFR 211.165(f)] For example...In addition, we note that the dissolution results using the new method are approximately […] higher than previous results or the same lots using the inappropriate method. You have … not provided your risk analysis of the lots that were analyzed with the current method, or your determination of the acceptability of product analyzed using the former apparently inappropriate method."

"Your firm has not established separate or defined areas or such other control systems as necessary to prevent contamination or mix-ups during aseptic processing. [21 C.F.R. § 211.42(c)]. For example,
a) Your firm lacked an adequate assessment of the cross-contamination risks posed by the manufacture of several potentially hazardous compounds (e.g., beta lactam antibiotic and steroid products) at your facility. Deficiencies were observed in the shared manufacturing areas where you manufacture potentially hazardous compounds and sterile ophthalmic drug products intended for the U.S. market. You should ensure that a documented justification and a well-designed contamination prevention strategy has been put in place to minimize the possibility of contamination. FDA encourages sound risk assessment approaches to address hazard identification, exposure consequences, and implement controls designed to prevent and detect cross-contamination. To achieve an acceptable level of risk requires sound and risk-based assurance that one drug does not contaminate another drug."

Fazit: Das Thema Risikomanagement wird präsenter in den FDA-Warning Letters. Auffällig ist aber, dass in den Warning Letters des Fiskaljahres 2010 der Fokus noch sehr auf der Risikoanalyse/-Betrachtung liegt. Allerdings sind die Fälle, auf die eine Risikoanalyse/-Betrachtung anzuwenden sind, nicht mehr nur, wie in der Vergangenheit, auf den Themenkreis Validierung/Qualifizierung bezogen.  

Autor:
Sven Pommeranz
CONCEPT HEIDELBERG

PS. Auf der Concept-Veranstaltung ICHQ9/Annex 20 Kurs am 17./18. März 2011 in Mannheim lernen Sie Beispiele für Risikoanwendungen in der Praxis kennen. Sie sind eingeladen, eigene Beispiele aus Ihrem Unternehmen im stattfindenden Workshop zu bearbeiten, um die Ergebnisse dann direkt im Unternehmen anwenden zu können.