Qualification

Ciara Turley, Inspector

HPRA GMP Conference

7 February 2017

Dublin

Agenda

1• Annex 15 & Key Concepts in Qualification

2• Trends seen in inspection

3• Common deficiencies cited

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Annex 15 and Key Concepts

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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

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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

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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

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• 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:

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• 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:

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• 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:

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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

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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

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Trends seen in inspection

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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

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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

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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

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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

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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

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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?

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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)

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Deficiencies Cited

Common Deficiencies In Qualification

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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

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Example Deficiency - Documentation

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• 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

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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

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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

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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

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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

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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

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Thank You