Capa

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Introducción al sistema de gestión CAPA

R.Castillejo / CAPA System 1

Ricard CastillejoJefe de Gestión de Terceros‐Calidad Externa

Boehringer Ingelheim España, S.A.+34 93 4 045 3 95

ricardo.castillejo@boehringer‐ingelheim.com

Sistema CAPA

• Corrective Actions Preventive Actions

• CAPA es un sistema de Calidad GMP cuyos objetivos son– Evitar que las investigaciones de las no‐conformidades sean débiles, favoreciendo la

búsqueda de las verdaderas causas raíz

– Mediar la eficacia de las acciones correctivas o preventivas que se emprenden para asegurar su eficacia

– Extender la investigación a todo el ámbito potencialmente afectado por la no‐conformidad

– Buscar las causas raíz comunes de las no‐conformidades de distintos sistemas de calidad GMP con el fin de evitar la incidencia o la re‐incidencia.

– Asegurarse de que el Management está informado

– Sistematizar el sistema de seguimiento de acciones correctivas o preventivas

– Realizar un estudio de tendencias de los eventos de calidad


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Breve historia sistema CAPA

• El concepto fue definido por la FDA americana en los años ’90 para solventar las observaciones continuas relativas a sus objetivos (transparencia #2)

• Aplicado en primero lugar en los “Medical Devices” en su ISO 13.485 [1996, en su primera versión]

• Se introdujo como parte de las inspecciones de “Medical Devices” para evaluar su nivel de cumplimiento de la “Quality System Regulation” (21 CFR 820, Quality System Regulation) [1996]

• Se introdujo en la “Guide to Inspection of Quality Systems, QSIT” [1999]

3R.Castillejo / CAPA System

Sistema CAPA

La guía para inspecciones de losinspecciones de los sistemas de calidad: QSIT


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CAPA en la QSIT


Necesidad del sistema CAPA

• El sistema CAPA es un sistema GMP cuyo lugar natural es un espacio superior al de los otros sistemas GMP y cuyo objetivo es velar para que los demás sistemas se apliquen correctamente, a tiempo, con la profundidad necesaria, con un espíritu de mejora continua que permita evitar la reincidencia de los problemas, etc.

CAPA

6R.Castillejo / CAPA SystemCalibraciones Auto‐inspecciones Liberaciones

Control de Cambios Desviaciones Investigación de OOS

6R.Castillejo / CAPA SystemCualificación de Proveedores

Mantenimiento Preventivo

Formación

PQR Auditorías Externas Reclamaciones/Retirada …

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Requerimientos normativos

Sistema CAPA


Requerimientos Normativos

Citas en Regulaciones

• ISO 13 485: 2003 “Medical Devices – Quality Management• ISO 13.485: 2003 Medical Devices – Quality Management Systems – Requirements form Regulatory purposes

• 21 C.F.R. § 820 (1997) Quality System Regulation (Medical Devices)– 21 C.F.R. § 820.100 Corrective and preventive action.

• Guide to Inspection of Quality Systems QSIT (1999) Quality System Inspection Techniques (Medical Devices)System Inspection Techniques (Medical Devices)

Referencias indirectas– 21 CFR 210 / 211 cGMPs

– EU GMPs8R.Castillejo / CAPA System

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21 § 820.100 Corrective and preventive action.(a) Each manufacturer shall establish and maintain procedures for(a) Each manufacturer shall establish and maintain procedures for

implementing corrective and preventive action. The procedures shall include requirements for:

(1) Analyzing processes, work operations, concessions, quality audit reports, quality records, service records, complaints, returned product, and other sources of quality data to identify existing and potential causes of nonconforming product, or other quality problems. Appropriate statistical methodology shall be employed where necessary to detect recurring quality problems;

(2) Investigating the cause of nonconformities relating to product, processes, and the quality system;


21 § 820.100 Corrective and preventive action.


(3) Identifying the action(s) needed to correct and prevent recurrence of nonconforming product and other quality problems;

(4) Verifying or validating the corrective and preventive action to ensure that such action is effective and does not adversely affect the finished device;

(5) Implementing and recording changes in methods and procedures needed to correct and prevent identified quality problems;

(6) Ensuring that information related to quality problems or nonconforming product is disseminated to those directly responsible for assuring the quality of such product or the prevention of such problems; and

(7) Submitting relevant information on identified quality problems, as well as corrective and preventive actions, for management review.

(b) All activities required under this section, and their results, shall be documented.


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Guide for Inspection of Quality Systems QSIT


CAPA System : Purpose/Importance

The purpose of the corrective and preventive action subsystem is to collect information, analyze information, identify and investigate product and quality problems, and take appropriate and effective corrective and/or preventive action to prevent their recurrence. Verifying or validating corrective and preventive actions, communicating corrective and preventive action activities to responsible people, providing relevant information for management review, and documenting these activities are essential in dealing effectively with product and quality problems, preventing their recurrence, and preventing or minimizing device failures. One of the most important quality system elements is the corrective and preventive action subsystem.


21 CFR Part 211.22 (Quality Control Unit)

ibiliti f lit t l it t th t


• responsibilities of a quality control unit...to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated.

Part 211.92 (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 theinvestigated…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 recordof the investigation shall be made and shall include the conclusions and follow‐up.


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EU GMPs


Producción

1. Las diferentes operaciones de producción se llevarán a cabo de acuerdo con instrucciones y procedimientos previamente establecidos y de conformidad con las prácticas correctas de fabricación. Deberá disponerse de recursos adecuados y suficientes para la realización de controles durante el proceso de fabricación. Las desviaciones del proceso y los defectos de los productos se documentarán y serán objeto de una p y jinvestigación en profundidad.


EU GMPs


Punto 1.3

x) es necesario examinar las reclamaciones sobre los productos comercializados, investigar las causas de los defectos de calidad y tomar las medidas convenientes respecto a los productos defectuosos y para evitar la repetición de estos casos.


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EU GMPs


Capítulo 1: Revisión de la calidad del producto

1.5 Es necesario que se realice una revisión periódica de los parámetros de calidad, incluyendo productos para exportación, para poner de relieve cualquier tendencia y para identificar las mejoras del producto y del proceso…… Estas verificaciones periódicas deben incluir por lo menos:verificaciones periódicas deben incluir por lo menos:

iv) Una revisión de las desviaciones significativas o no conformidades de sus investigaciones y de la eficacia de las acciones correctoras y preventivas que se tomaron.


EU GMPs


Capítulo 8: Reclamaciones y Retiradas del Mercado

8.4 Si se descubre o sospecha un defecto en un lote, habrá que considerar si es necesario comprobar otros lotes para determinar si se han visto también afectados. En especial, deberán investigarse otros lotes que puedan contener partes reelaboradas del lote defectuoso.


Otras Ref.

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Observaciones en Inspecciones FDA

Sistema CAPA


Necesidad del sistema CAPA

• El sistema CAPA es un sistema GMP cuyo lugar natural es un espacio superior al de los otros sistemas GMP y cuyo objetivo es velar para que los demás sistemas se apliquen correctamente, a tiempo, con la profundidad necesaria, con un espíritu de mejora continua que permita evitar la reincidencia de los problemas, etc.

CAPA

18R.Castillejo / CAPA SystemCalibraciones Auto‐inspecciones Liberaciones

Control de Cambios Desviaciones Investigación de OOS

18R.Castillejo / CAPA SystemCualificación de Proveedores

Mantenimiento Preventivo

Formación

PQR Auditorías Externas Reclamaciones/Retirada …

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Observaciones en Inspecciones FDA relacionadas con el sistema CAPA

Sistema CAPA

relacionadas con el sistema CAPA


Quotes from Current FDA Warning Letters & 483

• “Your firm fails to implement and maintain corrective and preventive action (CAPA) procedures that include requirements for analyzing processes work operations concessions quality audit reports qualityprocesses, work operations, concessions, quality audit reports, quality records, service records, complaints, returned product, and other sources of quality data to identify existing and potential causes of nonconforming product, or other quality problems as required by 21 CFR 820.1 00(a)(1).” (WL)


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• “Your firm fails to establish and implement corrective and preventive action (CAPA) procedures that include requirements for identifying the


act o (C ) p ocedu es t at c ude equ e e ts o de t y g t eaction(s) needed to correct and prevent recurrence of non‐conforming product and other quality problems as required by 21 CFR 820.100(a)(3)” (WL)


• “All activities required by 21 CFR 820.100 must be verified or validated to ensure that such action is effective and does not adversely affect finished devices and the results of these activities shall be documented as


devices, and the results of these activities shall be documented as required by 21 CFR 820.100(a)(4) and (b). Your firm's CAPA procedures fail to document how analysis is done and fails to require verification/validation that CAPA does not adversely affect finished devices (FDA 483, Item #8).” (WL)


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• “Your quality control unit has failed to follow applicable written procedures [21 C.F.R § 211.22(d)]. For example, ….. your QCU failed to


follow your draft standard Operating Procedure (SOP), 10‐008.00, for ensuring Problem analysis and Corrective Action Reports (PACARS) were assigned a target completion date. Your SOP requires a target completion date to be assigned when corrective actions require more than (b)(4) days to complete. Sixty percent (33 of 55) PACARS (documenting corrective and preventive actions) generated between January and October 2009, were incomplete at the time of our inspection. One PACAR was open for 11 months without an assigned target completion date ” (WL)months without an assigned target completion date. (WL)

…. Cont…….


…. Cont…….


• “In your response, you state you will revise your CAPA tracking process to include such items as the assignment of an owner responsible for executing the CAPA, assignment of due dates, tracking each CAPA to conclusion and verification of completion by the quality unit, and a management process for monitoring the monthly progress of CAPAs. However, this is a repeat observation from the 2007 inspection of your facility.” (WL)


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Observaciones en Inspecciones FDA relacionadas con Auto inspecciones

Sistema CAPA

relacionadas con Auto‐inspecciones


• “Internal quality audits conducted by your firm failed to verify that the quality system was effective in fulfilling quality system objectives (FDA 483 Item #2) ”


483, Item #2).”


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Observaciones en Inspecciones FDA relacionadas con Formación

Sistema CAPA

relacionadas con Formación


• “You do not state how the effectiveness of the training on …. procedures will be assessed and what corrective action will take place if the training is


not effective .” (WL)


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• “…. Again, your firm does not give any dates for reassessment of this training program and how the effectiveness will be measured . In your


initial response dated ……, you state that a Corporate Corrective and Preventive Action (CAPA) plan is being prepared to enhance quality systems and manufacturing controls at ….. facilities . However, your quality team had performed an audit of your firm and did not discover that these …. units had been shipped even though an Investigation Internal Report had been generated for the deviation of the missing answers …..Performing a complete audit as a corrective action may determine the status of compliance with your firm's quality program but unless thestatus of compliance with your firm s quality program, but unless the management of your firm and the training of your employees is sufficient to prevent the shipment of such units, deviations to the FDA regulations will continue to occur.” (WL)


Observaciones en Inspecciones FDA relacionadas con OOSs

Sistema CAPA

relacionadas con OOSs


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• “Failure to establish and follow adequate written procedures applicable to the Quality Control unit [21 CFR 211 .22]. For example, …. requires that QA


verify implementation of corrective actions . Corrective action was not implemented in response to CAPA 05‐00044, which was initiated in response to OOS investigation 05‐1‐2‐0025 . The OOS investigation, dated October 14, 2005 identified …. The CAPA was issued on October 18, 2005 and QA verified corrective action on March, 1, 2006. However, the proposed corrective action had not yet been implemented at that time . Effective corrective action, replacement of the scale, was not implemented until March 31 2006 after three additional out ofimplemented until March 31, 2006, after three additional out of specification pre‐fill assays were assigned the same root cause .” (WL)


• “Regarding the OOS investigation referenced in FDA 483 Observation #2 (b)(1), your response states that “the original result was invalidated on


establishing enough scientific evidence.” There are additional instances, in response to Observations #2 (e)(1) and #2 (e)(2), where your response fails to provide evidence to support analytical error as your root cause determination during OOS investigations.” (WL)


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• “With regard to OOS investigations, there were instances where your firm determined the root cause to be analytical error. We expect that any


analytical error be fully documented, and that without a definite root cause determination, the original OOS results would be considered to be legitimate and would be included as part of the decision to release the associated batch”. (WL)


• During the accuracy test in the validation of ….. Impurities method, the


g y p100% standard showed unknown peaks that were not shown on the ….. standards. Even though you obtained atypical chromatograms, you failed to perform an investigation to identify the source of the contamination.


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• Quality investigations into out‐of‐spec (OOS) data were incomplete. Unexplained OOS data were not adequately investigated by the QC lab. ….. Investigations did not extend to other products.


Observaciones en Inspecciones FDA relacionadas con el Sistema de

Sistema CAPA

relacionadas con el Sistema de Reclamaciones


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• ”…. For example, your firm has written procedures that mandate performance of a "global investigation" in response to multiple complaints


or discrepancies of a similar nature . However, your response and our inspection indicate an incomplete commitment to identify global issues .Please note that management review of product quality issues and adverse trends is integral to identifying and promptly correcting problems Review and appropriate global response to adverse trends ensures ongoing control of manufacturing by promptly correcting root causes . Such activities are a fundamental part of the Quality Control Unit oversight role and are underpinned by a vigilant management reviewoversight role and are underpinned by a vigilant management review system . Ongoing assurance of quality and trends help identify appropriate management action to ensure sustainable quality and prevent deviations, failures, and defects .” (WL)


Observaciones en Inspecciones FDA relacionadas con PQR

Sistema CAPA

relacionadas con PQR


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• The Quality Review Annual Summary Report documented that 4 of 5 lots


y y pfailing to meet in‐house potency release specs were lots that were frozen and thawed. The report stated that the practice of freezing and thawing product would be discontinued until deemed appropriate..

Although there was no resolution to this action, the practice of freezing and thawing bulk lots has been resumed.

SOP ….. Quality Review does not include a mechanism for tracking and follow‐up of open corrective / preventive actions identified during the product quality reviews.



Sistema CAPA

relacionadas con el Sistema de Desviaciones


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• “Failure to maintain written standard operating procedures (SOP) including all steps to be followed in the collection, processing,


compatibility testing, storage and distribution of blood and blood components for transfusion and manufacturing purposes [21 CFR 606 .100(b)] . For example:

– You failed to follow SOP #6405 entitled "Temperature Management" for initiating corrective and preventive actions (CAPAs) . Under the section "Freezer Temperature Monitoring" of your SOP, you are required to generate CAPA reports using form 8520‐2 in instances regarding temperature excursions/alarms . However, CAPA reports were not generated on form 8520‐2 for five instances of temperature excursions/alarms on /6/06, 3/31/06, 5/30/06, 8/12/06, and 6/24/07 “. (WL)


• “….Please explain the reason for the delay in implementing these corrective actions. Furthermore, we have concerns that the deficiencies


listed above are similar to violations documented during the FDA inspection of your firm in December 2005 and provide evidence of recurring CGMP deficiencies related to investigations for incidents of particulate matter contamination. In addition, please provide information related to the investigation for particulate matter contamination in Lot# (b)(4).” (WL)


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• “Regarding FDA 483 Observation# 1.3(d), four deviation reports (PB04008, PB05002, PB05006, and PB07008) were initiated to document particle


contamination incidents during aseptic production operations. Your response references a probable cause related to the “low impact” designations for particulate matter contamination incidents, but failed to provide documentation to support this justification. Please include this documentation in your response.“ (WL)


• “Your firm failed to follow its procedures for the preparation of master production and control records as required by 21 CFR § 211.186(a). Your


firm's "Batch Record Recording Procedure" states that only blue or black ink can be used to record information in the Batch Record Book. However, for at least six lots, the Master Packaging Instruction sections of the batch records contained reconciliation and disposition data written in pencil, erased, and then rewritten in ink. In addition, some data that had been rewritten in ink was different from the original data that had been written in pencil. You indicated in your response that the Quality Control Unit (QCU) member associated with this practice is no longer working for the(QCU) member associated with this practice is no longer working for the firm; however, your proposed corrective action did not include a review of other production and control records to ensure that this practice did not occur in other instances, particularly where the QCU inspector could have advised production employees to use pencil.” (WL)


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• Eight final product lots ….. failed to meet internal specifications for post


g p p plyophilization potency. Each of these lots were either destroyed or designated for experimental use only.

However, no investigations into the root cause of these failures were initiated and no corrective / preventative actions have been implemented.


• Upon compression, several products exhibited process deviationswhich


p p p presulted in batches being reworked even though the root cause was not identified.

Lot number ….. was reworked after the tablets were found to be sticking. The investigations indicates that this was ‘possibly’ due to high moisture content. The rework involved re‐drying the product and re‐blending with additional magnesium stearate. There was no corrective action actiontaken to prevent future occurrences.


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• Foreign matter was found during the Quality Control release testing of lot


g g y g….. This lot was subsequently rejected ….. for the presence of foreign matter.

However, there was no investigation that evaluated the manufacturing process to identify possible causes for the foreign contamination. Additionally, there were no corrective or preventative actions initiated to prevent future occurrences.


• On ….., the lyophilizer transducer malfunctioned and the chamber aerated


y pto non‐sterile air during the lyophilization of lot ….. This lot was scrapped and the transducer was replaced.

However, there was no QI into the root cause of this failure and no assessment was made regarding the adequacy of the calibration / maintenance program.


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• There is no documentation that corrective and preventive actions were


pinstituted into validation failures of pH and conductivity due to operator errors, especially when the validation errors involved the same operator.



• Firm has no system in place for tracking open environmental and water monitoring excursions. SOPs require excursion logs to be maintained, however, they fail to describe responsibilities regarding timely review and closure of investigations. Several investigations were found to be open for greater than one year.


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• The firm’s investigations were inadequate in that the investigations failed to evaluate the scope of the problem to assure that the manufacturing deviation did not extend to other batches of the same API or other APIs associated with the specific failure or discrepancy.



Sistema CAPA

relacionadas con el Sistema de Liberaciones


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• “There is no assurance that the coating process for XXXX tablets can reproducibly meet the finished product specifications for appearance.


Partial lot rejections have been documented for seven lots that failed to meet the in‐process AQL for such defects as rough coating and white specks. For example, 43% of XXXX tablets, lot CPI874, from coating pan (b)(4) were found to contain coating defects.

The practice of releasing partial batches (after sorting and rejecting tablets with identified coating defects) without a thorough understanding of the cause of the defect is not acceptable. You must identify the root cause and validate and implement corrective actions (e g process or components)validate and implement corrective actions (e.g., process or components). In your response, you state that you have a "project" in place to address coating deficiencies. However, your response is inadequate because you did not commit to discontinue this practice or sorting defective batches while you complete the corrections.” (WL)



Sistema CAPA

relacionadas con el Sistema de Cualificación de Proveedores


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• There is lack of assurance that the cleaning assessment method for ….. is


gsuitable for use. The percent swab recovery between the contract testing lab and the firm’s analytical R&D lab was outside the acceptance criteria of ….. The result of average swab recovery at the outside testing lab was 91.0% while the average swab recovery at the firm’s analytical R&D lab was 97.9%. The method transfer study concluded that this difference was statistically insignificant although there was no investigation to evaluate why the acceptance criteria of ….. was not met.


2009: Observaciones 483 (Medical Devices)


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2009: Warning Letters (Medical Devices)


Dedicación durante inspecciones


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Estructura del Sistema CAPA

Sistema CAPA


Evolución histórica

1. Orientación al lote: Cuando aparecía una problema se arreglaba la no‐p p gconformidad sobre el lote o el objeto de la no‐conformidad.

2. Orientación al proceso/sistema afectado: (1) + Se elimina la causa por la que ha ocurrido para evitar la recurrencia de la no‐conformidad.

3. Orientación a otros procesos/sistemas similares: (2) + Se eliminan las causas en otras áreas para evitar que la no‐conformidad ocurra en ellas.


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Definiciones

• NO‐CONFORMIDADl d / f óNo cumplimiento de un requerimiento / especificación

(relacionado con el producto/proceso/Sistema de Gestión de la calidad).

Ejemplos:

1) Aparece una ampolla defectuosa durante el llenado de ampollas

2) Aparece una calibración con un parámetro fuera de rango


Definiciones

• CORRECCIONó d l f d d d dAcción de eliminar una no‐conformidad detectada• Ej: re‐trabajar el producto, re‐procesarlo.

• Una corrección puede ser realizada conjuntamente con una acción correctiva.

Ejemplos:

1) Se muestrean las ampollas para ver si se supera el AQL fijado y, en su caso, se inspecciona el resto de ampollas

2) Se arregla el problema en el lazo de medición y se revisan las mediciones realizadas en estas condiciones para evaluar el impacto posible en productos ya procesados.


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Definiciones

• ACCION CORRECTIVAAcción de eliminar la causa raíz de una no‐conformidadAcción de eliminar la causa raíz de una no conformidad detectada (ya ha ocurrido)

• Ej: re‐validación, cambios frecuencia mantenimiento, instalar un nuevo IPC, etc.

• Puede haber más de una acción correctiva para una no‐conformidad.

• La acción correctiva está dirigida a evitar la recurrencia.• Esta enfocada al sistema afectado.

Ejemplos:

1) Se revisa y corrige la configuración de los mecheros de cierre de ampollas en la máquina de llenar ampollas.

2) Se estudia el sistema de cumplimiento del plan de calibración del instrumento afectado y se implementan las mejoras necesarias para asegurar que se pueda cumplir (frecuencias, recursos, etc.)


8.5.2 Corrective Action – Corrective actions shall be

Definiciones: ISO 13.485:2003

appropriate to the effects of the nonconformities encountered. A documented procedure shall be established to define requirements fora) reviewing nonconformities (including customer complaints)b) determining the cause of nonconformitiesc) evaluating the need for action to ensure that nonconformities to not recur

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d) determining and implementing action needed, including, if appropriate, updating documentation

e) recording of the results of any investigation and of action taken, andf) reviewing the corrective action taken and its effectiveness

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Definiciones

• ACCION PREVENTIVAAcción de eliminar la causa/s raíz de una no‐conformidadAcción de eliminar la causa/s raíz de una no conformidad potencial (todavía no ha ocurrido)

• Puede haber más de una acción preventiva para una no‐conformidad.

• La acción preventiva está dirigida a prevenir la ocurrencia.• Está enfocada al sistema afectado y a los que pueden estar afectados por similitud.

Ejemplos:

1) Se revisa el sistema de ajuste de los mecheros de esa máquina y de otras de forma que se asegure que el sistema de ajustes de mecheros está bien parametrizado.

2) Preventivas2.1) Se revisa todo el plan de calibración (más instrumentos) para evaluar la necesidad de corregirlo en para que sea posible cumplirlo2.2.) Se revisan las tendencias de los instrumentos de medición críticos para averiguar si puede haber situaciones de aviso que ayuden a prevenir el problema.


• 8.5.3 Preventive action – The organization shall determine action to eliminate the causes of potential nonconformities

Definiciones: ISO 13.485:2003

action to eliminate the causes of potential nonconformities in order to prevent their occurrence. Preventive actions shall be appropriate to the effects of the potential problems.

• It is also determine potential nonconformities and their causesa) evaluating the need for action to prevent occurrence of nonconformities

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) g pb) determining and implementing action neededc) recording of the results of any investigations and of action taken, andd) reviewing preventive action taken and its effectiveness

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FUENTES DEL SISTEMA CAPA

Fuentes i

Fuentes E

Fuentes i

Fuentes E

Mejora ContinuaMejora Continua

• Proveedores• Audits Externos• Reclamaciones

Literat ra

• Desviaciones• OOs• Audits Internos

Análisis de

Sistema CAPA

internas Externas

Causa/sRaíz

Sistema CAPA

internas Externas

Causa/sRaíz

Monitorización de procesos y Productos

Monitorización de procesos y Productos

• Literatura• …..

Análisis de tendencias

• Monitorización• PQR• ……

Sistema de Control de Cambios


ProcessUnderstanding

CAMBIO: Mejora de Procesos y Productos

Process Understanding

Sistema CAPA

Ciclo CAPA de Mejora Continua

Mejora de Procesosy Productos

• Fallos

• Deficiencias

• Malfuncionamientos

• Rápida

• Específica

• Apagar fuegos

CORRECCION MONITORIZACION

• Evitar Recurrencia (CA)

• Mejorar el Sistema (PA)

ACCION CORRECTIVA / PREVENTIVA

1

4

5


• Problemas

• Reclamaciones

• Origen / Causa

• Análisis Causa Raíz

fuegos

• „Salvar el lote”

INVESTIGACION

Detección Incidencia

2

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Factores de éxito del Sistema CAPA

• Investiagación efectiva de la causa raíz (evidencias científicas)

• Enmarcar correctamente el ámbito de la investigación (objeto afectado y g ( j yobjetos potencialmente afectados)

• Evaluación completa del impacto del evento (otros productos, otros lotes, otros equipos, otros procesos, otros sistemas, etc.)

• Communicación & documentación (QA, Personas con el „expertise“,

• „Tracking“ de las Correcciones, Acciones Correctivas y Acciones Preventivas (cumplimiento de las „due dates“ por los responsables asignados). Imortancia de las herramientas informáticas para relacionar


g ) ptodas las CAPAs y analizar posibles causas raíces comunes)

• „Trending“ para verificar la eficacia del sistema CAPA. Todos los eventos deben ser capturados. Análisis por producto, proceso, sistema, causa, impacto, etc.)

Linked slides


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DESIGN CONTROLS (Major subsystem)

• Purpose/Importance

The purpose of the design control subsystem is to control the design process to assure that devices meet user needs, intended uses, and specified requirements. Attention to design and development planning, identifying design inputs, developing design outputs, verifying that design outputs meet design inputs, validating the design, controlling design changes, reviewing design results, transferring the design to production, and compiling a design history file help assure that resulting designs will meet user needs, intended uses and requirements.

Guide to Inspection Quality Systems, QSIT (1999)


Corrective and Preventive Actions (CAPA) (Major

subsystem)


The purpose of the corrective and preventive action subsystem is to collect information, analyze information, identify and investigate product and quality problems, and take appropriate and effective corrective and/or preventive action to prevent their recurrence. Verifying or validating corrective and preventive actions, communicating corrective and preventive action activities to responsible people, providing relevant information for management review, and documenting these activities are essential in dealing effectively with product and quality problems, preventing their recurrence, and preventing or minimizing device failures. One of the most important quality system elements is the corrective and preventive action subsystem.

Guide to Inspection Quality Systems, QSIT (1999)R.Castillejo / CAPA System 72

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Production and Process Controls (Major subsystem)


The purpose of the production and process control subsystem is to manufacture products that meet specifications. Developing processes that are adequate to produce devices that meet specifications, validating (or fully verifying the results of) those processes, and monitoring and controlling the processes are all steps that help assure the result will be devices that meet specifications.



Facilities and Equipment Controls

Todos aquellos aspectos que tienen que ver con

– Infraestructura p.ej. Salas limpias

– Medios de fabricación (máquinas/equipos de proceso o servicios) p.ej. Cualificación, Mantenimientos Preventivo, etc.

– Instrumentos de medición p.ej. Calibración– Etc.



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Records, Documents & Change Control


– Sistemas de Registros

– Sistema documental

– Sistema de Control de Cambios para mantener toda la infraestructura, procesos, equipos, etc. bajo control



Materials Control


– Demostrar que los materiales están bajo control en cualquier fase del proceso

– Reconciliaciones

– Rendimientos

– Control de inventarios

– Desviaciones de inventario

– Etc.



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Management Controls (Major subsystem)

Purpose/Importance

The purpose of the management control subsystem is to provide adequateThe purpose of the management control subsystem is to provide adequate resources for device design, manufacturing, quality assurance, distribution, installation, and servicing activities; assure the quality system is functioning properly; monitor the quality system; and make necessary adjustments. A quality system that has been implemented effectively and is monitored to identify and address problems is more likely to produce devices that function as intended. A primary purpose of the inspection is to determine whether management with executive responsibility ensures that an adequate and effective quality system has been established (defined, documented and implemented) at the firm. Because of this, each inspection should begin and end with an evaluation of this subsystem.

Guide to Inspection Quality Systems, QSIT (1999)R.Castillejo / CAPA System 77

EU GMPs


Section 1. Quality Control

1.4 (iv) Records are made, manually and/or by recording instruments which demonstrate that all the required sampling, inspecting and testing procedures were actually carried out. Any deviations are fully recorded and investigated.

1.4 (vi) … Product assessment includes a review and evaluation of relevant production documentation and an assessment of deviations from specified procedures.


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EU GMPs


Section 4. Batch Processing Records

4.17 (i) … notes on special problems including details with signed authorisation for any deviation from the manufacturing formula or processing instructions.

Section 4. Batch Packaging Records

4.18 (h) … notes on any special problems or unusual events including details, with signed authorization for any deviation from the Manufacturing Formula and Process Instructions.


EU GMPs


Section 5. Production

5.4 Damage to containers and any other problem which might adversely affect the quality of a material should be investigated, recorded and reported to QC.

5 15 Any deviation from instructions or procedures should be avoided as5.15 Any deviation from instructions or procedures should be avoided as far as possible. If a deviation occurs, it should be approved in writing by a competent person with the involvement of QC when appropriate.


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EU GMPs


Section 5. Production

5.39 Any significant deviation from the expected yield should be recorded and investigated.

5.55 Products which have been involved in an unusual event should only be reintroduced after special inspection investigation and approvalbe reintroduced after special inspection, investigation and approval…

5.56 Any significant or unusual discrepancy observed during reconciliation… should be investigated


EU GMPs

S i 8 C l i


Section 8. Complaints

8.4 If a product defect is discovered or suspected in a batch, consideration should be given to checking other batches in order to determine if they are affected.

Section 9. Self inspections

9.3 All self inspections should be recorded … and where applicable, proposals for corrective measures should be made.


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EU GMPs


Annex 1.Sterile products

6. Appropriate alert and action levels should be set for the results of particular and microbiological monitoring. If these limits are exceeded, operating procedures should describe corrective action.

42 Validation of aseptic processing should include a process simulation42. Validation of aseptic processing should include a process simulation test… the manufacturers should establish alert and action levels. Any contamination should be investigated.


EU GMPs


Annex 11 Computerised Systems

16. Any failures and remedial action should be recorded.

17. A procedure should be established to record and analyse errors and to enable corrective action to be taken.


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EU GMPs


Annex 16 Duties of the QP

8.1 (d) … any deviations or planned changes in production or QC have been authorised.

8.1 (h) … take into account any other factors which are relevant to the quality of the batchquality of the batch.


EU GMPs


Annex 18 GMP for APIs

2.16 Any deviation from established procedures should be documented and explained. Critical deviations should be investigated and its conclusions documented.

2 18 Procedures should exist for notifying responsible management in a2.18 Procedures should exist for notifying responsible management in a timely manner of serious GMP deficiencies, product defects, quality related complaints, recalls…


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EU GMPs



2.50 Regular quality reviews of APIs should be conducted … such reviews should be annual and include at least:• Failed batches• Critical deviations• Complaints/recalls• Adequacy of corrective actionsAdequacy of corrective actions…


EU GMPs



5.35 Deviations from approved standards of calibration on critical instruments should be investigated…

5.46 Incidents related to computerised systems that could affect the quality … should be recorded and investigated.


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EU GMPs



6.61 Complete records should also be maintained for … out of specification (OOS) investigations

8.15 Any deviation should be documented and explained. Any critical deviation should be investigateddeviation should be investigated.

12.22 A validation report should be prepared … including recommending changes to correct deficiencies.


Back up slides I


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Elementos del PQS: Sistema de Monitorización del Producto y el Proceso y Mejora Continua

Contenido ICH Q10: Mejora Continua

Diagrama Del Proceso RA

Q9

Plan deControl

Datos HerramientasDe Análisis de Datos

FeedbackCAPA +Análisis

MantenerEl Eº de Control

Identif. Fuentes de

SCP Validación de Procesos

Mejora C

HerramientasAnálisisba

ck +

Fee

dfor

war

d


Análisis deDatos

Fuentes deVariaciónProducto./ Proceso

FeedbackEn Calidad deProducto

ProcessUnderstanding

DOE, AM..

Continua

EspacioDe Diseño

Q8

AnálisisDe Fallos(7H’s, 7M’s....)

CAPA

Feed

b

Backup slides II


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Batch Record Review

CORRECTION CORRECTIVE / PREVENTIVE ACTIONS

• Process deviations (times/temps/speeds etc.)• Process yield deviation• Major equipment problems• Operator errors• Unusual events, observations


CORRECTIONBatch-specific, e.g.• reject• retest• sort outNon batch-specific, e.g.• retrain operator• repair equipment

CORRECTIVE / PREVENTIVE ACTIONS• Revise training system• Revise maintenance period• Change process

Complaints

PHARMACEUTICAL MEDICAL

INVESTIGATION

NOT JUSTIFIEDJUSTIFIED

CORRECTIVE / PREVENTIVE CORRECTION


ACTIONS• Revalidate process• Requalify equipment• Retrain operators• Change process/equipment • Add in process controls• Rewrite SOPs/batch records

• Replace product• Reject batch and other affected batches / products• Recall batch• Notify customers

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Material OOS

CORRECTIVE / PREVENTIVE

INVESTIGATE

CORRECTIONR j t


CORRECTIVE / PREVENTIVEACTIONS• Qualify supplier

•Re-validate process•Train operators

• Change supplier• Change specification

• Reject• Sort out

• Consider impact on other batches• Involve supplier

Calibration Failure


INVESTIGATE

CORRECTION


CORRECTIVE / PREVENTIVE ACTIONS• Change calibration frequency • Add redundant device• Check similar devices for calibration

CORRECTION• Isolate any/all affected batches• Test any/all affected batches• Recalibrate device• Replace device

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System Validation Review

(e.g. WFI system)


Breakdowns

Changes

OOS

Unusual events /occurrences

CORRECTION


ACTIONS• Requalify equipment • Increase monitoring frequency• Replace/rebuild/refurbish• Retrain operators

CORRECTION• Usually none – each event is supposed to have been corrected at the time it was observed

• Update documents; SOPs, drawings

Inspections

CUSTOMER AUDITS


SELF INSPECTIONS

OFFICIAL INSPECTIONS

CORRECTIONS


CORRECTIVE / PREVENTIVE ACTIONS• Evaluate / Change system • Change equipment• Change premises• Reorganise•Evaluate similar systems, cases

CORRECTIONS• Write SOPs• Change documents • Repair / refurbish• Calibrate• Qualify• Validate• Train operators

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Monitoring

ENVIRONMENTAL MONITORING

ALERT

OUT OF ACTION LIMIT

OUT OF ALERT LIMIT

TREND ANALYSIS


CORRECTIVE / PREVENTIVE ACTIONS• Rebuild areas • Change HVAC parameters• Re-qualify

CORRECTIONS• Re-clean area / re-test area• Identify organisms• Investigate impact on batch• Test batches more intensely• Retrain operators

Capa

Documents

Transcript of Capa