GCLP: Quality Management

Contents
1. Contents
2. Introduction
1. What is a Quality Management System (QMS)
3. Regulatory Requirements and Expectations
4. Clinical Trial Guidance and Quality Management Systems
1. What does ICH GCP state about Quality Management and Quality Management
Systems?
2. A Risk-based Approach
3. Other guidances about Quality Management and Quality Management Systems that
relate to laboratories
5. Requirements of a Laboratory QMS
1. Management Responsibility
2. Documentation
3. What SOPs do we need?
6. Specific guidances
7. Summary
8. Quiz
9. Referencias

Introduction
In this session, we discuss the requirements for quality management and associated systems as
applicable to Good Clinical Practice (GCP). GCP applies to laboratories that analyse samples from
clinical trials. Additional guidance (often referred to as Good Clinical Laboratory Practice) has
been produced by several institutions and regulatory bodies (e.g. WHO, EMA, UK MHRA) to assist
laboratories in achieving compliance with GCP.

First, we need to understand what is meant by the terms Quality Management and Quality
Management Systems.

Let’s begin by looking at the words 'Quality' and 'Management'

The term ‘quality’ can mean different things to different

people. Some examples are:

How good or bad something is

A high standard
If something is fit for use and/or purpose
An item that is free of any defects
The degree to which a commodity meets the
requirements of the customer at the start of its life (ISO
9000)

Within the pharmaceutical industry, the International

Committee on Harmonisation has produced several
guidance documents, and the following definitions of
Quality comes from these (Reference source ICH Q6A,
Q9 and Q10).

Quality is the degree to which a set of inherent properties of a product, system or process fulfils
requirements

Quality is the suitability of either a drug substance (this is the active pharmaceutical ingredient)
or drug product (this is a product that includes the drug substance, that has been processed in
some way to produce a dosage form that is intended for consumers) for its intended use. This
term includes such attributes as the identity, strength, and purity.

In the analytical laboratory, quality is accurate, reliable and produces results in a timely manner
as well as following the ALCOA+ principle.

Management can also have different meanings, but the definitions are essentially similar

The process of dealing with or controlling things or people

The control and organisation of something

The activity of controlling something, or of using or dealing with something in a way that
is effective

A good description would be the organisation and coordination of people, other resources and
processes to achieve defined objectives with the desired outcome.

We then bring these terms together as Quality Management. So what does this
mean?

Quality management is the act of overseeing activities needed to ensure (control) the consistent
delivery of a product or service to a desired standard (fit for purpose/its intended use).

Within the pharmaceutical industry, the only real definition of Quality Management can be found
within the Good Manufacturing Practice (GMP) sector, which describes Quality Management as a
wide-ranging concept that covers all matters, which individually or collectively influence the
quality of a product. It is the sum total of the organised arrangements made with the objective
of ensuring that medicinal products are of the quality (purity and strength) required for their
intended use (Ref: EudraLex Volume 4, Chapter 1). This principle applies through the lifecycle of
a product, from its development through to commercialisation.

Although there is reference to Quality Management in Good Clinical Practice (ICH GCP E6 (R2)),
ICH E6 (R2) does not actually define what Quality Management means.

What is a Quality Management System (QMS)

A QMS can be described as a formalised system
that documents processes, procedures, and
responsibilities for achieving quality policies and
objectives. A QMS helps coordinate and direct an
organisation’s activities to meet customer and
regulatory requirements and improve its
effectiveness and efficiency on a continuous
basis.

But it is more than just the documentation; these

documents (e.g. Standard Operating Procedures (SOP), Specifications) exist in support of the
QMS. It also includes other elements, such as a establishing a quality culture within an
organisation, setting quality objectives and a means to monitor the progress of these, e.g.
through key performance indicators and management review, installing a system for continuous
improvement, and more.

Within the pharmaceutical industry the term Pharmaceutical Quality System (PQS) is often used
as an equivalent term for QMS. The PQS has been defined as “the management system to
direct and control a pharmaceutical company with regard to quality” (reference ICH Q10, taken
from ISO 9000:2005).

In the context of a laboratory that analyses samples from clinical trials, QMS is the
entire system of managing samples in compliance with the approved protocol,
study manuals, and any regulations or industry guidance. Thus, it would apply to
these aspects of clinical trial sample management:

collection
receipt
storage
labelling
processing
analysis
transport
destruction

The quality objective of this QMS is to produce results that are accurate, complete and reliable,
as these results will be used to make vital decisions in the drug development and
commercialisation of a product that will have a direct impact on the safety of trial subjects and
consumers. An example of this is in dose escalation studies where laboratory data is used in
making a decision to increase the strength or number of tablets given to trial subjects.

Regulatory Requirements and Expectations

So why do we need to implement Quality Management and Quality Management
Systems within the Laboratory?

It is a regulatory requirement or expectation. This

requirement applies to all of the GxPs (good pharmaceutical
practices); GLP (good laboratory practice), GCP (good clinical
practice), GMP (good manufacturing practice), GDP (good
distribution practice), GVP (good pharmacovigilance practice).
However, it should not just be seen as something that has to
be done because that is what the regulators require. Think
about the patient who is end user of a medicinal product. If
you were the patient, what would you want? You would
probably want a product that is safe and effective at treating
your condition. The safety and effectiveness of a
experimental product relies on a strong contribution from the
laboratory analysis of a clinical trial. Strong Quality
Management with a robust QMS should enable an organisation to consistently contribute to the
accurate assessment of an experimental product. It will also have other benefits to the
organisation, such as more efficient workflows, increased productivity, and reduced needs to
investigate possible errors or unexpected results.

For clinical trials (GCP), the requirement to implement effective quality management with an
appropriate QMS applies to all organisations involved in the conduct of a clinical trial. This
includes trial sponsors and all types of contract research organisations (CRO). Laboratories also
fall into this category. Regulatory authorities and Institutional Review Boards (IRBs) responsible
for authorising trials and performing ethical reviews should have an appropriate QMS, also.

The requirement to implement a QMS is not always clear within regulations and guidance
documents. Often these requirements are implicit in the language used, calling for procedures
to be in place to assure a certain quality outcome.

For example, in the U.S. federal regulations on research:

21 CFR Part 11– Electronic Records; Electronic Signatures, requires procedures to be

implemented that ensure the authenticity, integrity, and, when appropriate, the
confidentiality of electronic records.

21 CFR 50- Protection of Human Subjects requires the IRB to ensure that procedures are in
place to provide the trial information approved by the IRB to each subject or the subject's
legally authorized representative, as part of the informed consent process.

Another example within Europe is that there is a more definite requirement. The current
European GCP Directive 2005/28/EC states:

“The necessary procedures to secure the quality of every aspect of the trials shall be complied
with” (Article 2 (4).

However, the new European Regulation 536/2014 on clinical trials of medicinal products for
human use shall replace 2005/28/EC (as well as the clinical trials Directive 2001/20/EC); current
estimates for the regulation coming into force are late 2020/early 2021. Whilst this regulation
removes the explicit statement in 2005/28/EC, it does refer to procedures being needed
throughout the document, e.g. for recruiting and consenting of trial participants. It also now
explicitly requires (point 43) the ICH guidelines on good clinical practice to be taken
appropriately into account as the appropriate standard when applying of the rules set out in the
regulation in the absence of any other guidance.

Clinical Trial Guidance and Quality Management Systems

The most widely recognised guidance when it comes to clinical trials is the Integrated
Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2) which has now been
adopted by all major ICH countries, including those from Europe, Japan, USA, Canada and
Switzerland. ICH E6 (R2) is mandatory in many countries (e.g. it is stated within the new EU
Clinical Trial Regulation), whilst in the USA it is a non-binding recommendation. A major revision
of the ICH E6 (R2) is now underway, but it is likely to be some years before we see ICH E6 (R3).

What does ICH GCP state about Quality Management and

Quality Management Systems?
One of the main principles of ICH GCP in the original version (E6(R1)) has always been that:

2.13 “Systems with procedures that assure the quality of every aspect of the trial should be
implemented”.

With the release of ICH E6(R2), this was further clarified to state that:

“Aspects of the trial that are essential to ensure human subject protection and reliability of trial
results should be the focus of such systems”.

This terminology introduced a more risk-based approach, emphasising those systems that are
necessary for the rights, safety and wellbeing of the trial participants to be preserved, whilst
ensuring the integrity of the trial data.

ICH E6(R1) had always required Sponsors and Contract Research Organisations (CROs) to
implement Quality Assurance and Quality Control systems to ensure that the trial was conducted
and the data was generated, documented and reported in compliance with the trial protocol,
GCP and applicable regulatory requirements. It required these systems to be described in
written procedures.

Quality Assurance was defined within the guideline as:

“All those planned and systematic actions that are established to ensure that the trial is
performed, and the data are generated, documented (recorded), and reported in compliance
with Good Clinical Practice (GCP) and the applicable regulatory requirement(s)”.

And Quality Control was defined as:

“The operational techniques and activities undertaken within the quality assurance system to
verify that the requirements for quality of the trial-related activities have been fulfilled”.

With the release of ICH E6(R2), a more complete concept of Quality Management and Quality
Management Systems was introduced. Section 5 of the guideline that relates more specifically
to Sponsors (and of course to CROs) now states:

"The sponsor should implement a system to manage quality throughout all stages of the trial
process. Sponsors should focus on trial activities essential to ensuring human subject protection
and the reliability of trial results. Quality management includes the design of efficient clinical
trial protocols and tools and procedures for data collection and processing, as well as the
collection of information that is essential to decision making.”

What does ICH GCP state about Quality Management and Quality
Management Systems?
One of the main principles of ICH GCP in the original version (E6(R1)) has always been that:

2.13 “Systems with procedures that assure the quality of every aspect of the trial should be
implemented”.

With the release of ICH E6(R2), this was further clarified to state that:

“Aspects of the trial that are essential to ensure human subject protection and reliability of trial
results should be the focus of such systems”.

This terminology introduced a more risk-based approach, emphasising those systems that are
necessary for the rights, safety and wellbeing of the trial participants to be preserved, whilst
ensuring the integrity of the trial data.

ICH E6(R1) had always required Sponsors and Contract Research Organisations (CROs) to
implement Quality Assurance and Quality Control systems to ensure that the trial was conducted
and the data was generated, documented and reported in compliance with the trial protocol,
GCP and applicable regulatory requirements. It required these systems to be described in
written procedures.

Quality Assurance was defined within the guideline as:

“All those planned and systematic actions that are established to ensure that the trial is
performed, and the data are generated, documented (recorded), and reported in compliance
with Good Clinical Practice (GCP) and the applicable regulatory requirement(s)”.

And Quality Control was defined as:

“The operational techniques and activities undertaken within the quality assurance system to
verify that the requirements for quality of the trial-related activities have been fulfilled”.

With the release of ICH E6(R2), a more complete concept of Quality Management and Quality
Management Systems was introduced. Section 5 of the guideline that relates more specifically
to Sponsors (and of course to CROs) now states:

"The sponsor should implement a system to manage quality throughout all stages of the trial
process. Sponsors should focus on trial activities essential to ensuring human subject protection
and the reliability of trial results. Quality management includes the design of efficient clinical
trial protocols and tools and procedures for data collection and processing, as well as the
collection of information that is essential to decision making.”

A Risk-based Approach
The guidelines further describe the risk evaluations sponsors should make before and during a
trial, stating that “The quality management system should use a risk-based approach”. This
means identifying, evaluating, reviewing, controlling, and communicating/reporting on risks
during the trial.

(Click to enlarge)

The guidelines also introduced more clearly the requirement of Sponsors to have oversight of
any trial tasks that were outsourced to a CRO and this applies equally to CROs who may
outsource some of the duties transferred to them by the Sponsor to another CRO. This is
essentially Quality Management of the CROs.

Section 5.5 of the guideline on Trial Management, Data Handling, and Record Keeping, provided
further guidance on QMS requirements for electronic data handling systems. Whilst ICH E6(R1)
had required that the Sponsor/CRO maintained Standard Operating Procedures (SOPs) for using
such systems, ICH E6(R2) provided further details as to what the SOPs should cover.

“The SOPs should cover system setup, installation, and use. The SOPs should describe system
validation and functionality testing, data collection and handling, system maintenance, system
security measures, change control, data backup, recovery, contingency planning, and
decommissioning. The responsibilities of the sponsor, investigator, and other parties with
respect to the use of these computerized systems should be clear, and the users should be
provided with training in their use.”

This section directly applies to many of the processes in the clinical trial laboratory, especially
the instrumentation comprising hardware and software used to generate, capture, report and
store trial data from the analysis of samples for safety, pharmacokinetic / pharmacodynamic
(PK/PD) and biomarkers.

Other guidances about Quality Management and Quality Management

Systems that relate to laboratories
So, what other guidance do we have about Quality Management and Quality
Management Systems that specifically relates to laboratories?

In 2009 the World Health Organisation acquired the copyright to GCLP guidelines that were
originally published in 2003 by a working party of the Clinical Committee of the British
Association of Research Quality Assurance (BARQA; now RQA), with the aim of disseminating
them widely in developing countries and developing related training materials. This 2009
guideline was more closely aligned to the Organisation for Economic Co-operation and
Development (OECD) Principles of Good Laboratory Practice. The 2009 guidance applied certain
requirements on the management of a laboratory and the person within the laboratory who has
been designated responsible for the overall conduct of the work at the laboratory.

In February of 2012, the EMA released a final 'Reflection paper for laboratories that perform the
analysis or evaluation of clinical trial samples' following a guidance that was produced in 2009
which helped laboratories to maintain quality management systems according to regulations.

Therefore, the two main guidance documents that are now followed in relation to GCLP are
those produced by WHO in 2009 and EMA in 2012. Both should be considered when
implementing Quality Management and a QMS within the laboratory. Further specific guidances
is available in the section titled "Specific Guidances" within this module.

Requirements of a Laboratory QMS

What are the specific requirements needed to implement Quality Management and a
documented QMS within the laboratory?

In this section, we examine management responsibility, documentation and the SOPs that may
be required to implement Quality Management and a documented QMS in the laboratory.

Management Responsibility
Senior management within the laboratory must establish a quality culture through the
performance of the QMS and in order to facilitate the commitment of all staff to quality.
Management has overall responsibility for ensuring that an effective QMS is implemented. This
allows the laboratory to achieve quality objectives and support the QMS using documented
procedures. Laboratory management must also define the roles and responsibilities with the
appropriate authority to undertake the various task required for the analysis and reporting of
samples from clinical trials. This should be communicated to all laboratory staff.

Roles and responsibilities within a laboratory should be established and documented prior to the
initiation of analytical work. These will include but not be limited to identifying personnel that are
responsible for:

laboratory management,
quality assurance,
scientific analysis,
reporting and archiving.

To document this, a laboratory organisation chart (or organogram) should be established

showing the different functions or departments, job titles and numbers of staff and their
reporting lines. This document should be version controlled by a version number or date so that
the current document can be identified.

Roles and responsibilities should be defined in written job descriptions that are provided to the
employee. While not mandatory, it is helpful to have both the employee and the manager sign
the job description, in line with the local regulation, to confirm their mutual understanding and
acceptance of the employee’s role and responsibilities.

Management’s general responsibilities include:

Participating in the design, implementation, monitoring and maintenance of the QMS,

including writing, reviewing, tracking changes to QMS documents

Showing support and commitment to the QMS by ensuring that it is implemented and
complied with throughout the laboratory

Ensuring systems are in place to escalate quality issues to the appropriate levels of
management in a timely manner

Establishing an independent quality unit or structure with authority to fulfill certain QMS
responsibilities. This can sometimes be challenging in small organisations. Consider use of
staff within an organisation that are not allocated to a particular project to perform quality
activities related to the project or using external independent consultants to audit the
quality systems

Conducting management reviews of process performance and product quality and of the
QMS. This is typically done once or twice per annum and considers topics such as:
results of audits and inspections,
 review of quality metrics and key performance indicators (KPIs),
quality Issues and corrective/preventative actions (CAPA management),
review of complaints,
change management activities,
regulatory updates,
laboratory investigations and unexpected results, etc.

Management should decide what is necessary to ensure the quality objectives continue to
be met in compliance with the Quality Policy.

Being an advocate of continual improvement

Ensuring resources for the laboratory to perform the work properly to the desired quality

Ensuring that staff have the necessary qualifications, experience, and training for their role
throughout their employment

Assigning a person to each trial who has the appropriate qualifications, training and
experience to manage and oversee the work. This person is typically called the Analytical
Project Manager, but different organisations may use different terms for this role. The
Analytical Project Manager will have the responsibility for the day to day Quality
Management of the trial work being conducted.

Documentation
A typical documented QMS is shown in the diagram below and consists of a Quality Policy and
Quality Manual supported by documented procedures etc

ICH GCP E6(R2) requires (documented) procedures however ICH Q10 requires a Quality
Policy and Quality Manual to be established. That will assure the quality of every aspect of the
trial to be implemented. These procedures should support the Quality Policy and Quality
Manual.

Documented procedures are often called Standard Operating Procedures (SOPs), but other
terms or types of document used by laboratories include:

Work Instructions,
Working Practices,
Guidelines,
Forms and Templates.

There is no mandatory requirement as to how document types should be named and this
decision is up to the individual laboratory as documented in their SOP of SOPs. The records of
these procedures/work instructions, etc. provide evidence that the requirements of the QMS are
being met. Records may include

(a) the results of the analysis,

(b) environmental monitoring

(e.g. temperature to show that clinical trial samples and the materials and reagents used in their
analysis were stored correctly),

(c) records to confirm that samples were processed correctly

(e.g. date/time of sample collection, date/time in and out of a centrifuge, and date/time into a
freezer), and

(d) equipment calibration and maintenance records.

The Quality Policy should describe the overall intent and direction of the laboratory to achieve
the desired quality. It should include expectations for compliance with all applicable regulatory
requirements and foster an environment of continual improvement within the laboratory.

The Quality Manual should describe the QMS of the laboratory and how it has been organised
to achieve the quality goals and objectives. It should include but not be limited to the following:

Include or make reference to, the Quality Policy

Define the scope of the QMS, e.g. that it applies to all the systems and tasks performed by
the laboratory in the receipt, handling, storage, analysis, reporting and destruction of
clinical trial samples

Establish Quality Objectives for the laboratory with systems to monitor their progress, e.g.
through frequent review of key performance indicators

Identify the key elements of the QMS processes put in place to achieve the quality
objectives. ICH Q10 recommends that this includes presenting them in a format that is
sequential to the processes involved and how different processes are linked/are
interdependent on each other. It also suggests using process maps and flow charts to
illustrate the QMS processes in a visual manner
Define Management’s responsibilities within QMS

Whatever documentation is implemented by a laboratory as part of its QMS, the management

should have in place processes for managing the documents and the requirement to periodically
review them to ensure they remain relevant to the laboratory. The frequency of review is up to
the laboratory to determine in their SOP of SOPs. Typically a two-year review period is set by
laboratories, but there also may be different review periods for different documents depending
on the risk they represent to the overall objectives of the QMS.

What SOPs do we need?

This will depend on exactly what work the laboratory is performing. Many of the procedures that
are needed would be general and applied across all trials, but it may be necessary for the
laboratory to create trial-specific procedures, including specific test methods that should have
been developed and validated.

Examples of typical general procedures that should be in place include:

The preparation and review of contracts and agreements. This may include use of the
laboratory format contracts, or those of the Sponsor/CRO delegating the work to the
laboratory. It should define responsibilities within the laboratory for review and approval of
contracts, and it should also include the requirement to periodically review then to ensure that
they remain compliant with the trial protocol and regulatory requirements. A point to note is
that when a trial protocol amendment occurs, the impact of the amendment on the contract
should be considered including any change in time and budget

An SOP of SOPs. This would describe the procedure for the preparation, review, approval,
distribution and withdrawal of SOPs and associated documents such as polices, work
instructions, guidelines, forms, and templates. It should also include the requirements for
formatting, assigning a unique code or identifier to the document and how different versions of
the same document will be managed, and how periodic review will be managed

Training of staff. This should include (as applicable) how training is managed as a function e.g.
through the use of electronic Learning Management Systems or paper-based systems, how
new employees are inducted in to the laboratory, job function specific training including
competencies needed for that function, how training in SOPs and other QMS documents is
managed, training in regulatory requirements such as GCP and GCLP, IATA training for persons
responsible for shipping samples to other facilities, review of training requirements and
individual training records, and the structure/format of training records

The way in which the analysis or evaluation of clinical trial samples is performed and reported.
This may often be described in a Bioanalytical Plan or similar document which the Analytical
Project Manager would be responsible for generating before the analysis of any trial samples.
There should be a procedure that describes how to prepare the Bioanalytical Plan

Procedures for the receipt, storage and processing of samples and reference materials. Details
that are specific to a trial can be specified in the Bioanalytical Plan

Labelling of materials and reagents, such as Quality Control (QC) standards, blanks, etc

Preparation of clinical kits. Some laboratories will be responsible for assembling kits that clinical
sites will use to collect the trial samples specified in the trial protocol
How issues that could impact patient safety should they occur would be handled, such as out of
range or unexpected results e.g. PK results that could indicate a dosing error

How additional and/or unexpected samples would be handled. Laboratories are required to
abide by the trial protocol, but the Investigators at the clinical sites may order additional tests
for the purposes of subject safety. Confirmation should be provided to the laboratory that the
extra samples are for these purposes, but until this is obtained, it should not delay the analysis
as these could be important results relating to the safety of a participant

Procedures for unblinding samples, if requested. For trials that are blinded (this is where one or
more parties is blind to the trial treatment), sometimes laboratories are asked by the Sponsor
to unblind the samples so that they analyse certain samples only, e.g. they do not analyse
samples from participants on placebo. There should be procedures for how this will be
managed, to include the mechanism that will be used, receipt and storage of the codes used to
break the blind, unblinding and re-blinding, reporting of results to persons authorised by the
Sponsor to receive them. In relation to this, some laboratory results may result in inadvertent
blinding, e.g. antibody titers, PK results etc. A mechanism to avoid this may need to be
described in one of the SOPs

Procedures for handling poorly labelled samples, including samples that my inadvertently
identify a trial subject, resulting in a loss of confidentiality

Informed consent and withdrawal of consent. Laboratories are required to only analyse the
samples and parameters for which participants have consented to, as per the trial protocol. It
is important therefore that the laboratory has receipt of the trial protocol and a blank copy of
the Informed Consent Form in order to perform due diligence that the samples they will be
analysing are covered by the protocol and subject consent. It is usual to include clauses in the
contract with the Sponsor/CRO relating to informed consent, to include a statement that the
laboratory will be notified in a timely manner should they withdraw their consent to prevent the
further analysis of their samples

Data Governance and Data Integrity (refer to the UK MHRA guidance)

Reporting of trial results

Waste management

Disposal of trial samples

General housekeeping and cleaning

Maintenance, servicing and calibration of equipment. Reference can be made to individual

equipment manuals, but systems should be established to ensure that routine maintenance,
servicing and calibration of equipment is carried out according to the equipment
manufacturer/supplier instruction and that this is documented. It is good practice for each
piece of equipment to have its own usage logbook or file that can be used to record this

Procedures that control the installation and validation of equipment and computerised systems

The retention of trial data and non-trial-specific records, and of samples

Quality Assurance and Quality Control functions

Some of these will require specific details that are applicable to a trial which should be
documented in the Bioanalytical Plan, or similar document. A list (e.g. SOP Index) of the current
general procedures (non-study-specific) should be maintained.

Specific guidances
The following important guidelines may help when developing a QMS in a laboratory.
WHO Guideline - Laboratory Quality Standards and their Implementation (2011)

OECD Principles of Good Laboratory Practice: intended for laboratories performing nonclinical
toxicology studies, but useful for laboratory Quality Management and QMS:

https://www.oecd.org/chemicalsafety/testing/good-laboratory-practiceglp.htm

ICH Q9 Quality Risk Management and ICH Q10 Pharmaceutical Quality System: applicable across
the GxPs and provide general considerations for Quality Management and Quality Management
Systems:

https://database.ich.org/sites/default/files/Q9%20Guideline.pdf
https://database.ich.org/sites/default/files/Q10%20Guideline.pdf

There is also other specific guidance that laboratories should consider when building their QMS,
and these include:

FDA Guidance for Industry May 2007: Computerised Systems used in Clinical Investigations:
https://www.fda.gov/media/70970/download

FDA Guidance for Industry: Bioanalytical Method Validation 24-May-2018

https://www.fda.gov/files/drugs/published/Bioanalytical-Method-Validation-Guidance-
for-Industry.pdf

EMA reflection paper on expectations for electronic source data and data transcribed to
electronic data collection tools in clinical trials
https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/reflection-
paper-expectations-electronic-source-data-data-transcribed-electronic-data-
collection_en.pdf

EMA Guideline on bioanalytical method validation 21-Jul-2011

https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-bioanalytical-
method-validation_en.pdf

UK MHRA GxP Data Integrity Guidance and Definitions Mar-2018

https://assets.publishing.service.gov.uk/government/uploads/system/uploads/

There are also many internationally recognised Quality Management System standards that
laboratories can follow when implementing a Quality System.

ISO 9000:2015 is one of the most widely known when it comes to Quality Management, which
describes the fundamental concepts and principles of quality management and is universally
applicable across all types of organisation.

But there are other quality standards that are more applicable to laboratories, some of which
are listed below.

ISO 15189:2012 Medical laboratories — Requirements for quality and competence

https://www.iso.org/obp/ui/#iso:std:iso:15189:ed-3:v2:en

SO/IEC 17025:2005. General requirements for the competence of testing and calibration
laboratories
https://www.iso.org/obp/ui/#iso:std:iso-iec:17025:ed-2:v1:en

The Clinical Laboratory Improvement Amendments (CLIA) in USA

https://www.cdc.gov/clia/index.html

College of American Pathologists (CAPs) Laboratory Accreditation Program

https://www.cap.org/laboratory-improvement/accreditation/laboratory-accreditation-
program

Laboratories can either choose to follow the requirements of these standards, or they can
choose to become formally certified or accredited. In some countries it is a mandatory
requirement to be accredited in analysing clinical samples.

Summary
The senior laboratory management is responsible for ensuring an environment in the laboratory
that properly supports the QMS in the laboratory.

There are many guidelines available to assist laboratories in establishing a QMS. The two main
guidance documents that are now followed in relation to GCLP are those produced by WHO/TDR
in 2009 and EMA in 2012. Both should be considered when implementing Quality Management
and a QMS within the laboratory.

In summary, each laboratory involved in the analysis of clinical trial samples must implement a
Quality Management System underpinned by the principles of good Quality Management, to
ensure that the conduct of the work is performed to a high standard. In doing this, the
laboratory can take a risk-based approach, but it must consider those activities that could have
an impact first and foremost on the safety of the trial participants and the integrity and
reliability of the trial data.

Quiz
Please ensure you have answered all questions before clicking the ‘submit’ button

1. What document types can be part of a documented QMS?

Quality Policy
Quality Manual
SOP
Work Instruction

2. Does management have to demonstrate their support and commitment to the QMS and
ensure that it is implemented and complied with throughout the laboratory?

Yes
No

3. What is the main principle of ICH GCP that relates to a laboratory needing to implement a
documented QMS?

ICH GCP Principle 2.13

ICH GCP Principle 2.1
ICH GCP Principle 2.7

4. What is the ISO standard that relates to Medical Laboratories?

15189:2012
9001:2015
22000

5. Should the QMS system follow a risk-based approach?

Yes
No

6. A QMS is the formalized system that documents processes, procedures, and responsibilities
for achieving quality policies and objectives. Correct?

Yes
No

7. If a laboratory is involved in the management of clinical trial samples (in which ever way),
which guidelines should be adhered to:

GCP
GLP
GCLP (GCP+GLP)

8. Quality Management is important because:

The accurate assessment of the safety and effectiveness of an experimental

product relies heavily on the laboratory’s analysis of the trial samples and reporting of
the results
It will ensure that the data provided by the laboratory is accurate, reliable, and of
high integrity
To comply with applicable local and international regulations
All of the above

9. 21 CFR Part 11 is a regulation for GCP and the conduct of clinical trials that includes:

The management system that directs and controls a pharmaceutical company

Electronic records, electronic signatures, and other procedures that ensure the
authenticity, integrity, and the confidentiality of electronic records
Identification of equipment used to perform sample analysis
A chain of custody of a sample to enable automatic tracking

10. The two main guidance documents that are now followed in relation to GCLP are those
produced by

FDA and NIH

MHRA and BARQA
WHO and EMA
EMA and FDA

11. To be established ICH Q10 requires

Quality Policy and Quality Manual

 Assignment of a qualified person to each trial
Proper sample labelling to ensure the identity of the sample
Disposal of trial samples

12. The Quality Manual should describe the QMS of the laboratory and how it has been
organised to achieve the quality goals and objectives. It should:

Include or make reference to, the Quality Policy

Define the scope of the QMS, e.g. that it applies to all of the systems and tasks
performed by the laboratory in the receipt, handling, storage, analysis, reporting and
destruction of clinical trial samples
Establish Quality Objectives for the laboratory with systems to monitor their
progress, e.g. through frequent review of key performance indicators
All of the above

Submit

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