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1 Quality Assurance in Cancer Biobanking Anne Carter 1 * and Fotini Betsou 2 1 Anne Carter onCore UK Devonshire House Manor Way Borehamwood Herts United Kingdom 2 Fotini Betsou Integrated Biobank of Luxembourg 6, rue Ernest Barblé L- 1210 Luxembourg *Corresponding author E-mail [email protected] Tel: +44 (0)208 731 4595 Fax: +44 (0)208 731 4587

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1

Quality Assurance in Cancer Biobanking

Anne Carter1* and Fotini Betsou2

1Anne Carter

onCore UK

Devonshire House

Manor Way

Borehamwood

Herts

United Kingdom

2Fotini Betsou

Integrated Biobank of Luxembourg

6, rue Ernest Barblé

L- 1210 Luxembourg

*Corresponding author

E-mail [email protected]

Tel: +44 (0)208 731 4595

Fax: +44 (0)208 731 4587

2

Introduction

Biobanking is recognised as a critical area requiring development if progress is to be

made in identifying clinically useful markers of disease and disease progression,

discovering new drug targets and understanding the mechanisms of disease in cancer.

Researchers continue to report that they are unable to obtain sufficient high quality,

well annotated samples of diseased and control tissue, blood and other biological

materials1,2. At the same time, funders of research, and especially funders of

biobanks, are looking to obtain best value from their investments in sample and data

collection. There is a need to increase the availability to researchers of large numbers

of high quality, well annotated samples of diseased and control tissue, blood and other

biological materials and in this way accelerate cancer research.

Researchers report two major problems; the ability to get access to sufficient numbers

of samples and the fact that the available samples are not always suitable for their

research. The Cancer Genome Atlas (TCGA) group in the US, for example, reported

at a meeting of the International Cancer Genomics Consortium that biobanks typically

overestimated the quality of the cancer tissue samples they hold3.

Research by the European Commission’s Joint Research Centre and Institute for

Prospective Technological Studies4 recognised the need for improved collaboration

and networking amongst biobanks. Currently, networks of biobanks, such as the

Confederation of Cancer Biobanks in the UK, CNIO Tumour Bank Network in Spain,

the Danubian Biobank Consortium, Canadian Tumour Repository Network and the

Australasian Biospecimen Network, are working to develop harmonised methods and

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quality assured procedures to address these issues. The ultimate aim of these

networks is to increase the numbers of high quality, well annotated samples that are

available to researchers and so accelerate cancer research.

The need for quality assurance is recognised as an essential part of any scientific

endeavour5,6 and it is especially important when different organisations work

together7. If donors, researchers, funders and the biobanks themselves are to be

assured that samples and data are of high quality, “inter-operable”, made available

and used in research there is a need to define sample and data quality, define best

practice for biobanks and set up a scheme to confirm that biobanks are following best

practice guidelines and achieving high quality.

This paper will discuss the components of a quality assurance system in a biobank,

the availability and usefulness of currently available written standards and guidelines

and will give some examples of work in this field. Whilst many of the examples used

come from cancer biobanking, the principles of quality assurance are applicable to all

biobanks storing human tissue or data for research. The paper will give an overview

of current thinking on the need for and use of quality assurance in biobanking of

human tissue and data.

What is quality assurance?

The simplest definition of quality is “fit for purpose”. The purpose of a biobank is to

collect, store and distribute high quality samples and data and it may, in addition,

process and test the samples. The way in which the biobank performs these tasks

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needs to be controlled, so that all of the operations of the biobank, including the ways

in which the biobank is managed and in which legal and ethical requirements are met,

are “fit for purpose”.

Organisations control the quality of their activities by implementing a quality

management system (QMS). The QMS defines the organisation’s quality policy and

objectives and ensures that these are achieved through quality assurance (QA) and

quality control (QC). QA focuses on the processes through which the product is

obtained whereas QC focuses on the product.

Most scientists are familiar with QC, which is “that part of quality assurance that

focuses on fulfilling quality requirements” and perform QC as a routine part of their

day-to-day activities. QC consists of specific tests defined by the QA or QMS

programme to be performed to monitor procurement, processing, preservation and

storage, specimen quality and test accuracy. These tests may include but are not

limited to: performance evaluations, testing and controls used to determine the

accuracy and reliability of the biobank’s equipment and operational procedures as

well as monitoring of the supplies, reagents, equipment and facilities.

The concept of QA is less familiar than QC and often meets some resistance from

scientists who are proud of their scientific knowledge and achievements. So what is

QA, why is it important and what can a cancer biobank gain from implementing a QA

programme?

5

Quality assurance is defined as “that part of quality management that focuses on

providing confidence that quality requirements will be fulfilled”8. QA requires the

systematic monitoring and evaluation of all aspects of the biobank’s processes; it

covers the way in which the biobank is operated as well as the quality of the samples

and data held.

The quality of any product or process can be demonstrated by comparison with a

quality standard and organisations who can show that they meet the requirements of

the standard can gain certification or accreditationi. The international standard, ISO

9001:20089 (ISO 9001), sets out the internationally accepted requirements for a QMS

that can be applied to any type of organisation. It is based on Deming’s Shewhart

cycle of “plan, do, check, act” (figure 1) and covers management requirements as

diverse as defining quality objectives, documenting procedures, controlling

documents and records, contracting, purchasing, handling complaints, correcting and

preventing problems, internal auditing, training and committing to improvement.

The organisation is able to set its own quality objectives and decide for itself (and its

stakeholders) what its product or service should look like. Compliance with ISO 9001

does not, by itself, ensure that scientifically valid methods are used and samples and

data are “fit for purpose” because this standard does not give any technical

requirements for the quality of the samples or the scientific aspects of a biobank’s

work. It does not cover, for example, qualification of equipment, validation of

methods, measurement traceability, use of control and reference materials,

participation in proficiency testing schemes and handling of samples and data. As

well as having a management system that ensures that the biobank’s core processes

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are “fit for purpose”, a biobank must ensure that the samples and data it provides are

“fit for purpose” (figure 2).

Quality standards

There is no international standard for technical quality in a biobank, so the Marble

Arch Working Group on International Biobanking (MAWG) studied the requirements

of the available ISOii standards containing technical requirements that could be

applied to biobanks as well as available guidelines/best practice documents. The

standards selected were ISO 17025:2005 (ISO 17025), the standard for testing and

calibration laboratories10, and ISO guide 34, for reference material producers11, which

contain the quality management system requirements present in ISO 9001 and

additional technical requirements relevant to the subject area. The MAWG looked

also at biobanking “best practice” guidelines published by the OECD12, NCI13 and

ISBER14 to determine what additional technical requirements are needed for

biobanking. ISO standards contain technical requirements but do not mandate how

those requirements should be met, whereas best practice guidelines give detail on the

best ways to achieve such requirements. Best practice guidelines are not compulsory

for organisations seeking certification or accreditation if the organisation can justify

why they have taken an alternative approach.

None of the guidelines/best practice publications examined by the MAWG was found

to be sufficient as an international standard for biobanking so the MAWG compiled

i Certification is the procedure by which a third party gives written assurance that a product, process or service conforms to specific requirements. Accreditation is the procedure by which an authoritative body gives formal recognition that a body or person is competent to carry out specific tasks. iiISO is the Geneva-based International Organisation for Standardisation. This organisation produces and publishes written standards according to the perceived needs of the international community.

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elements from them into the format of an ISO standard specific for biobanks15. The

document produced contains the requirements for an international standard for

biobanking. However, a biobanking standard has not been adopted as a “work item”

by an ISO Technical Committee yet.

The only existing national biobank-specific standard is the French standard, NF S 96-

900 Quality of biological resource centres (BRC) – Management system of a BRC and

quality of biological resources of human and microbial origin, published in July

2008. Its design was based on ISO 9001, and it includes some additional specific

technical requirements. It is applicable to the wide activities of research tissue banks

and is suitable as a certification, but not as an accreditation, standard. Certification

against either ISO 9001 or NF S 96-900 is requested of research tissue banks by the

French research infrastructures funding organisation (IBISA) and so far 47

organisations have been certified against NF S96-900, of which a majority are

research tissue banks. The French standard has not been used outside of France but

its application in France shows that a specific standard designed for research tissue

banks is useful and applicable.

In the absence of a widely applicable biobank-specific standard, many biobanks have

obtained certification of their quality management systems against the requirements of

ISO 9001 (for example UK Biobank, UK DNA Banking Network, Spanish HIV

Biobank, Invidumed (Hamburg), Norwegian Mother and Child Cohort Study biobank,

Biobanque de Picardie, Biobank Graz (Austria), Singapore Bio Bank and others).

Interestingly, the Karolinska Institute biobank and the National Reference Cell

Standards are sponsored by a national standardisation body (the British Standards Institute in the UK,

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Culture Centre of Instituto Zooprofilattico Sperimentale della Lombardia dell’Emilia

Romagna – Brescia, have been accredited to ISO17025 and the ATCC has been

accredited to both ISO17025 and ISO Guide 34. No such example exists for a cancer

biobank yet. ISO 9001 is described in the Molecular Medicine Ireland’s (MMI)

Guidelines for standardised biobanking16 as “the recognised international quality

standard that biorepositories are working to implement”. The MMI guidelines have

been accepted by BBMRIiii as a first version of a BBMRI Laboratory Manual, thus

giving increased authority to this publication.

The MAWG publication and the French biobanking standard provide an excellent

starting point for the development of an ISO standard specifically for biobanks. ISO

standards are aimed primarily at reducing barriers to international trade and co-

operation, thus development and implementation of an ISO for biobanks will ensure

that samples and data collected in any biobank which conforms to the ISO

requirements are suitable for use in local, national and international research projects.

Harmonisation, standardisation and best practice.

Biological materials and their derivatives are fragile, they can change rapidly when

removed from the living host, they need to be conserved ex vivo with as little

modification as possible in relation to their in vivo state, and they need to correspond

to the researchers’ needs. Standardisation of procedures is an essential part of quality

assurance; a biobank will determine and document its ways of working in standard

for example) and agreed, by consensus, with representatives of the community to which they relate. iii BBMRI is the European Biobanking and BioMolecular Resources Research Infrastructure, currently in its preparatory phase. It is supported by the European Union Framework Programme 7 and aims to

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operating procedures (SOPs) to ensure that samples and data are collected and

handled consistently. If researchers are to be able to use samples and data from more

than one biobank, however, samples and data sets held by different biobanks must be

comparable. If they are not comparable, differences discovered during the research

may be due to the ways in which the samples and data have been obtained and

handled, rather than to physiologically relevant differences in vivo.

Harmonisation is a process through which procedures and practices are aligned so that

they are compatible with one another. This would allow researchers to have

knowledge of the differences between samples and take these into account during

their research. Standardisation is the process of defining and agreeing upon technical

standards, so that samples and data obtained from one biobank are equivalent to those

from other biobanks using the standardised methods. Both rely upon biobanks having

a common aim and willingness to work together and adapt pre-existing practices.

The definition of a high quality specimen or dataset can be a problem for a biobank.

A researcher working on a specific project, using specific sample types and

experimental techniques, can determine which factors will affect his work and ensure

that samples and data are collected appropriately to suit his needs. A biobank, in

contrast, is collecting samples and data for future, unspecified research and does not

know what techniques will be used, what factors will affect the suitability of the

samples or what data will be needed. Samples that are suitable for one technique may

not be suitable for a different technique – there is no single way of handling samples

that will suit all users. The biobank must decide which factors are most important to

lay the basis for unified biobanking across the EU. It brings together some 250 biobanks from

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control, and select procedures that provide a balance between the predicted needs of

any potential researchers and the available resources within the biobank. There is

little scientific evidence supporting one protocol over another thus it is difficult to

find justification for the methods chosen and equally difficult to persuade a biobank to

change so that it is in line with others.

There is a need for biospecimen research to define evidence-based best practices.

This need is recognised by the biobanking community but funding for this type of

research is hard to come by; much of the current research is funded in the USA by the

National Cancer Institute (NCI) through the Office of Biorepositories and

Biospecimen Research (OBBR) where it is a strategic priority17 and in the EU through

an FP7 project, SPIDIAiv. Few institutions, like the Integrated Biobank of

Luxembourg or the Van Andel Research Institute have an internal biospecimen

research focus. To achieve inter-operable samples and data, practices must, as a

minimum, be standardized inside each biobank and harmonised between biobanks. In

the meantime, the best that can be done is to validate procedures and keep meticulous

records so that any differences between samples can be attributed to the sample itself

rather than the way in which it was collected, processed and stored.

At present, many researchers validate the samples they receive from biobanks because

they are not able to rely upon the suitability of samples that they have not collected

European Union (EU) member and associated states. See: www.bbmri.eu. iv SPIDIA is a 4-year project, funded by the European Union FP7 which aims to tackle the standardisation and improvement of pre-analytical procedures for in-vitro diagnostics. The proposed research and standardisation activities cover all steps from creation of evidence-based guidelines to creation of tools for the pre-analytical phase to testing and optimisation of these tools through the development of novel assays and biomarkers.

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themselves. The purpose of harmonisation and standardisation is to ensure that

samples are collected, transported, processed, tested and stored in ways which gives

consistently high quality samples and consistently accurate data. This makes the

samples and data acceptable to researchers without further testing.

Harmonisation with respect to sample variability

The differences between samples are multi-factorial. Pre-analytical factors affecting

the samples occur in-vivo, due to differences between the donors, and after the

samples have been removed from the donors, during transport, stabilisation,

processing and storage. Examples of pre-analytical variables are shown in figure 3.

Pre-analytical factors are often outside the control of the biobank. To allow such

samples to be used by researchers it is necessary to keep meticulous records and make

them available to the researcher. A system for annotating samples with data about

pre-analytical factors has been developed by the ISBER Working Group on

Biospecimen Science and published as a standard pre-analytical coding for

biospecimens (SPREC)18. The criteria used to annotate solid tissue samples are

shown in figure 4. This system allows samples to be annotated by a code that

describes how they have been obtained and processed, allowing pre-analytical factors

to be compared by the researcher. The application of a pre-analytical sample code can

not only facilitate a more effective inter- and intra- laboratory specimen utilization by

scientists from different biobanks supplying samples for common research and

validation exercises, but also allow more effective reporting of research results.

Validation

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Validation of biobank’s methods, samples and data

Validation can be defined as “establishing documented evidence which provides a

high degree of assurance that a specific process will consistently produce a product

meeting its pre-determined specification and quality attributes”19. Validation of

methods, samples and data will enable biobanks, funders and researchers to have

confidence in sample quality and so give added credence and reproducibility to the

results of research.

Validation can be applied to the “raw” biological material or data, the processing

methods used and any quality control testing performed. The objective of validation

is to demonstrate that the samples, data and methods are suitable for their intended

purpose. Equipment, also, needs to be validated (validation of equipment is usually

referred to as equipment qualification). Information and guidance about validation is

available from IUPAC20, the International Committee on Harmonisation21, NIST22,

ISO 572523 and ISO 17025, covering validation of the methods of performing

analyses, traceability of measurements, evaluating uncertainty of measurement and

defining the accuracy and precision of results. Elements to consider when validating

testing methods are shown in figure 5.

Validation of processing methods looks at pre-analytical variables that have the

potential to affect the outcome of results but are not related to the inherent sample

differences of interest to researchers. Validation aims to design methods that

minimise and control these differences. The problem for biobanks is that whilst

potential confounding factors can be postulated, their effect on research results is not

known. This makes it essential to carry out biospecimen research to identify which

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processing steps are critical to sample quality, which sample attributes are important

and so develop appropriate quality control assays24.

Some of the elements of biospecimen research that can support QA in biobanking are

already within the scope of biobanks and/or associated laboratories. Indeed, it is

possible to evaluate the uncertainty of measurements that biobanks may be

performing. It is also possible to evaluate the impact of several pre-analytical

variables on downstream analyses25 . However, some of the elements which might be

essential to the implementation of an integral quality assurance program are still

missing. One such element is international Proficiency Testing programs for the

evaluation of the accuracy and precision of the different types of measurements that

biobanks often carry out for the characterization of their samples. Another missing

element is reference materials. Reference materials are necessary for validation of the

accuracy of a testing method11.

Validation of data requires verification of all clinical and biological annotations, use

of standard ontologies, checks on accuracy of transcription, eventually through double

entries, and implementation of data security systems, for example compliance with

the EU Directive on the protection of personal data and the EU-US Safe Harbour

principles26,27.

Indirect validation of biobank’s impact

Whilst this section has concentrated on the quality of samples and data, this is only

one aspect of the quality issues in biobanking. The funders of biobanks seek to

maximise the return on their investment. Ensuring the quality of the sample and its

suitability for use by the researcher is one way that this investment can be maximised,

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but the funder is interested, also, in ensuring that samples reach the researcher, and so

has an interest in the access policies and scientific review procedures that are used

when biobanks grant access to samples and data to researchers. From the funders’

perspective, numbers of samples used in research and numbers of publications from

those samples are also markers of the quality of a biobank. Best practice guidelines

are broad based and cover every aspect of running a biobank, considering, for

example, legal and ethical issues, sustainability of funding, appropriate levels of

anonymisation and methods of determining who has access to samples and data.

These are often the areas where best practices devised in one country may not be

applicable elsewhere, since legal and ethical requirements differ between countries,

but their control is essential to give confidence to donors, funders and researchers.

Benchmarking of biobanks

Once standards and best practices are defined, it is possible to benchmark biobanks.

In 1999, the OECD suggested that national governments “should support the

development of an accreditation system for biobanks based upon scientifically

acceptable objective international criteria for quality, expertise and financial

stability”. This is one way in which biobanks can be benchmarked but there are

several options for benchmarking of biobanks, namely self-assessment, peer review or

through a formal certification or accreditation procedure.

Self assessment is the simplest and least expensive route. A series of questions can be

drawn up based on the required standards and the biobank can rate itself against the

questionnaire. ISBER members, for example, have access to a web-based self-

assessment tool designed to allow biobanks to assess their compliance with the

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ISBER best practice guidelines. The main drawback to self assessment is the lack of

consistency and transparency in assessments.

Peer review consists of inspection and assessment of compliance with the required

standards by experts in the field, such as staff from another biobank or associated

organisation. This system is more expensive, requiring staff to be released from their

normal work to visit the biobank that is seeking assessment. Its advantage over self

assessment is that the assessors can be trained so that assessments are consistent and

the relative independence of the assessors gives greater assurance of the validity of

the results of the assessment. The assessors, however, are not truly independent since

they assess one another’s banks; there is a natural “professional courtesy” between

such assessors that is to the detriment of the perception of independence since the

person whose bank you are assessing today may come to assess your bank next time.

In addition, there are problems with ensuring confidentiality and protecting

intellectual property if the assessors are your “competitors”. This is handled in most

instances by requiring assessors to sign confidentiality agreements but some

commercial organisations are not willing to permit peers from competitor

organisations on site. Great care is needed when using competitors as assessors.

Certification and accreditation are widely recognised as the “gold standard” ways to

assess organisations. The terms certification and accreditation tend to be used

interchangeably by “lay” people, however they have different meanings.

Certification is the proof of consistency in the procedures followed. Accreditation is

the proof of the competence, the impartiality and the independence of a certification

body or laboratory in view of existing norms. Thus an organisation can be certified as

16

having a quality management system that conforms to the requirements of ISO 9001

and can seek accreditation against ISO 17025 to demonstrate its competence in

carrying out specific testing or calibrations (as defined in its “Scope of

Accreditation”). Organisations that gain accreditation against ISO 17025 are

recognised as complying with the requirements of ISO 9001 since a quality

management system is an integral requirement of ISO 17025. Formal certification

and accreditation are expensive to implement and maintain. They depend upon an

international consensus to devise appropriate standards but grant international

recognition to organisations that are certified or accredited.

There are several national and international initiatives looking at certification and

accreditation schemes to assess biobanks but, as discussed above, only in France is

there an official national standard. The need for a certification and accreditation

working group was proposed and strongly supported at the ISBER 2010 meeting, held

in Rotterdam last May. The Canadian Tumour Research Network is launching a

certification scheme for Canadian tumour biobanks at a meeting in Vancouver in

January 2011. The National Centre for Tumor Diseases (NCT) in Heidelberg has

obtained accreditation against ISO 17020:2004 General criteria for the operation of

various types of bodies performing inspection. ISO 17020 is not an obvious choice as

a standard for a biobank; it was used to accredit the competence of pathologists to

examine tissue but does not cover other biobank activities28. Its use is another sign of

the need for a biobank-specific ISO standard. Work Package 3 of the BBMRI project

aims “to provide support for the development of a European framework facilitating

harmonization of standards through certification and accreditation procedures”

(http://www.bbmri.eu/index.php/workpackages/wp-3). The American Association of

17

Tissue Banks offers “accreditation” to research tissue banks based on its own criteria

(http://www.aatb.org/accreditation). The College of American Pathologists is

exploring the possibility of developing an accreditation scheme for American tumour

banks. These schemes are not interchangeable, therefore whilst biobanks within a

scheme will have confidence in each others’ samples and data others outside the

scheme, or in a different scheme, will not have the same assurance. The need for an

international (ISO) standard for accreditation of research tissue banks is long overdue.

The breadth and depth of interest in biobanking at present make exciting times for

cancer biobanks. Donors, funders, researchers and governments are showing that the

need for high quality, well annotated samples of human tissue and its derivatives are

widely recognised as a key to enhancing cancer research. Quality assurance is the key

to providing confidence in the quality of samples and data, enabling collaboration

between biobanks and furthering the research effort.

Acknowledgments:

The authors wish to express their thanks to Dr Sabine Lehmann, Quality Manager at

IBBL, for critically reading and making helpful comments on the manuscript.

18

Figure 1 Deming’s Shewhart Cycle

Do

Act

Plan

Check

19

Figure 2 Requirements for a quality management system and technical

requirements for quality assurance in a biobank

Standard Norm

Technical require-ments

Manage-ment

require-ments

• Scope• Terms and definitionsIntroduction

Biobank norm

• Supply• Ethics

• Privacy• Informed consent• Access• Custodianship• Intellectual property

Additional require-ments

Solid samples Liquid samples Derivatives

• cell lines• nucleic acids• microbial strains• protein extracts• …………….

• Accommodation and environmental conditions

• Test and calibration methods/method validation

• Equipment• Measurement traceability• Sampling• Handling of test and calibration

items• Assuring the quality of test and

results• Reporting of results

• Biobank management issues

• Ethical, Social governance issues

• IT issues

• Organization• Management system• Document control• Review of requests, tenders,

contracts• Subcontracting• Purchasing services and supplies• Service to the customer• Complaints• Control of non conformity testing• Improvement• Corrective actions• Preventive actions• Control of records• Internal audits• Personnel

20

Figure 3 Potential pre-analytical variables affecting samples collected by a

cancer biobank.

Patient information • Gender • Age • Diet • Genetics • Medical background • Health background • Special conditions (pregnancy,

medications) • Social history (alcohol; smoking) • Type of anaesthesia • Position • Fasting • Smoking • Stress • Circadian rhythms • Menstrual cycle • Pregnancy • Physical exercise

Collection • Biopsy • Surgery • Aspiration • Autopsy

Clamping • Vessel clamping • Wedge resection • Ultrasonic shears

Collection device • Tube or bag • If tube, glass or plastic • Gel or non-gel separator • Other additives • Manufacturer and device information

Tissue derivative and processing • Sample type frozen vs. fixed • If frozen, milking • If fixed, fixative used • Details of processing (protocol)

Storage • Frozen before analysis • Elapsed time and temperature, prior

to freezing • Short or long term storage • Storage temperature • Expiration dating • Storage materials (glass vs. plastic) • If plastic, type of plastic

21

Figure 4. SPREC for solid tissue samples

Data originally published in Cancer Epidemiol Biomarkers Prev 2010;19:1004-1011

22

Figure 5. Elements to consider during method validation

Quantitative testing methods

Qualitative testing methods Processing methods

Specificity Accuracy Sensitivity Contamination between samples Robustness Reference values precision Linearity Domain of analysis Stability Interferences Correlation with reference method

Specificity Sensitivity Contamination between samples Robustness Stability Interferences Correlation with reference method

Reproducibility Robustness Stability Domain of application

23

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21 The International Committee on Harmonisation Validation of Analytical Procedures : text and

methodology (Q2 (R1)), ICH

25

22 NIST Guidelines for evaluating and expressing uncertainty of NIST measurement results (NIST

technical note 1297, 1994 edition)

23 ISO 5725, Accuracy and precision of results and measurement methods, 1994/1996

24 Betsou F, Barnes R, Burke T et al. Human Biospecimen research: Experimental Protocol and Quality

Control Tools. Cancer Epidemiol Biomarkers Prev 2009;18:1017-1025.

25 Spruessel A, Steimann G, Jung M et al. Tissue ischemia time affects gene and protein expression

patterns within minutes following surgical tumor excision. BioTechniques 2004;36:1030-1037.

26 EU Directive 95/46/EC

27 http://www.export.gov/safeharbor/eu/index.asp28 Carter A, Betsou F, Clark BJ. Quality

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