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Agenda
1• Annex 15 & Key Concepts in Qualification
2• Trends seen in inspection
3• Common deficiencies cited
07/02/2017 2
Key Concepts in revision of Annex 15 related to Qualification
• Decisions on the scope & extent of qualification & validation should be based on a
justified & documented risk assessment of the facilities, equipment, utilities
Focus on quality risk management application
• Appropriate checks should be incorporated into qualification work to ensure the
integrity of all data obtained
Reference to data integrity
• All phases in the life of a product, equipment or facility from initial development or
use through to discontinuation
Reference to lifecycle of the product
07/02/2017 4
Key Concepts in revision of Annex 15 related to Qualification
Data supporting qualification which were obtained
from sources outside of the manufacturers own
programmes may be used provided this approach
has been justified & there is adequate assurance
that controls were in place throughout the
acquisition of such data
07/02/2017 5
Stages in Qualification
Design Qualification DQ:
• Documented verification that the design of the equipment, facilities, utilities or systems is suitable for the intended
purpose, including compliance of the design with GMP. This step defines what user wants from the system and makes
sure that requirement is met. A key document, the user requirement specification (URS) is established
Installation Qualification IQ:
• Documented verification that the equipment/systems, as installed/modified, comply with the approved design,
manufacturer’s recommendations &/or user requirements. Aspects may be performed as part of factory acceptance
testing (FAT) / site acceptance testing (SAT)
Operational Qualification OQ:
• Documented verification that the installed facilities, systems & equipment performs as intended throughout the
defined operating ranges
Performance Qualification PQ:
• Documented verification that the facilities, systems & equipment performs effectively & reproducibly based on the
approved process method & product verification – in some cases, it may be appropriate to perform it in conjunction
with OQ or process validation
07/02/2017 6
• Verification of correct installation against drawings,
specifications & pre-defined criteria
• Collection & collation of supplier operating & working
instructions & maintenance records
• Calibration of instrumentation
• Verification of materials of construction
IQ should include, but is not limited to:
07/02/2017 7
• Tests that have been developed from the knowledge of
processes, systems & equipment to ensure that a system is
operating as designed
• Tests to confirm upper & lower operating limits, and/or
worse case conditions
• OQ should include verification of operating system working
• May be part of combined IOQ
OQ should include, but is not limited to:
07/02/2017 8
• Tests using production materials, qualified substitutes or simulated product
proven to have equivalent behaviour under normal operating conditions
with worse case batch sizes
• Tests should cover the operating range of the intended process unless
documented evidence from the development phases confirming the
operational ranges is available
• The frequency of sampling used to confirm process control should be
justified
• May be appropriate to perform it in conjunction with OQ or process
validation
PQ should include, but is not limited to:
07/02/2017 9
Planning for Qualification
• All qualification and validation activities should be planned and take the life cycle of facilities, equipment, utilities, process and product into consideration
• VMP or QMP – summary of facilities, systems, equipment and processes to be validated / qualified
• Clear definition of terms and approach – IQ, OQ, IOQ, FAT / SAT, PQ or PV
• A quality risk management approach should be used. There should be justification for approach to qualification including decision not to qualify, e.g. has it an impact on the product / would malfunction impact directly on product quality?
• There should be appropriate quality oversight over the whole validation life cycle
07/02/2017 10
Execution of Qualification
• Protocol and report – the protocol should specify critical steps and acceptance criteria. Any changes to the plan as defined in the protocol should be documented with appropriate justification and change control
• Guidance on developing acceptance criteria – previous experience, critical quality attributes (CQAs) of product, manufacturer recommendations. The equipment controls and variables behind critical process parameters (CPPs) should be understood and tested
• Vendor recommendations for upper and lower operating limits should be considered and if exceeded the impact of this should be assessed
• Don’t need to test to failure - operating parameters can be selected based on scale up studies, design studies, previous product experience (and improvements) & risk analysis
• The completion of a successful qualification should allow the finalisation of calibration, operating and cleaning procedures, operator training and preventative maintenance requirements. It should permit a formal ‘release’ of the facilities, systems and equipment
07/02/2017 11
Use of Vendor Data
• Paragraph 3.6 of Annex 15 – where appropriate and
justified, documentation review and some tests could be
performed at FAT or other stages without the need to
repeat on site at IQ/OQ if it can be shown that the
functionality is not affected by transport and installation
• Vendor protocols may be supplemented by additional
documentation / test protocols before use
07/02/2017 13
Use of Vendor Data
• Where documentation is supplied by a third party providing validation services, appropriate personnel at the manufacturing site should confirm suitability and compliance with internal procedures before approval
• Paragraph 1.8 of Annex 15 - appropriate checks should be incorporated into qualification and validation work to ensure the integrity of all data obtained
• Oversight of vendor work as per Chapter 7 of GMP Guide - the Contract Giver should be responsible for reviewing and assessing the records and the results related to the outsourced activities
07/02/2017 14
Key Issues When Using Vendor Data
Was GMP applied
when gathering
data?
Reliability of data –
data integrity
Training /
competence of the
vendor
Standards applied
by the vendor
Equipment affected
by transport /
installation on site?
Quality oversight of
vendor
Responsibilities as
per Chapter 7
07/02/2017 15
Changes To Acceptance Criteria In Qualification
• Any significant changes to the approved protocol during execution, e.g.
acceptance criteria, operating parameters etc. should be documented as a
deviation and be scientifically justified
• The review and conclusions of the qualification should be reported and the
results obtained summarised. Any subsequent changes to acceptance
criteria should be scientifically justified and a final recommendation made
as to the outcome of the qualification
07/02/2017 16
Re-qualification
• Annex 15 - equipment, facilities, utilities and systems should be
evaluated at an appropriate frequency to confirm that they remain in
a state of control
• A combination of paper based analysis of control measures on the
equipment and physical testing and sampling of processes.
• The frequency for re-qualification should be justified. The time
period may depend on criticality of equipment
07/02/2017 17
Aspects For Consideration In Re-qualification
• Re-qualification should be considered after a change, as part of change control
• Is functional testing required in re-qualification activities?
• Equipment / components do have finite lifespans. Aging equipment – performance at set limits still reliable? The possibility of small changes over time should be assessed
• Consider what are you trying to assess - what are critical process parameters, what are CQAs, what was scope of initial qualification –does this meet current GMP requirements?
07/02/2017 18
Aspects For Consideration In Re-qualification – Not Exhaustive
Define and justify
criteria for evaluation
Review of preventive
maintenance logs and
calibration activities
Review of
modifications /
changes
Review of whole
system including
software
SOP adequacy check
Review of performance
of the equipment
(review of historical
data, deviations,
operator observations)
07/02/2017 19
Common Deficiencies In Qualification
07/02/2017 21
Lack of consideration of impact of changes – inadequate change control & risk assessment
Deviations from protocol & report not managed appropriately
Leveraging from vendor data with inadequate justification
URS not updated during qualification activities
Inadequate GMP applied
Lack of calibration of tools used during qualification studies
Inadequate re-qualification strategy
Example Deficiency – Deviation Management, Change Control
And Calibration
In relation to the installation qualification of the filling machine;
• The change of lubricants, post installation qualification, was not handled via change control
• Non-conformances were documented during initial execution of the IQ relating to product contact parts drawings, operator and maintenance manuals. The conclusion in the IQ was that these were to be addressed in the OQ. It was noted that when an IOQ was re-executed these items were marked as ‘not applicable’
• Critical instruments used to control parameters influencing fill weight (line speed, auger speed, and stirrer rate) were not calibrated as part of the IQ. The relevant section of the protocol was marked as ‘not applicable’ and this was not considered to be justified
07/02/2017 22
Example Deficiency - Documentation
07/02/2017 23
• Change Control CC_XXX, for the introduction of XX
manufacturing equipment, was at impact assessment & the
risk assessment was at draft stage at the time of inspection.
However, the equipment was already on site & had been
commissioned
Example Deficiency – Re-qualification
The company approach to requalification was considered inadequate as the review of the reactor did not include:
• an assessment of previous qualification to ensure it met with current regulatory standards (e.g. Annex 11)
• a review of the completion and effectiveness of corrective actions relating to deviations and preventative maintenance issues
• any functionality testing and this was not justified in the report
07/02/2017 24
Example Deficiency - Requalification
• In the 2015 review of the qualification status of the packaging line, the extent of overall change made to the line since the 2009 qualification had not been assessed to determine whether any additional qualification was required. In addition, the procedure in place for the review of qualification status of equipment, SOP XX, did not adequately address the review of change controls for their overall impact on the qualification status
• There was no programme in place to periodically evaluate whether IT systems (such as the Distributed Control System and Building Management System) continued to operate in a valid manner, or whether they required any level of revalidation or requalification
07/02/2017 25
Example Deficiency – Risk Assessment
In the water system assessment document WFIDOC-XX01, the risk
classification did not meet the categorisation procedure e.g. ‘materials
not of the right standard’ was given a high impact and low likelihood
which according to procedure gave a medium risk, but the actual risk
applied was high. There was lack of documented justification / rationale
for the likelihood / impact ratings assigned
07/02/2017 26
Example deficiency – Use Of Vendor Data
As part of the qualification process the company utilised vendor documentation as per the ASTM E2500-07 standard, however the company had not audited vendors and there was no assessment of the vendor quality system and vendor technical capability to ensure that information obtained from the vendor was accurate and suitable to meet the purpose of verification
The HVAC user requirement specification (URS), which was the document used by the company to define responsibilities with the contractor ‘HVAC Ltd’, did not specify the requirements for oversight of contractor and the responsibility of the company in the review of the work performed
07/02/2017 27
Example Deficiency – Acceptance Criteria
The following deficiencies were identified with respect to qualification
activities:
• In the ‘Performance Qualification Protocol Air Handling Units Main Plant’,
the acceptance criteria for the differential pressure monitoring was defined
as NLT 5 Pa and air velocity / change rate as NLT 20, which were not the
acceptance criteria assigned during the exercise
• The qualification of the camera system on packaging line 4 did not define
user operational specifications, critical operating parameters with
associated limits and no controlled recipe was generated at this time
07/02/2017 28
Example Deficiency – Acceptance Criteria
At the end of the batch, approximately 300 filled bottles had
out of specification fill weights, and maintenance work was
required to address the issues that were encountered.
Following that work the qualification had to be repeated, yet
this PQ was assigned a passing result – this was not
considered justified
07/02/2017 29
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