Gravierende Mängel in der Qualitätssicherung
Die Qualitätssicherungseinheit, Quality Control Unit, ist ein zentrales Organisationselement in pharmazeutischen Betrieben, die Fertigarzneimittel oder Wirkstoffe herstellen. Der 21 CFR 211 definiert in Paragraph 22 die Verantwortlichkeiten der Quality Control Unit wie folgt:
There shall be a quality control unit that shall have the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products, and the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated. The quality control unit shall be responsible for approving or rejecting drug products manufactured, processed, packed, or held under contract by another company.
Die Qualitätssicherungseinheit steh immer im Fokus einer FDA-Inspektion und es ist daher nicht verwunderlich, dass ein hoher Anteil der Warning Letters, die in einem Fiskaljahr versendet werden, Mängel im Qualitätssicherungssystem beschreiben.
Im Fiskaljahr 2022 lag der Anteil an Warning Letters mit Beschreibungen von GMP-Verstößen gegen die Anforderungen des 21 CFR 211.22 mit 56 % besonders hoch.
Die Grafik auf dieser Seite veranschaulicht den zunehmenden Trend in der Häufigkeit der zitierten Mängel im Bereich Qualitätssicherung für einen Zeitraum von 5 Fiskaljahren. Sie enthält ebenfalls die Trends der weiteren GMP-Mängel, die sich stets unter den 5 meist zitierten befinden.
Im Folgenden werden beispielhaft typische Zitate aus drei Warning Letters beschrieben, die jeweils deutlich machen, inwiefern die Qualitätssicherungseinheit nach Einschätzung der FDA-Inspektoren versagt hat. Dazu wird eine themenbezogene Darstellung verwendet, die in 4 Abschnitte gegliedert ist:
• die Beschreibung des GMP-Verstoßes
• die Rückmeldung der Firma (Company’s response),
• das Feedback FDA (FDA’s Feedback)
• die Nachforderungen von Dokumenten/Nachweisen der FDA
| Your firm's quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22). |
| Sanitor Corporation Stanton, CA, United States, 29 Nov 2021 |
Seminarempfehlung
Amsterdam, The Netherlands27-29 November 2024
You contract manufacture over-the-counter drug products including benzalkonium chloride-based hand sanitizer. Multiple batches of hand sanitizer drug product failed microbial total plate count (TPC) testing with results of Too Numerous to Count (TNTC). Your quality unit (QU) failed to adequately investigate and identify the root cause for the microbial contamination in your hand sanitizer drug product. Instead of conducting a thorough investigation and implementing corrective action to prevent contamination, your QU:
- Approved the addition of an antimicrobial preservative to batches that initially failed microbial TPC testing, and were then released for distribution by your customer; and
- Approved the addition of an antimicrobial preservative to batches not yet tested for microbial TPC so that they would yield a passing result, and were released for distribution by your customer.
Additionally, stability samples of a batch of hand sanitizer drug products (previously released without the addition of the preservative) failed the three-month stability test interval for microbial TPC with a result of TNTC. You stated that you notified the customer and recommended a voluntary recall of the drug product. Your customer declined to do so and informed you that the lot was sold and consumed. No further actions were taken.
Company's response
In your response, you stated that you have performed a management review with your consultant and determined that your procedures were "inadequately robust and/or detailed."
FDA's Feedback
Your response is inadequate in part, because you did not provide a thorough investigation into the microbial failures. You also did not provide adequate details of your consultant's review and remedial actions. Further, your QU did not exercise its duties and oversight to ensure that future investigations are thorough, including root cause determination and appropriate corrective action strategies.
What the company should provide
In response to this letter, provide the following:
- A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, out-of-specification results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, corrective action and preventive action (CAPA) effectiveness, QU oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.
- Complete investigations into all batches with potential objectionable microbial contamination or an out-of-specification microbiological result (whether or not later invalidated). The investigations should detail your findings regarding the root causes of the contamination.
- An independent assessment and remediation plan for your CAPA program. Provide a report that evaluates whether the program includes effective root cause analysis, ensures CAPA effectiveness, analyzes investigation trends, improves the CAPA program when needed, implements final QU decisions, and is fully supported by executive management.
| Your firm's quality control unit failed to approve or reject all procedures or specifications impacting on the identity, strength, quality, and purity (21 CFR 211.22). |
| Health Plus Inc. Chino, CA, United States, 29 Dez 2021 |
You failed to establish, review, and approve all procedures, including those which may impact the safety, identity, strength, quality, and purity of your drug product. Specifically, your QU failed to implement SOPs that are critical to ensure the quality of the drug product, such as the SOPs for operating the equipment used to manufacture the drug product.
Company's response
In your response, you stated that you will create and revise corresponding SOPs.
FDA's Feedback
Your response is inadequate because you failed to provide supporting documentation (e.g., draft SOPs, training). Additionally, you provided similar responses to repeat or similar observations in the 2012, 2013, and 2018 inspections. Therefore, we have no assurance that your corrective actions will be implemented.
What the company should provide
In response to this letter, provide the following:
- A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include, but not be limited to:
- A determination of whether procedures used by your firm are robust and appropriate
- Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices
- 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 products - A complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed CAPA plan that comprehensively remediates your firm's documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous records throughout your operation.
- Your action plan to address any product quality or patient safety risks for your drug product in U.S. distribution, including potential customer notifications and recall.
| Your firm's quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22). |
| Clinical Resolution Laboratory Inc. Brea, CA, United States, 1 March 2022 |
Seminarempfehlung
Amsterdam, The Netherlands28/29 November 2024
Qualified Person Forum 2024
Your firm lacked an adequate quality unit (QU). For example, your quality unit failed to establish procedures describing QU roles, responsibilities, and authorities. Furthermore, your QU's oversight of your drug manufacturing operations was inadequate. For example, your QU failed to perform the following:
- Provide adequate CGMP training to personnel.
- Evaluate and investigate discrepancies and out-of-specification results.
- Maintain and investigate customer complaints.
- Establish and maintain adequate procedures with your contract testing laboratories, for example a quality agreement.
Company's response
In your response, you stated that you have faced difficulties in recruiting qualified personnel for QU functions during the COVID- 19 pandemic.
FDA's Feedback
Your response is inadequate. Many of the failures of the QU were observed during the previous inspection, dated May 8 to May 15, 2018. Many of your commitments from that inspection were not implemented.
What the company should provide
In response to this letter, provide a comprehensive independent assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include, but not be limited to:
- A determination of whether procedures used by your firm are robust and appropriate.
- Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices.
- Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products.
Also, describe how top management supports quality assurance and reliable operations, including but not limited to timely provision of resources to proactively address emerging manufacturing/ quality issues and to assure a continuing state of control.
In diesen Beispielen werden typische Fehlleistungen der Qualitätssicherung deutlich, mit denen FDA-Inspektoren häufig konfrontiert sind:
- Untätigkeit bei nicht bestandenen Tests bzw. nicht erfüllter Spezifikation
- Das Fehlen von Arbeitsanweisungen/SOPs für qualitätskritische Herstellungsschritte sowie für die Verantwortlichkeiten der Quality Unit wird toleriert
- Die Ursachenforschung für Prüfergebnisse außerhalb der Spezifikation (Out-of-Specification Results, OOS) wird verschleppt oder nicht durchgeführt; Chargen werden trotzdem freigegeben.
- Eine Oberaufsicht auch über externe Dienstleister (z. B. Prüfung im Lohnauftrag) findet nicht statt.
Jeder Warning Letter enthält eine Liste von Dokumenten, die von der betreffenden Firma nachzuliefern ist. Im Fall der hier beschriebenen Defizite im Qualitätssicherungssystem sind das im Wesentlichen immer folgende Nachweise:
- Eine vollständige Bewertung des Managements von Abweichungen
- Ein Maßnahmen-Plan zur Verbesserung der Ursachenforschung bei Abweichungen
- Eine unabhängige Bewertung des CAPA-Programms sowie ein Plan zu dessen Optimierung
- Eine Bewertung des Dokumentations-Systems
Wichtig bei diesen Bewertungen ist, dass sie von unabhängiger Seite, also nicht von der betroffenen Abteilung, durchgeführt werden sollen; dies zeigt sich in der stets wiederkehrenden Formulierung: "…provide a comprehensive independent assessment…"
Diese Dokumentenliste kann als nützliche Hilfe für die Vorbereitung auf eine FDA-Inspektion dienen.
| Die Datenaufbereitung der FDA Warning Letter Analyse Im Rahmen der regelmäßigen systematischen Analyse der in den jeweiligen Fiskaljahren veröffentlichten Warning Letters zu Verstößen gegen cGMP erarbeitet CONCEPT Heidelberg Statistiken ("Top Ten-Listen der häufigsten GMP-Mängel") sowie themenbezogene Auszüge aus den Warning Letters in der in diesem Artikel verwendeten Gliederung, (z. B. zu Quality Unit failures, Stability, OOS-Results etc.). Gegliederte Darstellungen zu weiteren relevanten Themen sind in Arbeit. Des Weiteren wurde eine Keywords-Liste für das Fiskaljahr 2022 erstellt, die wichtige Stichwörter zu cGMP mit der jeweiligen Zuordnung zu den betreffenden Warning Letters enthält. Diese Dokumente sind im Mitgliederbereich der ECA verfügbar. |
Über den Autor:
Dr. Gerhard Becker
... ist seit 2002 bei CONCEPT HEIDELBERG und seither Fachbereichsleiter für die Themen Wirkstoffe und Dokumentation.
