visual nspection - aventri...gmp conference 12th november 2014 ... manual inspection - training •...

Visual nspection

Denise Coakley

GMP Conference

12th November 2014

Parallel Session 1A – Sterile Manufacture

212th November 2014

EU GMP Annex 1:

‘Filled containers of parenteral products

should be inspected individually for

extraneous contamination or other defects.’

312th November 2014

EU GMP Annex 1:

‘When inspection is done visually, it should be

done under suitable and controlled

conditions of illumination and background.’

412th November 2014

EU GMP Annex 1:

‘Operators doing the inspection should pass

regular eye-sight checks, with spectacles if

worn, and be allowed frequent breaks from

inspection.’

512th November 2014

EU GMP Annex 1:

‘Where other methods of inspection are used,

the process should be validated and the

performance of the equipment checked at

intervals. Results should be recorded.’

612th November 2014

Manual inspection – Ph. Eur. 2.9.20

712th November 2014


• A matt black panel of appropriate size held in a vertical

position,

• A non-glare white panel of appropriate size held in a vertical

position next to the black panel,

• An adjustable lampholder fitted with a suitable, shaded,

white-light source and with a suitable light diffuser (a

viewing illuminator containing two 13 W fluorescent tubes,

each 525 mm in length, is suitable). The intensity of

illumination at the viewing point is maintained between

2000 lux and 3750 lux, although higher values are preferable

for coloured glass and plastic containers.

812th November 2014


• Remove any adherent labels from the container and wash

and dry the outside. Gently swirl or invert the container,

ensuring that air bubbles are not introduced, and observe

for about 5 s in front of the white panel. Repeat the

procedure in front of the black panel. Record the presence of

any particles.

What else do we look for…….??

912th November 2014

Eye Test

GE T

Y O U

R E Y E S C

H E C K E D

1012th November 2014

Manual Inspection - Training

• Frequency/Duration

• Test kits

• Management of test kits

• Line speed

• Unit size

• Qualification/disqualification


Manual Inspection

Maintenance

• Procedure for back ground lighting

• Lux levels

Personnel

• Frequent breaks


Training

• Line speed during training

• Unit sizes

• Duration of training

• Challenge set – management


Manual Inspection - Defects

• Defect classification

-Particles

-Cracks

-Cosmetic

• Procedure for management of rejects


Semi- Automated Visual Inspection

• Removes the requirement for handling by the operator

• Units are fed/spun by conveyor for operator viewing

What do we look for…….??

• Exact same as for manual inspection


Automated Visual Inspection

- It is important to know the capabilities and limitations of equipment.

- Camera – Light reflection

- Static division -Light transmittance

- ‘Qualified’ – what does this mean?


Automated Visual Inspection

• URS

• Validation

• Detectability

• Repeatability

• How is the machine challenged

• Particles need to be moving to be detected by both SD and camera

• Equipment maintenance

• Management of rejects


Are there more specific requirements???....

• Defect classification

• Particle size – visible, sub visible

• Route of administration

• What is meant by ‘‘practically free”

• Risk based approach


Manual/Semi-Automated and Automated

• It is accepted that neither the machine or

the human can be 100% effective

• Whatever the system of inspection –

when a defect trend is detected the

production process and where necessary, the

inspection process must be investigated and

reassessed.


When things go wrong and they sometimes will....

• What is the procedure

• Deviation

• Re-inspection: Line speed, frequency

• At what stage is the batch considered rejected

• What is the source of the defect – container closure or production process

• Is the product compatible with the container closure – glass, rubber

• What is the impact to product on site

• What is the impact to product on the market

• Risk Management


Risk Assessment


Risk Assessment

• Critically assess what has happened and why.

• Do not play down the severity rating of the defect.

• Do not increase the level of detection rating if the defect has poor or no detectability.

• Do not decrease the probability of occurrence rating if there is a trend of the defect occurring.

• State the facts.

• It is better to identify the problem and fix it.


”Mistakes are the portals of

discovery.”

James Joyce


Risk Assessment

Deviations should be avoided but.....

...they can drive change and improvements.


Risk Assessment

Don’t just Risk Assess the ‘problem OUT’........

.....Risk Assess the ‘solution IN’


Risk Assessment

• Improve the manufacturing process by building in preventative

controls that scientifically support low probability of occurrence

ratings for particulates during risk assessments.

• Improve the inspection process and ensure that all high

detectability ratings assigned during risk assessments are

supported by scientifically sound detection-type controls.

• Identify the key risk-mitigating preventative and detection

controls that come out of such risk assessments, and ensure

that those controls are validated and proven effective.


Visual Inspection Deficiencies

• The controls in place with respect to the sites visualinspection programme were considered deficient in that:

• Investigations in relation to glass particulates were notconsidered to have been progressed in a timely manner

• The SOP was not followed in that the rig speed was notreduced to 50% upon identification of the tramp / loose glassdefect. There was no consideration given to re-inspection ofthe preceding vials that had been inspected up to that pointat such a reduced speed. A recurrence check for the previous3 months was undertaken. It was noted that a 3 monthrecurrence check was too confined a time limit to place onsuch assessments.

• IR X had been raised due to a loose glass defect. The rootcause of this defect was not identified.



• The inspection procedure did not require re-inspection of

preceding vials at reduced speed of 50% normal rate, when

critical defects, with low detectability, were identified.

• Where 2nd re-inspections identified additional defects, at no

point during the investigations was consideration given to

assessing the effectiveness of the visual inspection

programme nor was there any impact assessment performed

on those batches which were currently in date and on the

market.



• The investigations concluded that no corrective action was

required as the operators were validated to perform visual

inspection at a rate of xvpm for x minute intervals.

• This was despite the inherent issues identified with respect to

the sites visual inspection programme, as indicated by the

operators in the investigations.

• No due consideration was given to the statements from the

operators nor was there any consideration given to SOP X.



• The manner in which the trend analysis for defects was

conducted was considered deficient in that:

Data was not trended for all defect types e.g.

tramp/loose glass was trended as particles which

covered a number of other critical defect types

Additional rejects found during re-inspections were

not included in the trend analysis

The data captured for trending from visual inspection

was inputted by operators into the inspection log

database. There was no verification that this data was

inputted correctly.



• The ongoing issue in relation to glass particle defects and the potential impact to product on the market was not reported to the competent authority at the time of the inspection.

• There was no action taken in relation to the finished product visual inspection process or the post inspection AQL, following observations which confirmed that the visual inspection process was not effective in detecting the critical defect and that batches X, Y and Z, had passed the 100% inspection and post inspection AQL sampling but on subsequent 100% manual inspection, showed evidence of the particle defects.

• The timelines involved in the move to a tightened AQL for incoming inspection and the subsequent move to Unacceptable Quality Limit sampling was considered an unacceptable delay.



• In relation to Risk Assessment, X, it did not consider batches manufactured between MMM YY and MMM YY.

• The application of the same risk rating of ‘High’ to the detectability of ‘moving’ and ‘not moving’ particles, was not considered appropriate given that the system was not capable of detecting the latter and that batches had been noted to pass through the inspection process without such defects being detected.

• It was considered that the risk assessment placed an over reliance on the use of AQL sampling and statistical analysis of the same, to detect the critical defect

• There was no information in relation to the ongoing investigations in relation to this defect type in the APQR.


Conclusion

• Establish robust procedures

• Where equipment is used, know the capability and limitation

• Validation

• Appropriate defect classification

• Training

• Qualification/disqualification

• Equipment maintenance

• Risk Management – consider that the effectiveness of the current process may need to be critically assessed and improved.

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