Guidelines for Validation & Verification, including Change Control
Introduction
This is a general guideline aimed at providing RGL with a practical framework for the
introduction or use of any new or change of established processes, equipment, facilities or
systems. The following areas are covered in detail:
 Change Control - a formal system for managing proposed or actual change
 Validation - documented evidence that the requirements for a specified intended use
or application have been fulfilled i.e. a collection and evaluation of data from the
process design stage through to production which establishes evidence that the
process is capable of consistently delivering the required quality. It is about gaining
knowledge and an understanding of the product/process. This is generally the prepurchasing stage and provides assurance that product meets the needs of
stakeholders.
 Verification – documented evidence that specified requirements have been fulfilled
i.e. a collection and evaluation of data from production through to implementation,
which establishes evidence that the process is in reality consistently delivering the
required quality. In some quality standards this equates to Process Qualification.
Validation and verification is a requirement of ISO15189:2012 standard, 5.5.1. Selection,
verification and validation of examination procedures.
It is the intention of RGL to maintain critical processes and systems in the intended state for
which they were developed and which are in line with regulations, standards and guidelines
that underpin the quality management system.
For this reason, the RGL should:
 understand the process variations
 detect these process variations and assess their extent
 understand the influences on the process
 and control such variations depending on the risk they represent
It’s important to remember that a sound understanding of the process will not inherently lead
to a safe process. The validation and verification process needs to include evaluation of
materials, equipment, the environment, and personnel changes to ensure the process can
be maintained when in routine operation.
Change Control
Any new or changed process, equipment, facilities and systems must be through the change
control process. Uncontrolled change carries significant risk of loss of the validated state for
laboratory processes, equipment, facilities or systems. Requests for change may arise from:
 Planned change as a result of opportunities
 Review of current procedure
 Audit findings
 Incidents
 Complaints
Some laboratory changes may result of using new equipment of the same type or a
relocation of the process in which case the validation may be limited but must still be
documented.
Minor changes or amendments to documented procedures may not need to go through this
process, but will still be managed via the document control procedure.
Regarding new equipment see Equipment Management Guidelines (Equip 1)
Risk Assessment
A risk assessment must be completed to assess the possible consequences of the change
so that action can be taken to eliminate or mitigate the risk, and will inform the extent of the
validation and verification required. The risks need to be well defined and should identify
what might go wrong, what are the consequences if it goes wrong and what is the likelihood
of it going wrong. Consideration may also need to be made of the probability of identifying
when things are going wrong.
Specification
A documented specification is an essential document and should take account of the
opinions of all stakeholders. It needs to be produced before the purchase of equipment. The
specification needs to include:
 Purpose for which the new process, equipment, facilities or systems are required.
Also Include stakeholder requirements
 Describe essential and desirable requirements and functions
 Define the operating environment in which the system will operate to ensure staff
safety
 Define other requirements such as consumables, time/staff resources (inc. training)
and maintenance schedules and compliance with regulations and standards e.g.
EQA, UKAS, HTA.
Each requirement needs to be measureable or verifiable in some way.
It may be possible and desirable to prioritise or weight requirements.
The specification needs to be approved and authorised by an appropriate person.
Procurement
RGL will comply with the following trust and RGL Policy and Procedures:
 Trust ICT Procurement Policy
 Trust Standards of Business Conduct
 RGL Equipment Management Guidelines (Equip 1)
Validation & Verification Plans
A plan will be developed that defines the requirements for a small discrete validation and
verification process or in more complex changes a series of validation and verification
processes.
As a minimum:
 Summary of the change
 the responsibilities for the various activities should be stated
 a schedule for the activities to validate in line with specification
A summary report will be written detailing the outcome of the validation process and decision
to purchase will be made authorised and recorded.
Following purchase the plan needs to be extended to plan the initial verification
implementation and on-going verification phases.
Once all the SOPs, training and records are in place the new process can be authorised for
use. A summary report (see Appendix 1) will be written detailing the outcome of the
verification process will submitted and authorised and recorded.
Final authorisation before implementation will be made by the appropriate Consultant
Clinical Scientist.
If a process is to be developed in house then a more formal validation plan needs to be
developed. The plan needs to define and evaluate the following:
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Include the rational for why methods are sound with sufficient specificity, sensitivity
and accuracy to meet patient needs.
Demonstrate lab equipment is operating sufficiently
Controls and EQA
Parameters
Limits
Raw materials
What data needs to collected and what it will be used for
Each step must have a specific pass/fail instruction under defined conditions
Plans need to be more aggressive than would be expected in normal routine use
Evaluate inter and intra batch acceptance criteria, some guidelines suggest 3
batches need to be assessed.
If excluding outliers, the plan should explain in advance
Preventative Maintenance and calibration procedures
Reports must draw a clear conclusion as to whether or not the process is for purpose and
approved for use. It should also state any limitations and Uncertainty of Measurement (see
Process for assigning Uncertainty of Measurement)
Implementation
All documentation should be kept for a minimum of 11 years or the lifetime of the process,
equipment, facilities or system.
SOPs and record templates must be written and authorised immediately prior to the change
being made.
All staff involved in using the equipment must be trained before using the new process.
Training and competency records will be completed and records kept.
Once implemented considerations should be made and documented as to how the new
process will be maintained as intended.
On-going Verification
There needs to be a periodic review of trends in process and maintenance data when in
routine use. Unplanned process variations i.e. errors and incidents need to be reported and
prioritised and resolved, with regular review, until the new process has become established.
The trends in process data will establish the capability of the process and can be used for
future monitoring. The aim is to improve the process; however improvements need to be
made in a structured way in line with these guidelines.
Appendix I: Change request pro-forma
This form is intended for identifying and collating proposed changes in service affecting
processes, systems or equipment, in order to manage the change process to ensure all
documentation is completed in accordance with the ISO15189:2012 standard.
This form should be completed prior to any significant detailed investigation into the change
to ensure the utility of investigating the change request, in order to minimise any
unnecessary use of resource. More importantly, the completion of this form ensures that
any proposed change follows the specific validation/verification procedures required by the
RGL for compliance with the ISO standard 15189:2012.
1. Section 1.1 should be completed as far as possible to establish the goals of the change
request.
 There needs to be sufficient information to enable the authoriser to make a judgment
as to whether to proceed with the proposal or not.
2. Section 1.2 should be completed by the appropriate senior scientist in order to initiate
further detailed investigation of the change request.
 The authoriser needs to decide whether a full business case is required and what
detail is expected within this case.
 In the case of new equipment being required, the authoriser will need to request
whether a capital (>£5k) or non-capital business case is submitted through the
appropriate channel.
3. Section 1.3 will be completed once the business case has been submitted to the
appropriate persons for detailed consideration. This will be dependent on the type of
change requested and the potential associated cost. Once authorised the full
validation/verification procedure will be implemented.
 Authorisation level will depend on the associated cost and impact of the change.
1. Change Request Details
Request name
Internal descriptive name
Reference
Internal ref.
1.1 Change request details
Description of
change request
Outline the change being requested and the reasons why this action is
required.
Process/ System/
Equipment
Specify whether this is a change to a process, system or equipment.
Benefit
List any benefit to introducing this change, e.g. improved testing, better
results, streamlining, quality improvement, reduction in labour/consumable
cost, improved TAT
Needs
Investment in equipment (Capital v non-capital), reagents, staffing
SOP Details
Detail SOPs which change affects
References
List any relevant documentation both internal and external indicating the
derivation of the test and including performance specifications, publications
and any previous validations
1.2 Change request response
Full business case required
Capital business case required
Non-capital business case required
Rejected
Comments
Requires submission to RGL Capital Programme, SMT, EMT.
Authorisation
Name
Lead
Authoriser
Signature
Date
1.3 Change request outcome
Approved
Rejected
Comments
Proceed to full validation procedure.
Authorisation
Name
Authoriser
Signature
Date
Appendix II: Generic validation/verification pro-forma
This form is intended as a guide to aid the department in developing a suitable validation/
verification procedure. A suggested methodology for using the form has been given below.
1. Section 1 should be completed as far as possible to establish the goals and general
format of the validation/verification.
 Sections 1.1 “Intended use or application” and 1.2 “Requirements” must be
completed at the start of the procedure. The assessment of the validation/verification
depends formally on the confirmation, through the provision of objective evidence,
that these requirements have been fulfilled.
 If mentioned (1.2), the “Expected Performance” should be distinguished from the
“Requirements”, which must be shown to have been fulfilled.
o Example: the statement “should detect all known point mutations of hemophilia A”
could be included as a guide in the Expected performance; if it were stated as a
requirement, it would need to be proven!
2. Section 2 covers the validation of the new system which should be carried out for all
validations and verifications. In the majority of cases this section can be completed on
objective evidence from publications, developmental work, design procedures (e.g. SNP
checking primers) or by the use of limitations or controls in the on-going test. Where this
is not the case, work plans for relevant parameters should be prepared as in 3 below.
3. Appropriate parameters for experimental investigation should be identified with the aid of
appendix A – a checklist is also provided at the top of section 3. For each parameter
required, the investigating scientist develops a work plan based on section 3 (these are
referenced 3.1, 3.2 to 3.n) by completing copies of sections 3.n.1 (‘Aims’, ‘Samples’ and
‘Methodology’). It is suggested that these be maintained in a single document.
Note: several parameters may be tested in a single experiment, for example sensitivity
and specificity.
4. The work plan[s] should be agreed and authorised by the investigator and the senior
scientist/Authoriser by signing and dating in the boxes provided.
5. The experimental work is performed and analysed by the investigator who should then
complete the ‘experimental results’ and ‘interpretation’ sections 3.n.2.
6. The ‘outcome and limitations’ should be agreed between the investigating and senior
scientists by signing and dating in the boxes provided.
7. Points 3 to 6 should be repeated for each parameter to be tested.
8. If there is any non-compliance between the experimental results and the required
performance specification detailed in section 1.2 the parameter in question should to be
re-examined to determine if the methodology can be changed or new limitations
introduced to rectify the non-compliance. Any further work should be recorded in a new
section 3 work plan. Alternatively the implementation can be abandoned.
9. Once all the parameters have been satisfactorily investigated the investigating and
senior scientist can agree and sign off the final conclusions in section 4.
10. Assuming the validation / verification has been completed satisfactorily an independent
review can be performed and the whole process signed-off in section 5 by a Consultant
Scientist.
1. Validation / Verification (delete as appropriate) Details
System name
Internal descriptive name
Reference
Internal ref.
1.1 System details
Intended use or
application
Outline the intended results of the test and how they will be used including
any interpretative considerations; linked to 1.2 Performance Requirements.
Locus / Gene /
Marker
Specify analyte[s]
Reference
Sequence
e.g. NCBI accession number
Outline
methodology
Describe the technology and how it will be employed
SOP
Reference internal SOP
References
List any relevant documentation both internal and external indicating the
derivation of the test and including performance specifications, publications
and any previous validations
1.2 Validation/Verification details
Overall Aims
State clearly the overall aim of the validation/verification
Requirements
Define the levels of performance that must be attained (accuracy, precision,
and any other performance requirements such as robustness or maximum
failure rate). Linked to 1.1 Intended Use or Application. Link to equipment
specification if necessary.
Validation /
Verification
State whether the study is a validation or verification and the justification for
this course of action.
Type
State the type of test and if the validation is to be performed at
implementation or on an on-going basis.
Scope / limitations
List any pre-existing limitations (e.g. test to be performed on DNA extracted
from EDTA peripheral blood samples only)
Turn around time
The required TAT
Other
considerations
List any other factors that may affect the utility of the test for the intended
purpose. Expected performance can be mentioned here.
2. Validation of new system
System name
Internal descriptive name
Applicability of
measurements
Is what is being tested appropriate and sufficient to achieve the desired
results? Compared with specification.
Selectivity
Detail any test specific selectivity issues together with limitations and/or
control measures taken to ensure test utility. A validation work plan (section
3) should be drawn up for any specific potential selectivity issues that
cannot be eliminated by limitation or control measure[s].
Interferences
Detail any test specific interference factors together with limitations and/or
control measures taken to ensure test utility. A validation work plan (section
3) should be drawn up for any specific potential interference that cannot be
eliminated by limitation or control measure[s].
Cross-reactivity
Detail any test specific cross-reactivity together with limitations and/or
control measures taken to ensure test utility. A validation work plan (section
3) should be drawn up for any specific potential cross-reactivity that cannot
be eliminated by limitation or control measure[s].
Authorisation
Name
Investigator
Authoriser
Reference
Signature
Internal ref.
Date
3.n Validation / Verification (delete as appropriate) for [insert parameter]
A copy of this section should be filled in for all parameters to be tested.
Test name
Reference
Internal descriptive name
Internal ref.
Sensitivity
Accuracy
Trueness
Limit of
detection
Cut-offs
Specificity
Repeatability
Reproducibility
Robustness
Probability
3.n.1 Work plan
Section aims
Describe the specific aims of this section of the validation
Samples
Describe the samples to be used including [where relevant] numbers and
type[s] of mutations present, relevant physical characteristics and how the
sample status has been derived (i.e. the reference or ‘gold standard’ test).
It may be appropriate to reference another document or database here.
Methodology
Describe the method to be used to evaluate the specific parameter
Authorisation
Name
Signature
Date
Investigator
Authoriser
3.n.2 Partial results and conclusions
Experimental
results
Summarise the experimental results
Cross-reference to or include the data.
Interpretation
Summarise the interpretation of experimental results (e.g. estimated level of
accuracy with confidence limits)
Outcome /
limitations
 State whether the results fulfil the validation requirements listed in 1.2
 List any specific derived limitations to reproduce the outcome (e.g.
controls and how they should be used)
Authorisation
Name
Investigator
Authoriser
Signature
Date
4. Validation / Verification (delete as appropriate) Final Conclusions
Test name
Internal descriptive name
Overall
Conclusion
State explicitly if the requirements in 1.2 have been fulfilled;
give any other relevant conclusions.
Estimates of
accuracy and
measures of
uncertainty
Give experimentally-derived values for the relevant metrics.
Comment on the potential influence of the uncertainty on the reliability
of the result.
Limitations and/or
predictable
interferences
List all limitations and control measures required to maintain the ongoing test performance
Internal QC
Detail internal quality control measures to be implemented,
addressing in particular the limitations and interferences identified.
External QA
Details of external quality assurance measures
Authorisation
Name
Investigator
Authoriser
Reference
Signature
Internal ref.
Date
5. Implementation
Test name
Reference
Internal descriptive name
Internal ref.
5.1 Implementation Checklist
Details
Date
Complete SOP
Risk Assessment, inc COSHH
Order reagents, consumables
Training
Competence assessment
Report template
Subscribe to EQA
Update request forms
Update website
Billing procedure
LIMS functionality
Inform users and other stakeholders
5.2 Independent review
Authorisation
Consultant
Scientist
(Authorisation)
Name
Signature
Date introduced to service
…......................................................................................................
Date
Appendix III: Validation Parameters
Description
Sensitivity1
Examples
Specificity2
Accuracy3
Trueness
Precision
Limits of
detection
++
++
++
++
++
++
A
Truly quantitative tests where the
result can have any value between
two limits (including decimals).
Determination of methylation load (%),
characterisation of a mosaic mutation,
heteroplasmy of mitochondrial variant.
B
Semi-quantitative tests where the
quantitative signal is placed into one
of a series of [essentially] undefined
categories to give the final result.
Sizing a PCR product, Determination of
triplet repeat size in Huntington disease,
myotonic dystrophy, etc.
+
C
Semi-quantitative tests where the
quantitative signal is placed into one
of a limited series of predefined
categories to give the final result.
Determination of a specific copy number
using QF-PCR, qPCR, or MLPA. E.g.
chromosome copy number, exon deletion /
duplication in BRCA1, PMP22 gene dosage
in CMT1A and HNPP.
+
To establish correction
factors and/or cut-offs
D
Qualitative tests where the true
quantitative signal can have one of
many possible values, but the
required result can only have one of
two possible values.
Fluorescent DNA sequencing/ mutation
scanning for unknown mutations e.g. by high
resolution melting curve analysis.
++
++
+
To establish correction
factors and/or cut-offs
++
E
Qualitative tests where the true
quantitative signal can only have one
of two possible values
Genotyping for the presence or absence of a
specific mutation (e.g. F508del in CF or
C282Y in hemochromatosis).
++
++
+
To establish correction
factors and/or cut-offs
++
Legend
Metric used for implementation validation
Metric used for implementation or on going validation
Metric used for on going validation
++
+
Recommended parameter
Applicable parameter (less used)
v
Notes
1.
Sensitivity = True Positive / (True Positive + False Negative)
2.
Specificity = True Negative / (True Negative + False Positive)
3.
Accuracy = True Result / (True Result + False Result)
4.
The term ‘probability’ is used to describe situations where a
probability that the result is correct can be assigned – primarily in
on-going validation
Probability4
+
++
+
Appendix IV: Flowchart
Request for Change
(Complete Form 1)
Rejected
No further action
Approved
Complete & submit
business case
Rejected
No further action
Approved
Develop Specification
Document
Follow Validation proforma
Tender and review
possible suppliers in
line with specification
Plan, Purchase, Install
& train key staff
Perform verification &
document
Write SOPs
Implement
Verification Report
sign off
Training to SOPs
Competency
Assessment
Maintenance of
intended process