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Inspection Hot Topics

QP Forum, Trinity College

Ciara Turley, Inspector, HPRA

16th April 2015

2 15/04/2015

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

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

15/04/2015 6

0

20

40

60

80

100

120

140

critical

major

other

Quality system deficiencies

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0

5

10

15

20

25

30

35

40

45

50

critical

major

other

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

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0

10

20

30

40

50

60

70

critical

major

other

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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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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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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• 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

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0

2

4

6

8

10

12

14

sterile media fill visual inspection

data integrity line clearance

inspection cleaning validation general

critical

major

other

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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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 mix-ups 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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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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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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• 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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• 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.

15/04/2015 26

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