Good Clinical Practice in the Laboratory
Quality Manual
Purpose:
Samples collected from clinical trial participants that undergo analyses or evaluations which drive
clinical care (e.g. safety and eligibility screening), or which monitor the efficacy of Investigational
Medicinal Products and therefore impact on the evaluation of trial outcomes, are required to be
conducted to Good Clinical Practice in the Laboratory standards. The purpose of this Quality Manual
is to provide anybody involved in this activity with the knowledge and understanding of what this
involves so that they know what is expected of them.
Scope:
This Quality Manual applies to all staff members within the University of Birmingham who are actively
involved in clinical trial sample analyses or evaluations which drive clinical care (e.g. safety and
eligibility screening), or which monitor the efficacy of Investigational Medicinal Products and therefore
impact on the evaluation of trial outcomes, within laboratories at the University of Birmingham.
Implementation Plan:
This Quality Manual will be implemented directly after its issue date.
Issue date:
21-Apr-2015
Property of the University of Birmingham, Vincent Drive, Edgbaston, Birmingham, B15 2TT, United Kingdom.
Not to be printed, copied or distributed without authorisation
Copies are only valid for 14 days and may be subject to amendment at any time. Refer to the electronic
document management system for the latest version.
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GCP in the Lab Quality Manual
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Table of Contents
Summary .............................................................................................................................................. 3
1.
Abbreviations and Definitions ...................................................................................................... 4
2.
Introduction.................................................................................................................................. 5
3.
Policy on laboratory quality management and compliance ......................................................... 6
4.
Policy on organisation ................................................................................................................. 6
5.
Policy on training laboratory staff ................................................................................................ 6
6.
Policy on conduct during the analysis ......................................................................................... 7
7.
Policy on sample receipt, handling and storage ......................................................................... 7
8.
Policy on method validation ........................................................................................................ 7
9.
Policy on handling and reporting of analytical data..................................................................... 8
10.
Policy on facility and equipment .............................................................................................. 8
11.
Policy on computerised systems ............................................................................................. 8
12.
Policy for GCP compliance in external laboratories ................................................................ 8
13.
Related documents ................................................................................................................. 9
14.
References .............................................................................................................................. 9
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Good Clinical Practice in the Laboratory Quality Manual
Summary
This Quality Manual details the University of Birmingham policies which exist in order to achieve Good
Clinical Practice compliance in laboratories undertaking clinical trial sample analyses or evaluations
which drive clinical care (e.g. safety and eligibility screening), or which monitor the efficacy of
Investigational Medicinal Products and therefore impact on the evaluation of trial outcomes.
All staff members at the University of Birmingham involved in this activity within laboratories at the
University of Birmingham must adhere to these policies.
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1. Abbreviations and Definitions
Term
Description
Chief Investigator
Chief Investigator means:
(a) in relation to a clinical trial conducted at a single trial site, the
investigator for that site
(b) in relation to a clinical trial conducted at more than one trial
site, the authorised health care professional (doctor, dentist, nurse
or pharmacist), whether or not he is an investigator at any
particular site, who takes primary responsibility for the conduct of
the trial
CTOC
Clinical Trials Oversight Committee
CRCT
Clinical Research Compliance Team
GCP
Good Clinical Practice guidelines
IMP
See ‘Investigational Medicinal Product’
Investigational Medicinal
Product
A pharmaceutical form of an active substance or placebo being
tested or used as a reference in a clinical trial, including products
already with a marketing authorisation but used or assembled
(formulated or packaged) in a way different from the authorised
form, or when used for an unauthorised indication, or when used
to gain further information about the authorised form
Laboratory
A facility that conducts manipulation, analysis or evaluation of
samples collected as part of a clinical trial; such analysis or
evaluation may include the generation of pharmacokinetic or
pharmacodynamic data, safety data, primary efficacy data,
histopathology data or data used to support any other stated
primary or secondary end point.
MHRA
Medicines and Healthcare products Regulatory Agency; the
Competent Authority in the UK
Policies
Policies are developed to describe the approach of the UoB on
areas that are heavily regulated. Policies may also be developed
when there is ambiguity in how regulatory requirements should be
implemented in the QMS or when procedures to be captured in
the QMS address areas controversial within the UoB at the time of
implementation. Policies explain why the UoB has its procedures.
Policies should be read in conjunction with the relevant SOP.
Policies that are not part of a Quality Manual are coded up as
‘POL’.
Principal Investigator
The investigator is responsible for the conduct of a clinical trial at
a trial site. If a trial is conducted by a team of individuals at a trial
site, the investigator is the leader responsible for the team and
may be called the Principal Investigator.
QCD
See ‘Quality Control Documents’
QMS
See ‘Quality Management System’
Quality Control Documents
Quality Control Documents can be instructions, forms, templates
or checklists. They are developed to share best practices,
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promote standardisation to guarantee quality standards are
maintained and reduce resources otherwise needed to develop
similar documents. Unless indicated otherwise in the relevant
SOP, QCDs are not mandatory and are designed to be an
optional aid to UoB staff.
Quality Management System
A Quality Management System (QMS) is a system that includes
procedures and policies to describe how certain tasks should be
performed and that encapsulate any standards and/or regulatory
requirements that may apply to those tasks. By adhering to the
Quality Management System, the user and the UoB will be
assured that applicable regulations are adhered to.
R&KT
Research and Knowledge Transfer
SOP
See ‘Standard Operating Procedure’
Sponsor
An individual, organisation or group who take responsibility for the
launch, management, and/or financing of a research study.
Standard Operating Procedure Standard Operating Procedures are detailed written instructions to
achieve uniformity of the performance of a specific function. They
define tasks, allocate responsibilities, detail processes, indicate
documents and templates to be used and cross-reference to other
work instructions and guidance or policy documents. They are
standards to which the UoB may be audited or inspected.
UoB
University of Birmingham
UoB Principal Investigator
The primary researcher in a research project, who takes
responsibility for the conduct and delivery of those parts of the
research which are either carried out at or managed/overseen by
the UoB.
Note the term ‘Principal Investigator’ is also used in clinical
research, but has a different meaning.
2. Introduction
The University of Birmingham (UoB) has set up a Laboratory Quality Management System (QMS) for
laboratories required to follow the Good Clinical Practice (GCP) in the Laboratory standards. This
Quality Manual forms part of the Laboratory QMS. The QMS exists in order to ensure that the rights
and wellbeing of subjects participating in clinical trials are protected, that the trial data is credible, and
that the trial is conducted in compliance with the approved protocol/amendment(s), all applicable
regulatory requirements and GCP.
The analysis of samples collected from subjects participating in clinical trials forms a key part of the
clinical trials process. Sample analysis or evaluation provides important data on a range of endpoints,
for example, assessment of the pharmacokinetic or pharmacodynamic profile of an Investigational
Medicinal Product (IMP) and monitoring its safety and efficacy. Consequently, it is essential that
sample analysis or evaluation is performed to an acceptable standard which will ensure that patient
safety is not compromised and that data is reliable and accurately reported.
The transposition of the EU Clinical Trials Directive 2001/20/EC and GCP directive into UK law (The
Medicines for Human Use (Clinical Trials) Regulations 2004, Statutory Instrument 2004 No.1031. as
amended) provides provision for the inspection of laboratories that perform the analysis or evaluation
of samples collected as part of a clinical trial. The Medicines and Healthcare products Regulatory
Agency (MHRA) has responsibility for monitoring such laboratories for compliance with these
Regulations and in July 2009 published important guidelines.
‘Guidance on the maintenance of regulatory compliance in laboratories that perform the analysis or
evaluation of clinical trial samples’:
http://www.mhra.gov.uk/home/groups/isinsp/documents/websiteresources/con051910.pdf
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This Quality Manual details the University of Birmingham policies which exist in order to achieve GCP
compliance in laboratories undertaking clinical trial sample analyses or evaluations which drive clinical
care (e.g. safety and eligibility screening), or which monitor the efficacy of IMPs and therefore impact
on the evaluation of trial outcomes.
3. Policy on laboratory quality management and compliance
The UoB Clinical Research Compliance Team (CRCT) will develop a Laboratory QMS (labelled as
‘UoB-CLN-LAB-‘) covering key processes that must be followed when GCP compliance within the
laboratory is required. Any policies and Standard Operating Procedures (SOPs) will be approved by
the Clinical Trials Oversight Committee (CTOC). The UoB Laboratory QMS must be used in
conjunction with the overarching UoB QMS.
Both Standard Operating Procedures (SOPs) and Quality Control Documents (QCDs) will be
developed as part of the Laboratory QMS. The SOPs must be adhered to.
Researchers are expected to develop their own systems and written procedures (often clinical trialspecific) to ensure GCP compliance and the integrity of the research data produced. Some of these
procedures will be focussed on the maintenance of the facility and equipment, and some will describe
trial-specific processes. This may include quality checks and they can use the Laboratory QCDs for
this purpose. It is suggested that these procedures are periodically reviewed and authorised by an
appropriately qualified person.
The UoB CRCT will perform audits/quality checks in laboratories undertaking primary and/or
secondary endpoint analysis of clinical trial samples to ensure that the laboratory and associated
equipment used to conduct the analyses remain fit for purpose. The audits/quality checks may focus
on how trial specific SOPs are controlled, maintenance of training records and/or processes such as
sample receipt and tracking, temperature monitoring, equipment maintenance and calibration, and the
validation of computerised systems. They may also focus on a review of the handling and reporting of
analytical data. The CRCT will highlight any Serious Breaches of GCP for immediate action.
4. Policy on organisation
The UoB considers it best practice for roles and responsibilities within the laboratory to be established
and documented prior to the initiation of analytical work to include the identification of personnel that
are responsible for laboratory and equipment management, quality assurance and scientific analysis.
It is suggested that an organogram be produced for each clinical trial detailing this, and that each
individual involved has a current job description detailing their role and responsibilities.
Where there is a requirement for clinical trial sample analysis or evaluation to be performed to GCP
standards, the UoB expects this to be overseen by a named individual(s) who assumes responsibility
for the conduct and reporting of the work. The named individual(s) should be responsible for reporting
the results of the analysis or evaluation, for assessing risks to patient safety (such as security
breaches or out of range results), risks to sample and data integrity following adverse events, for
reporting any deviations from written procedures or the clinical protocol and for reporting Serious
Breaches in GCP. Reporting lines should be established and documented prior to the initiation of
analytical work.
There must also be a mechanism to ensure that the laboratory is informed in a timely manner if
consent is withdrawn to ensure that no further data is generated or collected. This must be considered
and documented prior to the initiation of any analytical work.
5. Policy on training laboratory staff
As outlined in the UoB Master Quality Manual, the UoB Principal Investigator (PI) is accountable for
ensuring that staff are adequately trained to carry out their duties. The PI may delegate training duties
as long as those delegated are competent to provide training. For example, laboratory staff may
receive training on a piece of equipment, or for a laboratory technique/analytical procedure, from a
more experienced researcher or technician. Researchers are advised to consider the most
appropriate training methods to use for laboratory based activities. It is expected that this will largely
involve demonstration followed by observation until competency is achieved.
It is recommended that staff working within laboratories required to work to GCP standards receive
training on any relevant policies, SOPs and QCDs, trial-specific procedures and current MHRA
laboratory guidelines. They should also receive GCP training commensurate with their roles and
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responsibilities, and periodic GCP refresher training (especially important following changes to
statutory regulations and associated guidance documents).
All training and competencies will be recorded and training records will be available for inspection.
6. Policy on conduct during the analysis
The UoB considers it best practice to provide the laboratory conducting clinical trial sample analyses
or evaluations to GCP standards with a copy of the trial protocol (and amendments relevant to the
laboratory analyses), or as a minimum, the sections of the clinical protocol which are relevant to the
activities undertaken in the laboratory.
It is strongly recommended, that prior to the initiation of sample analysis or evaluation, a document is
produced which details the methods and procedures which will be used to conduct the analyses. This
may take the form of a version controlled laboratory manual containing all written procedures from
sample receipt, sample analysis, through to review and reporting of analytical results. It is suggested
that actions to be undertaken following adverse events, following analytical failures, out of range
results, and following deviations from work instructions or the trial protocol are included.
The recommendation is that this document is reviewed and signed off by the Sponsor (or
representative) to ensure that the content does not contradict other documents such as the trial
protocol. Critically, the document must only include work that is covered by the informed consent
given by the trial participants. The UoB must be satisfied that if any adverse event or breach in GCP
or the protocol should impact on the integrity or reliability of the trial data, patient confidentiality,
patient consent or patient safety, appropriate procedures are in place to ensure the issue is reported
immediately.
7. Policy on sample receipt, handling and storage
Samples must be transported from the clinical site to the laboratory in such a way that their integrity
and viability remains unaffected (e.g. at the correct temperature and within the correct time period).
Written procedures must be developed to enable this and it is advisable to include an assessment of
sample integrity upon receipt, and actions to be taken if this has been compromised. Similarly, written
procedures must be developed to deal with (and document) missing, unexpected or poorly labelled
samples.
The UoB recommends that samples are anonymised at the clinical site before they are received by
the laboratory and that all laboratories develop procedures to enable each sample to be uniquely
identified. Robust mechanisms must be in place for tracking the movement of each sample from
arrival to analysis and/or disposal.
Sample storage areas must be adequate, and sample storage units (e.g. liquid nitrogen tanks,
freezers and fridges) must be monitored for compliance (e.g. temperature) and maintained and
serviced regularly. Temperature and service/maintenance records should be stored safely and
available for inspection. Equipment used to monitor temperature must be subject to periodic
calibration. It is recommended that clinical trial sample storage units and areas should be kept
separate, secured, and restricted to relevant personnel.
Trial-specific procedures must be written detailing the actions to be taken following failure of storage
units, to include information about who should be notified and how and where samples may be
transferred to. If there is a possibility that insufficient back up space may be available then the
recommendation is to decide a clear prioritisation of sample salvage (to include standards, controls
and reagents if they are affected also) and to include this in the written procedure.
8. Policy on method validation
Clinical trial sample analyses or evaluations being conducted to GCP standards must be properly
validated prior to undertaking the analysis or evaluation, and this must be documented. Acceptance
criteria for each assay and the circumstances that allow repeat analysis must be transparent and
clearly defined. Researchers are advised to get documented assay validation plans and reports
reviewed and signed off by an appropriate person, for example, someone with the appropriate
laboratory GCP expertise. They may also consider review and sign off by the Chief Investigator.
Safe and secure storage must be available for controls, standards and reagent used during primary
and secondary endpoint analyses. Records must be kept of batch numbers used during each
analytical run and expiry dates observed.
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9. Policy on handling and reporting of analytical data
It must be possible to trace back all analytical data produced to original records of data and the
procedures and materials used to obtain that data. Any change to the data should be made so as not
to obscure the previous entry and in line with GCP standards.
To ensure that data is reported accurately results may require cross-checking and review before
release and researchers are expected to produce written data handling procedures.
If data is generated, recorded, manipulated and stored or archived electronically, it is strongly
recommended an electronic audit trail should be maintained.
10.
Policy on facility and equipment
The UoB accepts that clinical trial sample analyses or evaluations being conducted to GCP standards
cannot always be undertaken in a dedicated standalone laboratory facility and will in some cases be
carried out in laboratories which are shared with other researchers. In either case, the UoB
recommends that access to the laboratory or laboratory area should be carefully considered and
restricted only to personnel who require it.
It is best practice to maintain laboratories or laboratory areas undertaking clinical trial sample analysis
in a sufficiently clean and orderly state to preclude contamination and mix-ups. All equipment used
during sample analysis or for the storage of samples, analytical assay standards, controls and
reagents must be adequately tested, calibrated and maintained. Records of this must be kept and be
available for inspection.
The UoB recognises that some pieces of equipment may be used for the analysis of clinical trial
samples which are shared with other researchers and researchers are strongly recommended to
ensure that all operators are trained to use and maintain these shared pieces of equipment to a
standard that will not compromise the integrity of clinical trial data.
Written procedures must be in place for adverse events occurring within the laboratory or laboratory
area (such as security breaches, equipment failure or equipment calibration failure). This must include
a process for assessing the impact of the adverse event on sample quality and/or the integrity of
analytical data.
11.
Policy on computerised systems
It is a strong recommendation that computerised systems used for the capture, processing,
manipulation, reporting and storage of analytical data should be validated and maintained in ways
which ensure the validity, integrity and security of the data.
Researchers are advised to perform computer system validation in accordance with a documented
plan which is linked to the level of functionality, and to archive all records associated with the
validation.
If a computerised system has been in use for some time, but has never been subject to any formal
validation, researchers should consider performing a retrospective assessment of its suitability.
Disaster recovery procedures will be implemented for all computerised systems and documented
policies which describe procedures following a system failure will be maintained.
Access to computerised systems will be controlled and the identity of those with specific access rights
to computerised systems will be documented and subject to periodic review.
12.
Policy for GCP compliance in external laboratories
It is anticipated that for some UoB sponsored clinical trials, sample analyses or evaluations may need
to be conducted to GCP standards at laboratory sites external to UoB. External laboratories may have
their own QMS which covers this activity, but the minimum standards as set out in the UoB SOPs will
need to be adhered to. The recommendation is that GCP compliance in external laboratories is
assessed at the outset. It may be necessary for a local staff member to cross-check and ensure that
the contents of the UoB QMS is covered, and to document this process.
Contractual agreements between the UoB and external institutions undertaking laboratory based
primary and/or secondary endpoint analyses will be put in place prior to the initiation of any work. The
agreement will delegate the responsibility for GCP compliance in the laboratory and adherence to
UoB SOPs to the external site.
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The laboratory agreement may be included in an overarching site agreement or may take the form of
a separate laboratory service level agreement.
13.
Related documents
 UoB-CLN-LAB-SOP-001
 UoB-CLN-CTM-QCD-001
14.
Procedures for GCP compliance in the laboratory
Glossary of Terms
References
 Guidance on the maintenance of regulatory compliance in laboratories that perform the analysis
or evaluation of clinical trial samples: http://www.mhra.gov.uk/home/groups/isinsp/documents/websiteresources/con051910.pdf
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Development summary:
Author:
Name:
Jane Steele
Function:
Director, Advanced Therapies Facility
Date:
See original copy
Reviewed by:
Clinical Trials Oversight Committee
Signature:
See original copy
Signature:
See original copy
Signature:
See original copy
Authorised by:
Name:
Professor Julian Bion
Function:
Chair of Clinical Trials Oversight Committee
Date:
See original copy
Name:
Wilma van Riel
Function:
Clinical Trials Quality Assurance Manager
Date:
See original copy
Issue date:
21-Apr-2015
Supersedes:
N/A
Reason for update:
N/A
Review of final version:
Date:
Reviewed by:
Signature:
Outcome:
N/A
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