CAPA

(Corrective Actions and

Preventive Actions)
Quality and GMP
June 2012

Quality and GMP

June 2012

Ms. Marlise Gyger

Pharmacy Museum,
Totengsslein 3, 4051 Basel

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

Quality and GMP

June 2012

Ms. Marlise Gyger

Pharmacy Museum,
Totengsslein 3, 4051 Basel

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,

Ms. Marlise Gyger

Pharmacy Museum,
Totengsslein 3, 4051 Basel

CAPA as part of the

Pharmaceutical Quality System
(ICH Q10)

Quality and GMP

June 2012

Ms. Marlise Gyger

Pharmacy Museum,
Totengsslein 3, 4051 Basel

Integrated Quality
Management
Solutions
Triggers

Non-conformity
(deviation, OOS)
CAPA
Complaint
Risk
Assessment

Audit Finding

Document
Control
Change
Control

Trending, Quality
Review

Training
Recall

Quality and GMP

June 2012

Ms. Marlise Gyger

Pharmacy Museum,
Totengsslein 3, 4051 Basel

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.

Quality and GMP

June 2012

Ms. Marlise Gyger

Pharmacy Museum,
Totengsslein 3, 4051 Basel

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.

Quality and GMP

June 2012

Ms. Marlise Gyger

Pharmacy Museum,
Totengsslein 3, 4051 Basel

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).
Quality and GMP
June 2012

Ms. Marlise Gyger

Pharmacy Museum,
Totengsslein 3, 4051 Basel

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 %

Quality and GMP

June 2012

Ms. Marlise Gyger

Pharmacy Museum,
Totengsslein 3, 4051 Basel

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

Quality and GMP

June 2012

Ms. Marlise Gyger

Pharmacy Museum,
Totengsslein 3, 4051 Basel

10

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)

Quality and GMP

June 2012

Ms. Marlise Gyger

Pharmacy Museum,
Totengsslein 3, 4051 Basel

11

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):

Ishikawa, Kaoru (1990); (Translator: J. H. Loftus);

Introduction to Quality Control; 448 p;
ISBN 4-906224-61-X OCLC 61341428
Quality and GMP
June 2012

Ms. Marlise Gyger

Pharmacy Museum,
Totengsslein 3, 4051 Basel

12

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,
Totengsslein 3, 4051 Basel

13

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.

Quality and GMP

June 2012

Ms. Marlise Gyger

Pharmacy Museum,
Totengsslein 3, 4051 Basel

14

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.

Quality and GMP

June 2012

Ms. Marlise Gyger

Pharmacy Museum,
Totengsslein 3, 4051 Basel

15

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.
Quality and GMP
June 2012

Ms. Marlise Gyger

Pharmacy Museum,
Totengsslein 3, 4051 Basel

16

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.

Quality and GMP

June 2012

Ms. Marlise Gyger

Pharmacy Museum,
Totengsslein 3, 4051 Basel

17

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?

Quality and GMP

June 2012

Ms. Marlise Gyger

Pharmacy Museum,
Totengsslein 3, 4051 Basel

18

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
Quality and GMP
June 2012

Ms. Marlise Gyger

Pharmacy Museum,
Totengsslein 3, 4051 Basel

19

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

Quality and GMP

June 2012

Ms. Marlise Gyger

Pharmacy Museum,
Totengsslein 3, 4051 Basel

20

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

Quality and GMP

June 2012

Ms. Marlise Gyger

Pharmacy Museum,
Totengsslein 3, 4051 Basel

21

CAPA Management Software

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

Quality and GMP

June 2012

Ms. Marlise Gyger

Pharmacy Museum,
Totengsslein 3, 4051 Basel

22

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.

Quality and GMP

June 2012

Ms. Marlise Gyger

Pharmacy Museum,
Totengsslein 3, 4051 Basel

23

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 shelflife for
the tubing based on individual experience.

Quality and GMP

June 2012

Ms. Marlise Gyger

Pharmacy Museum,
Totengsslein 3, 4051 Basel

24

Example (ctd)

Repetition of the investigation (problem):

Since the issue occurred already twice, it was decided to apply a systematic root
cause analysis.

Quality and GMP

June 2012

Ms. Marlise Gyger

Pharmacy Museum,
Totengsslein 3, 4051 Basel

25

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.

Quality and GMP

June 2012

Ms. Marlise Gyger

Pharmacy Museum,
Totengsslein 3, 4051 Basel

26

Example (ctd)

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

Quality and GMP

June 2012

Ms. Marlise Gyger

Pharmacy Museum,
Totengsslein 3, 4051 Basel

27

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.

Quality and GMP

June 2012

Ms. Marlise Gyger

Pharmacy Museum,
Totengsslein 3, 4051 Basel

28

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

Quality and GMP

June 2012

Ms. Marlise Gyger

Pharmacy Museum,
Totengsslein 3, 4051 Basel

29

Thank you for your attention

Quality and GMP

June 2012

Ms. Marlise Gyger

Pharmacy Museum,
Totengsslein 3, 4051 Basel

30