Inspection Hot Topics
QP Forum, Trinity College
Ciara Turley, Inspector, HPRA
16th April 2015
Content
• Hot topics = common deficiencies
• Data based on 100 inspections conducted
in 2014
• Inspections of non-sterile and sterile
finished product manufacturing sites, API
manufacturing sites and third country
manufacturers
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Critical Deficiency
• A critical deficiency is one which has
produced, or leads to a significant risk of
producing, either a product which is
harmful to the human patient, or in the
case of veterinary product, harmful to an
animal or which could result in a harmful
residue in a food-producing animal
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Major Deficiency
A non-critical deficiency is one which has produced or may produce a
product, which does not comply with its marketing authorisation;
or
which indicates a major deviation from EU Good Manufacturing
Practice;
or
(within EU) which indicates a major deviation from the terms of the MIA
or
which indicates a failure to carry out satisfactory procedures for release
of batches or (within EEA) a failure of the Qualified Person to fulfil their
legal duties;
or
a combination of several ‘other‘ deficiencies, none of which on their own
may be major, but which may together represent a major deficiency and
should be explained and reported as such.
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Other Deficiency
• A deficiency, which cannot be classified as
either critical or major, but which indicates
a departure from good manufacturing
practice.
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Breakdown of deficiencies cited in 2014
140
120
100
80
60
critical
major
40
other
20
0
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Quality system deficiencies
50
45
40
35
30
25
critical
20
major
other
15
10
5
0
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Deviation / CAPA deficiencies
• Lack of investigation detail documented
• Lack of consideration of reoccurrence
• No CAPAs raised
• Root cause not stated or lack of supporting evidence
for conclusions
• Impact on other batches / equipment not considered
• Lack of effectiveness checks
• Inadequate trending
• Lack of definition, particularly planned deviations and
‘events’
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Example of Quality System deficiencies
•
For Deviation X relating to a faulty magnetic stirrer, the report did
not include details of what had caused the stirrer to malfunction
and if the repair had dealt with this
•
Deviation Y related to breaking of vials in the in-feed zone and at
the crimping machine. There was no evidence in the file that
training recommended for engineers and a microbiologist had been
performed.
•
Deviations X, Y and Z related to cartons for product X (two
instances) and product Y sticking together. The recommendation for
each deviation was that Logistics would take the matter up with the
carton supplier. There was no record that this had been done.
•
Deviation Notification X referred to an issue with the belt on the
filling line a resulted in ampoule breakage. A new belt was
installed again. There was no investigation or discussion of the root
cause which was said to be due to the assembly of the belt.
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Examples of Quality System deficiencies
•
The root cause analysis was heavily weighted towards poor asepsis
of the operator in question for that isolated incident. This was not
considered a satisfactory assessment to determine the actual root
cause of the contamination event.
•
Deviation reports included a section for reporting whether the
deviation had occurred previously; the company were only entering
deviations in this section if they had occurred within the same
calendar year.
•
The root cause of the deviation (that a valve had not been
completely closed during micronisation) did not have a preventive
action assigned to prevent re-occurrence.
•
For deviation X the company had considered the impact isolated to
one batch even though the same solution had been used in the
manufacture of sixteen batches in total. There was no documented
risk assessment to support this conclusion
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Examples of Quality System deficiencies
The release disposition of batch X was not considered
appropriate as:
•
There was inadequate data to show that the process was
successfully revalidated and could consistently produce
product that met specification.
•
There was inadequate data to support the rationale for the
assigned root cause of the out of specification blend assay
•
There was no manufacturing investigation completed to
determine the root cause at the time of batch release
•
There was no comparison of revalidation data with results
from previous validation batches
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Premises and equipment deficiencies
70
60
50
40
30
critical
major
20
other
10
0
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Examples of Premises and Equipment deficiencies
With respect to the re-qualification of load X
• The justification to accept qualification loads with
breaches in the sterilization band during the hold
phase was not considered acceptable. The approach
did not consider the suitability of the cycle or ability of
the autoclave to control such loads e.g. min load for X
which contained a piece of tubing.
• A number of items used appeared to have been
previously subjected to sterilization. The controls in
place to ensure they represented a normal load were
not clearly described. E.g. stopper and crimp bags with
multiple taped punctures.
• Comparison to the original PQ was not performed.
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Examples of Premises and Equipment deficiencies
The cleaning and storage of equipment was deficient in that:
•
The size, design and condition of the wash room was deficient.
– The room was small and cleaned equipment was stored in close
proximity to dirty equipment
– The wash sinks were visually stained and contaminated as were
some of the surrounding walls
– The sinks were not flush and sealed against the walls
– There was a particularly contaminated recessed area observed
above the sink
•
Some balances and scales stored in another room had not been
stored in a clean state as white residues and streak marks were
observed on some of these items together with sticky residues
which remained after the removal of obsolete calibration stickers.
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Examples of Premises and Equipment deficiencies
Management of equipment maintenance at the site was
deficient in that:
• Unplanned maintenance activities had not been
recorded and there was no requirement for these
activities to be recorded under the company’s quality
management system at the time of the inspection;
• It was observed that the company’s investigations into
the high number of incidences of rogue tablets had not
considered that non-recording of unplanned
maintenance activities may have been a contributing
factor in this regard.
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Examples of Premises and Equipment deficiencies
• The company relied on previous equipment
qualification studies to determine the possibility of
rogues entering a finished batch rather than
challenging the packaging lines again during
investigation to verify that the systems for
identification and rejection of the rogues remained
effective.
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Production deficiencies
14
12
10
8
critical
major
6
other
4
2
0
sterile
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media fill
visual
data integrity
line
inspection
clearance
inspection
cleaning
validation
general
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Example of Production deficiencies
Incoming receipt checks for raw materials were inadequate as:
•
The Approved Vendors Listing (AVL) did not specify all actors
in within the supply chain, e.g. suppliers
•
The vendor / manufacturer address of product stored in the
warehouse did not match the address listed on the AVL
•
AVLs were generated from information on labels of material
stored in the warehouse rather than from the approved sites
listed by the planning / purchasing department
•
The company had sourced a number of batches of active
substance through a supplier that refused to disclose the
actual manufacturer of the active substance. The material
was used in the manufacture of aseptically prepared finished
medicinal product.
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Example of Production deficiencies
Labeling practices were considered to increase the overall risk
to product in that:
• It was accepted practice at the facility to place material labels
on container lids unfixed for a period on time. This was
considered to add undue risk to the process as labeling mixups would not be readily detected as SAP was utilized to
manage material from this point.
• Rejected material within the dispensary and warehouse was
not physically segregated. They were not clearly marked as
rejected. It was noted that reject materials were blocked on
SAP but this was used for ‘on hold’ status also. The
warehouse staging room was cluttered with a high volume of
rejected material outside of the ‘on hold’ area.
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Example of Production deficiencies
Aseptic process controls were considered deficient.
• It noted that vials unloaded from the Lyos, were not afforded
appropriate protection from the background environment
during transfer to the capping station, which was classified by
the company as Grade A, but which was considered Grade B
background by the inspector.
• There was no validated raised or displaced stopper detection
system in place. Reliance was placed on a visual check prior
to capping and vials were permitted to be stored in this area
for a period up to 48 hours.
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Example of Production deficiencies
During set-up activities on the it was noted that:
• component contact parts were exposed for excessive periods
of time in the background environment which was classified
by the company as a Grade A room, which was considered
the background Grade B to the Grade A critical zone and
were permitted to be carried from the autoclave trolley
across this room prior to transfer into the critical zone
• In general component parts were considered to have been
handled excessively and not in a manner conducive to good
asepsis
• Sporocidal agents were not proactively included in the
disinfectant rotation in the site’s sanitisation programme,
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Example of Production deficiencies
• The manner in which set up was conducted was considered
cumbersome and due to the positioning of the product lines,
the set up was made much more difficult to perform with a
satisfactory level of asepsis due to the fact that when
attempting to complete the aseptic connection, there was not
a clear line of sight or a clear path to enable the operator to
make a quick and clean connection.
• Two media fill failures had occurred where growth promotion
testing post filling failed. No growth had been obtained and
the investigation had not determined a root cause for this
failure.
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Example of Production deficiencies
• The particulate monitoring system for both the oncology and
non–oncology suites had been removed for repair from both
areas and had not been replaced at the time of inspection.
During the intervening period a mobile monitoring device
was introduced but it was only possible to perform
particulate monitoring in one location, the vial infeed
location, leaving the filling zone without any particulate
monitoring for an extended period.
• There was a report for 5cfu/plate for a settle plate obtained in
the sterility testing laboratory on the day after sterility testing
of the batch. There was no discussion of any relevant
implications of this result within the investigation report.
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Outsourced Activities
37 of 47 deficiencies related to technical
agreements.
• Absence of agreements
• Lack of designation of responsibilities
• Absence of key issues – e.g. Timelines
regarding reporting of significant
deviations
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Examples of deficiencies
• With regard to contractual arrangements with a QP
– the job description (dated August 2009) was not
reflective of the current responsibilities,
– approximately 48 SOPs were ‘read and understood’ over
two days in 2014.
• The contract QP was not formally required to read relevant
quality summary documents prior to recommencing QP
activities following long periods off site e.g. quarterly
management reviews, PQRs etc.
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Learning
• Review these elements as part of self
inspection programme
• Review investigations to ensure root cause,
impact assessment and CAPA well defined and
sufficient evidence included
• Review equipment and production deficiencies
within your own company processes
• Ensure technical agreements in place and
defined – review the content as part of PQR.
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