Module 4 Deviations RCA Tools CAPAs No Assessments2

Module 4
1. Deviations, RCA tools and CAPA
1.1 Module 4 Deviations, RCA tools and CAPA
Notes:
1.2 About this module
Published by Articulate® Storyline www.articulate.com

1.3 Objectives
Notes:
1.4 Introduction to deviations, RCA tools and CAPA

1.5 Definitions of deviation, incident and non-conformance
1.6 When can deviations, incidents, non-conformance occur?

1.7 What are corrective and preventative actions?
Notes:
1.8 What is a CAPA?

1.9 Key CAPA definitions
1.10 Corrective or preventative?
1.11 Quick quiz 1
(True/False, 10 points, 1 attempt permitted)

Correct Choice
True
X False
Feedback when correct:
That's right! You selected the correct response.
Feedback when incorrect:
You did not select the correct response.
Notes:

Correct (Slide Layer)
Incorrect (Slide Layer)

1.12 Deviation management
1.13 Categorization of deviations

1.14 Categorization of deviations (continued)
Notes:
1.15 Investigation management

1.16 Problem investigation
1.17 Initial actions after identifying an issue
Notes:

1.18 Corrections
1.19 Root Cause Analysis (RCA)

1.20 Steps involved in RCA
1.21 Tools of RCA: Checklists

1.22 Tools of RCA: Brainstorming
1.23 Tools of RCA: Chronology

1.24 Tools of RCA: Change analysis
1.25 Tools of RCA: Barrier analysis

1.26 Tools of RCA: 5 why's
1.27 Tools of RCA: Fishbone daigram

1.28 Tools of RCA: Comparison matrix
1.29 Probable root cause

1.30 No identifiable root cause
1.31 Risk management
Do we always need an investigation?
1.32 Quick quiz 2
(Multiple Response, 10 points, 1 attempt permitted)

Correct Choice
X 5 Why’s
Fishbone diagrams
Product quality reviews
X Brainstorming

1.33 Quick quiz 3
(Multiple Response, 10 points, 1 attempt permitted)

Correct Choice
X Stop manufacturing and quarantine product
Finish manufacturing and quarantine product
X Replace faulty part in equipment
X Stop the leak or clean up the spillage
Review and revise the preventative maintenance schedule
Implement a preventive action
All of the above


1.34 CAPA management
CAPA plan: Corrective action
1.35 CAPA plan: preventive action

1.36 Steps involved in CAPA management
Notes:
1.37 CAPA process flow

1.38 Responsibilities and authorities for the CAPA system
1.39 Responsibilities and authorities for the CAPA system (continued)

1.40 CAPA plan
1.41 CAPA plan considerations

1.42 Establishing CAPA effectiveness
1.43 Establishing CAPA effectiveness (continued)

1.44 Implementation of CAPAs
1.45 Change control

1.46 Implementation of CAPAs
1.47 Effectiveness vs implementation check

1.48 Effectiveness checks
1.49 How long does it take to measure effectiveness?

1.50 Effectiveness check outcome
1.51 Traceability

1.52 Investigation report management:
Investigation report
1.53 Investigation report (continued)


1.56 Case study: RCA – drug product stability
1.57 Description of the problem
Notes:
The subject of this case study is an event that took place during the stability testing of
batches of a biological drug product (DP) in pre-filled syringes (PFS). The 3 consistency
batches were under test. These batches were also earmarked for use in clinical trials if
needed and for commercial launch stock!
At the 9-month time point, at 2-8°C, product-related impurities, that were known
degradants, were seen at significant levels during Anion Exchange HPLC (AEX-HPLC)
chromatographic analysis. These impurities had never been seen before at 2-8°C at this
time point and with this formulation. The product was in late Phase 3 and therefore the
product stability was supposedly well understood. The degradants were also seen at
the accelerated storage condition of 25°C/60% RH in the 1- and 3-month samples, but

the levels seen were no higher than for previous batches. Low levels of these
degradants are normally seen after 2-3 years at 2-8°C or after exposure to light.
The stability samples were stored in cartons that provided protection from light.
The results were deemed to be out of trend (OOT) and therefore an out of specification
(OOS) / OOT investigation was initiated.
1.58 Laboratory investigation
Notes:
The laboratory investigation showed no laboratory error and did not produce an
assignable cause for the OOT results.
New samples were taken to confirm an OOT result. For this purpose 5 separate syringes
were taken, solutions were prepared and each sample was individually analyzed. 2 of
the 5 samples showed the impurities seen in the original samples.
The problem was intermittent and it was not at all clear what was going on and a root
cause investigation was initiated to determine the root cause.

1.59 RCA
Notes:
The investigation focused on why some of the syringes were normal (no impurities) and
some were not. A brainstorming session was held to try to identify possible causes.
Some possible causes were eliminated quickly but the following potential causes were
discussed in detail:
• It was possible that the product was interacting with tungsten in the syringe needles.
This is a known problem, but it had not been seen previously in this product so why
now? Was there a problem with the PFSs that resulted in a greater contact between
the product and the needle? It was not clear how tis could happen, but a decision was
made to look into this possibility albeit unlikely.
• More likely there could have been a larger amount of silicon in the syringe barrels or
on the stoppers that could have caused problems when in contact with the DP. Again
this had not been seen previously, but this could be a result of variation between lots
of syringes.
• It was also possible that an unreported temperature excursion or excessive light
exposure had occurred, during handling of the syringes in production.
The batch and stability records were closely reviewed as part of the investigation and it
was discovered that:
1.The original stability samples were taken and placed into stability storage at
same time as the batch release samples were taken. The batch release data
were taken as the T0 results.
2.The remainder of the batches were shipped to a secondary packaging site for

cartoning for commercial launch
3.It was discovered that additional samples were needed for stability studies and
these samples were shipped from packaging site at around the 6-month time
point
4. During
the investigation it was confirmed that these samples could not be
distinguished from the original samples and therefore differences in the
samples could not be investigated!
1.60 RCA (continued)
Notes:
Studies were set up to look at the impact of syringe needles and silicon on DP stability.
In the end these were determined not to be the root cause, but the studies were
completed since the information provided was useful.
The syringe vendor was contacted to determine whether there were any issues with the
syringe lots that were used. The vendor of the stoppers was also contacted.
The history of the batches and the storage records were also reviewed in greater detail
to check for anything that might have been missed.
Also further samples were requested from the packaging site for further analysis to
confirm or otherwise that something had happened to the syringes while at the
packaging site.

1.61 Findings
Notes:
As a result of the investigations performed, the following findings were made:
1.No issues had been observed by the vendor related to the syringe lots.
2.No temperature excursions were recorded either during the manufacturing
process, the finishing (visual inspection) or during shipping or storage at the
packaging site. There were also no excursions of the stability chamber.
3.When analyzed it was discovered that many of the syringes sent from the
packaging site had significant levels of degradants. These levels were even
higher than at the 9-month time point, yet they were only analyzed 3-4 weeks
later - not long enough to account for the differences if the storage conditions
were equivalent at both sites.
4.However, some of the syringes had no detectable degradants.
Again the data showed the intermittent nature of this problem. So syringes were
satisfactory and some syringes had failed the drug product specifications. Something
had happened to these syringes at the packaging site, but it was not clear what.
Therefore a decision was made for representatives of the investigation team to visit the
secondary packaging site.

1.62 Root cause
Notes:
During the visit to the packaging site it was discovered that the lights in the cold room
were left on permanently during the day. It was not at all clear why this was done! The
light sensitivity of the DP had been clearly communicated to the site prior to shipping
the batches. The solution that the site had decided upon was to store the syringes,
which were stored in racks awaiting packaging, by covering them with black poly
ethylene sheets. When these sheets were held up to the light a significant amount of
light was getting through. The sheets were affording very little light protection.
To evaluate the extent of the problem, samples were taken from the outer layers of the
racks and from the inner layers of the racks for analytical comparison. As expected, the
inner layers had very low levels of or no detectable degradants, and the samples from
outer layers had significant levels of degradants, many of them failing specifications.
It is important to note at this point that the packaging site had never handled biological
DP prior to these batches. However, that did not justify leaving the lights on in the cold
room!! But it did help to explain the lack of awareness of the instability of some
biologicals if not stored correctly.

1.63 CAPA
Notes:
The CAPA plan included:
• Placing all three batches in quarantine and when it was clear that the good
syringes could not be distinguished from the bad syringes, all three batches
were rejected and destroyed, at considerable cost to the company!
• This problem did not impact the process validation since all three batches met
all acceptance criteria for the validation protocol. However, new lots had to be
manufactured in order to provide the primary stability data needed for the BLA
submission and in order to replace the lost clinical and commercial stock.
• Changes to storage procedures were immediately implemented and a further
investigation was made to determine if any other batches stored at this site
were impacted.
• Intensive awareness training was performed to ensure that all packaging site
staff could appreciate the differences between small molecules and biologicals.
• A number of changes were made to the stability testing procedures, which
included:
• Ensuring that all new studies included extra samples to allow for retests
and investigations
• Prohibiting taking extra samples for stability studies after the study has
been set up, to ensure that such a problem does not recur and that all
samples in the study have experienced identical storage conditions
throughout their history

1.64 Lessons learned
Notes:
A number of salutary lessons were learned from this event, an event which cost the
company time money and wasted resources and materials. The main lesson learned
was that more care was needed when storing biologicals.
There seemed to be a “cavalier” attitude to product storage. The packaging site had
never handled biologicals before and had probably been lucky that a similar event had
not previously happened with a small molecule DP. It is also possible that other
products had been poorly stored and had degraded, but that the instability was never
discovered, since products are rarely tested once they have been packaged and bulk
product is rarely re-tested after packaging. A bigger problem could be waiting to
happen, such as a major product recall?
Some important lessons were learned about the conduct of stability studies:
• Taking extra samples to add to the study after it has been initiated is not an
acceptable practice and could lead to unforeseen problems as this case study
illustrates
• Taking extra samples at the initiation of a study is a far better approach, even if
some of the samples turn out not to be needed!
Leaving the lights on in a cold room, or in any storage area is a bad practice, as is the use
of black polyethylene sheets or any other untried method of protecting from light!

But perhaps the most important lesson learned was that biologicals need to be treated
differently from small molecules. Biologicals are not only more susceptible to poor
storage conditions and practices, they are also more susceptible to other environmental
factors and must be treated appropriately. Any site that has never handled biologicals
before should be given the necessary awareness training before they take on the
handling of biologicals, even if it is just to store them!
1.65 Final assessment
Notes:

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Module 4

1. Deviations, RCA tools and CAPA

1.1 Module 4 Deviations, RCA tools and CAPA

1.2 About this module

Published by Articulate® Storyline www.articulate.com

1.4 Introduction to deviations, RCA tools and CAPA

Published by Articulate® Storyline www.articulate.com

1.6 When can deviations, incidents, non-conformance occur?

Published by Articulate® Storyline www.articulate.com

1.8 What is a CAPA?

Published by Articulate® Storyline www.articulate.com

1.10 Corrective or preventative?

1.11 Quick quiz 1

(True/False, 10 points, 1 attempt permitted)

Published by Articulate® Storyline www.articulate.com

Feedback when correct:

That's right! You selected the correct response.

Feedback when incorrect:

You did not select the correct response.

Published by Articulate® Storyline www.articulate.com

Incorrect (Slide Layer)

Published by Articulate® Storyline www.articulate.com

1.13 Categorization of deviations

Published by Articulate® Storyline www.articulate.com

1.15 Investigation management

Published by Articulate® Storyline www.articulate.com

1.17 Initial actions after identifying an issue

Published by Articulate® Storyline www.articulate.com

1.19 Root Cause Analysis (RCA)

Published by Articulate® Storyline www.articulate.com

1.21 Tools of RCA: Checklists

Published by Articulate® Storyline www.articulate.com

1.23 Tools of RCA: Chronology

Published by Articulate® Storyline www.articulate.com

1.25 Tools of RCA: Barrier analysis

Published by Articulate® Storyline www.articulate.com

1.27 Tools of RCA: Fishbone daigram

Published by Articulate® Storyline www.articulate.com

1.29 Probable root cause

Published by Articulate® Storyline www.articulate.com

1.31 Risk management

Do we always need an investigation?

1.32 Quick quiz 2

(Multiple Response, 10 points, 1 attempt permitted)

Published by Articulate® Storyline www.articulate.com

Product quality reviews

Feedback when correct:

That's right! You selected the correct response.

Feedback when incorrect:

You did not select the correct response.

Published by Articulate® Storyline www.articulate.com

Incorrect (Slide Layer)

1.33 Quick quiz 3

(Multiple Response, 10 points, 1 attempt permitted)

Published by Articulate® Storyline www.articulate.com

X Stop manufacturing and quarantine product

Finish manufacturing and quarantine product

X Replace faulty part in equipment

X Stop the leak or clean up the spillage

Review and revise the preventative maintenance schedule

Implement a preventive action

All of the above

Feedback when correct: