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Quality and GMP June 2012

Ms. Marlise Gyger Pharmacy Museum,

Totengässlein 3, 4051 Basel

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CAPA (Corrective Actions and

Preventive Actions) Quality and GMP

June 2012

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Table of Contents

• Regulatory Expectations • CAPA as part of the Pharmaceutical Quality System (ICH Q10) • Integrated Quality Management • Corrective Action • Preventive Action • CAPA Process • CAPA Challenges • FDA 483 Observations Citations • CAPA Management Software • Example • Summary and Conclusion




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Regulatory Expectations

ICH Q10 <Pharmaceutical Quality System>

The pharmaceutical company should have a system for implementing corrective actions and preventive actions resulting from the investigation of complaints, product rejections, non- conformances, recalls, deviations, audits, regulatory inspections and findings, and trends from process performance and product quality monitoring. A structured approach to the investigation process should be used with the objective of determining the root cause. The level of effort, formality, and documentation of the investigation should be commensurate with the level of risk, in line with ICH Q9 <Quality Risk Management>. CAPA methodology should result in product and process improvements and enhanced product and process understanding.

Quality and GMP 2010

June 7-9 and June 14/15, 2010,



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CAPA as part of the Pharmaceutical Quality System (ICH Q10)




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Integrated Quality Management




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Non-conformity (deviation, OOS)

Complaint

Audit Finding

Trending, Quality Review

Recall

CAPA

Change Control

Document Control

Training

Risk Assessment

Solutions Triggers

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Corrective Action

• Corrective action is aiming to correct an existing non-conformity and to avoid reoccurrence of the same non-conformity.

• Corrective action may arise e.g. from manufacturing deviations, OOS investigations, complaints, audit findings, recalls.

• A systematic investigation should be performed to determine the reason(s) for the non-conformities and to agree upon appropriate corrective action.

• Agreed corrective actions should be closely followed-up and monitored until their completion.

• In the frame of the management review, management should be notified about the costs and impact of failure including the respective corrective actions.




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Preventive Action

• Preventive action is aiming to avoid the initial occurrence of a non-conformity by proactively implementing improvements.

• Preventive action may result i.e. from trending of in process data, of analytical data, of audit findings, trending of root causes for non-conformities or complaints, from product quality reviews (annual product reviews), quality risk analyses, etc.

• Similar to corrective actions, agreed preventive actions should be closely followed-up and monitored until their completion. Effectiveness of preventive actions should be reviewed regularly, i.e. as part of the product quality review (annual product review).

• Information regarding preventive actions including costs and cost savings should be regularly subject to management review in support of maintaining and improving the effectiveness of the Quality Management System.




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CAPA Process

1. Identification: Define the problem 2. Impact / Risk Assessment: Initial assessment of the impact

and the magnitude of the problem. 3. Immediate Action: Protect the customer from the problem. 4. Root Cause Investigation: Identify the root cause of the

problem by using a systematic approach. 5. Conclusion and Quality Decision: Final thorough

conclusion on the impact and magnitude of the problem, decision regarding the use of the product, etc.

6. Action Plan: Define corrective and preventive actions. 7. Implementation and Follow-up: Implement corrective and

preventive actions and verify their effectiveness (global approach).




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1. Identification


To enable an efficient root cause investigation, the problem has to be clearly defined. • Collect all available information, ask questions: Who, when, what, why, how • Summarize the problem in a detailed and concise description. Example: The stability of product XYZ failed. The assay result of the 24 months stability time point of batch 123456 of product XYZ is out of specification. Specification: 95.0 % -105.0 %, Result: 93.4 %



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2. Impact / Risk Assessment The problem must be evaluated to determine the need for immediate, corrective and preventive actions and the level of action required, based on the impact and risk of the problem. The evaluation should include: • Potential Impact of the problem. • Risk to its customers and/or the company (i.e. risk to the patient related to the quality, efficacy or safety of the product; risk for the reputation of the company; risk of adverse regulatory actions; financial risk) • Immediate action that may be required




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3. Immediate Action

Immediate action is necessary, when the quality, efficacy or safety may be compromised by the problem.

Examples for immediate action: • Product recall • Blockage of the stock of a product • Rejection of a batch • Interruption of the production (i.e. until problem is assessed and fixed)




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4. Root Cause Investigation

A systematic approach should be applied to ensure that no potential root cause is lost through focusing only on a few assumed root causes. Tools can be applied to facilitate the investigation, i.e.: •Start with a brainstorming, i.e. using an Ishikawa diagram (fishbone or cause and effect diagram):




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Ishikawa, Kaoru (1990); (Translator: J. H. Loftus); Introduction to Quality Control; 448 p; ISBN 4-906224-61-X OCLC 61341428

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4. Root Cause Investigation (continued) List all potential root causes and evaluate their likelihood (also using available supportive data and information):

– Likely – Possible (but less likely) – Remote, unlikely

If more than one root cause is likely, a simulation of the potential root cause can help to prove the root cause. Finding the primary root cause is essential for determining appropriate corrective and/or preventive actions. These “root causes” suggest that the failure investigation did not go far enough

– Training, operator error or similar „obvious“ root causes Quality and GMP

June 2012 Ms. Marlise Gyger

Pharmacy Museum, Totengässlein 3, 4051 Basel

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5. Conclusion and Quality Decision • Summarize the identified root cause(s). • Summarize the impact and the risk for the customer and/or

company. • Document the quality decision, i.e.

– No impact of the deviation on the product quality, efficacy or safety – product can be released.

– Product is rejected due to major impact of the failure on product quality.

– Product is recalled.




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6. Action Plan

• Based on the result of the root cause analysis, all tasks required to correct the problem and prevent a reoccurrence are identified and included in an action plan.

• The plan assigns responsibilities and due dates for implementation.

• Enough detail must be included regarding the required action and the expected outcome.

• Pay attention on correct order of activities.




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7. Implementation and Follow-up • The Action Plan is executed and all tasks are completed. • The actions that were taken are documented. • The appropriateness and effectiveness of the actions taken is

evaluated: – Have all recommended changes been completed and verified? – Have all objectives been met? – Has training been performed to ensure that all affected

employees understand the changes that have been made? – Was an assessment made that the actions taken have not had

an adverse effect on other properties or aspects of a product or process.

• Closure of CAPA after successful implementation.




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CAPA Challenges Key Questions

• One of the most fundamental steps in the CAPA process is

completing an evaluation of the actions that were taken. • This evaluation must not only verify the successful completion of the

identified tasks, but also assess and adequately document the appropriateness and effectiveness of the actions taken.




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CAPA Challenges Key Questions

• Have all of the objectives been met? Did the actions correct or prevent the problem with adequate assurance that the same situation will not happen again?

• Have all the recommended changes in enough detail been completed, verified, and fully documented?

• Has training and appropriate communications been implemented to assure that all relevant employees understand the situation and the changes that have been made?




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FDA 483 Observations Citations 47 Quotes in GMP-Trends from 2007 to 2012

2. …..Corrective and Preventive Actions (CAPA) for deviations are not always carried out or are not documented as having been completed. For example:

a. Unplanned Deviation, UD ….. documents an incident that occurred when a batch was released without a completed Final Batch Accountability document. CAPA ….. was issued on ….. The CAPA due date was ….. Corrective action was to retrain auditors but there is no documentation that this occurred. b. UD ….. documents a batch record that was released on ….. without noting that a formulation deviation was required. Corrective action was to retrain the operator. According to the firm it was done but not documented. c. UD ….. documents that the incorrect amount of WFI was used to bubble point test the non-sterile clarification filter on ….. CAPA….. was issued on ….. to counsel the operator. The CAPA was due on ….. The CAPA was not completed.

GMP TRENDS Online − Issue 767 − January 1, 2009




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FDA 483 Observations Citations (ctd)

2. …..Corrective and preventive actions (CAPA) have not been verified or validated to ensure that the action is effective and does not adversely affect the finished device. Specifically: a. There is no effectiveness check data contained in CAPA ….. The CAPA was signed by QA as closed/parked on ….. The CAPA lists the effectiveness check as “Monitor the service database for occurrence of ….. errors to verify corrective action was effective” and provides a due date of ….. No service data or analysis of service data is contained in the CAPA.

GMP TRENDS Online − Issue 776 − May 15, 2009




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FDA 483 Observations Citations (ctd)

1. …..Written records of investigations into the failure of a batch or any of its components to meet any of its specifications do not include the conclusions and follow-up. Specifically, investigations are not conducted in a timely manner and follow-up activities to confirm implementation and effectiveness of corrective actions are not conducted when needed. For example:

a. Investigation Reports ….. were initiated to investigate positive results for air sampling in formulation room ….. where ….. injection are formulated. The organisms found were identified as ….. and unidentified ….. The results exceeded the action limit of ….. A trend analysis submitted during the inspection shows that the same type of organisms have been recovered on a regular basis. Although product was not formulated during these dates, the firm has not extended the investigation to the production area to determine the cause of the contamination and identify preventive and corrective actions (CAPA).

GMP TRENDS Online − Issue 732 − July 15, 2007




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CAPA Management Software

Most companies use software to facilitate the CAPA process (i.e. TrackWise, SAP, etc.)




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Pro Contra Standardized process, simple step by step process

Not flexible (changes require an additional validation of the workflow)

Facilitates follow-up (email reminders)

Expensive, especially for only a few users

Facilitates trending and product review (APR / PQR)

Adds unnecessary formalism

Facilitates overviews, reports, and summaries for inspections, audits

Individual workflows need internal resources

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Example

• Description of the problem: The filling silicone tubing (machine to filling of empty glass barrels), which contains silicone oil to wet the glass barrels of the emtpy syringes, did have small cracks; therefore the volume of the siliconizing solution applied to the glass barrel was too small, which resulted in enhanced friction for the administration of the drug product after the baking of the silicone in the hot air oven.




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Example (ctd)

• Result of the initial investigation and CAPA (informal, not systematic, quick fix ): Several months earlier, a similar issue happened on the same machine, but with the supply silicone tubing containing silicone oil; QA and production experts did not apply a systematic root cause analysis, but suggested to implement a 1-year shelf–life for the tubing based on individual experience.




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Example (ctd)

• Repetition of the investigation (problem): Since the issue occurred already twice, it was decided to apply a systematic root cause analysis.




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Example (ctd)

• Systematic root cause investigation and CAPA : Systematic root cause investigation Collection of all available information (e.g. batch records, complaints, trending reports of discrepancies) Brainstorming session with a group of experts with different background using Ishikawa diagram to collect potential root causes, and assign possible likelihood of issue to happen (e.g. IPC-control may be inadequate, possible shedding of silicone particles into glass barrels, silicone type) Confirmation of likely root cause; shelf life of silicone tubing not adequate for this purpose. Confirmed root cause after consultation with the supplier of the silicone tubing CAPA Shelf life of silicone tubing not adequate for this purpose; implementation of more stringent preventive measures (quarterly change of silicone tubing, silicone change date documented in individual executed batch record), monitoring of discrepancies on this machine for one year, if issue happens again.




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Example (ctd)

• Result: Appropriate CAPA identified and implemented; issue did not happen again.




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Example (ctd)

• Lessons learned: The initial inappropriate investigation and CAPA implementation lead to additional work and cost. A thorough investigation including consultation with all experts including supplier could have improved quality through an enhanced understanding of the process.




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Summary

Regulatory Expectations CAPA as part of the Pharmaceutical Quality System (ICH Q10) Integrated Quality Management Corrective Action Preventive Action CAPA Process CAPA Challenges FDA 483 Observations Citations CAPA Management Software Example




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Thank you for your attention




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