**4. External quality assurance programs**

Alternatively, laboratory mission, vision, and policy can include issues related with market positioning, so that specific objectives should be defined regarding to certification and accred-

Benefits from implementation of ISO 9001, ISO/IEC 17025, and ISO 15189 in the laboratory are

**Benefits ISO 9001 ISO/IEC 17025 ISO 15189**

X X X

X

Improvement of the company image X X X Allow to gain market share X X X Improvement of business efficiency X X X Improvement of qualification to access tenders X X X Improvement of internal processes X X X Achievement of strategic objectives X X X

Achievement of customer satisfaction X X X Customer loyalty X X X Allow formal recognition of technical competence X X International recognition of trials X X Commitment of staff in meeting customer requirements X X Development of staff competencies X X

**Table 2.** Benefits from implementation of ISO 9001, ISO/IEC 17025, and ISO 15189 in the laboratory adapted from [6].

**Figure 1.** Similarities and differences between certification and accreditation.

Establishment of mechanisms for the continuous improvement of service

Fulfilled requirement for the registration of the laboratory in

itation in each case.

28 Quality Control in Laboratory

shown in **Table 2** [6].

quality

governmental organisms

"External quality assurance or assessment" (EQA) programs are a tool designed by different providers (usually medical or scientific societies) with an educational, training, and helping purpose. They allow the evaluation of the analytical performance for every variable involved (staff, equipment, reagents, and method) in comparison with the expected results. Similarly, EQA schemes are an educational tool to evaluate the competence of the laboratory in relation with specific variables. In addition to internal quality control (IQC), EQA is complementary in the quality management system. Alternatively, proficiency testing (PT) is used as external quality assurance with a regulatory purpose for laboratory licensing and/ or accreditation [9].

EQA programs allow comparing the laboratories' results and informing on global variation with the objective of working toward the harmonization. This goal is extremely important because medical decisions are based on comparisons of analytical results with time or a reference interval [10].

In this sense, international societies recognize the importance of EQA provision [11]. The World Health Organization has an available manual for organizing a national EQA program for health laboratories and other testing sites, providing guidance on the international standards ISO 17043:2010 Conformity assessment—general requirements for proficiency testing and ISO 13528:2015 Statistical methods for use in proficiency testing by interlaboratory comparison. Contrary to expectations, not enough evidences of quality improvement of the analytical performance as a result of EQA participation have been reported [12].

The EQA participation process is summarized in **Figure 2**. Samples prepared by the EQA provider are sent to the laboratories for their analysis. These samples of unknown nature are handled by the laboratory from their reception until the report emission as usual samples, although trying to participate each analyzer in the whole program [9]. EQA provider receives the analytical results from all of the laboratories and prepares a confidential report with the identified deviation regarding to an assigned value [13]. Optionally, report may establish acceptance limits for the assigned value in accordance with analytical performance specifications [14] and inform about the performance evaluation of the several methods employed by participants.

Acceptance limits have been classified as [13]:


In case of nonregulatory EQA participation, the laboratories should decide the proper limits for the proposed objective. When the acceptance limit is defined as the "fitness for purpose", such purpose must be specified based on external requirements [15].

The optimal EQA participation frequency has not already established, but targeted high-quality schemes with a proper number of samples are preferred instead of many schemes with a

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Quality of EQA programs depends on the properties of their design [16]. The use of validated commutable samples and the assigned value definition based on a reference measurement procedure or by comparison with a certified reference material makes an EQA program

An EQA sample is commutable when the result after the analysis by a variety of methods is equivalent to the result obtained from patient samples with the same amount of analytes. In other words, the results for different methods are comparable because there are no matrixrelated biases in commutable samples [17, 18]. However, commutability is not always possible since enough volume of EQA samples with relevant concentrations must be prepared in

Additionally, to use biological samples as reference material is necessary in their certification precise information about their characteristics (processing, purity, characterization, "fitness for purpose", homogeneity, stability) and about their original clinical, biological, and pathological diagnosis. Only in this way, application of ISO Guide 34 requirements for reference

If commutable samples are not available, it is not possible to evaluate method accuracy. In this sense, laboratories are evaluated and classified by groups of participants with the same method and expected matrix-related bias (peer groups) because comparison to the same assigned value is impracticable. The assigned value is the group mean or median after outliers' removal or by using robust statistical tools and deviation is calculated. It is worth mentioning that the uncertainty of the estimated assigned value would be larger in a small peer group than in a bigger one [13]. Another disadvantage is that peer group evaluation is made impossible to identify a poor performance result when all reagents from the participants are affected. This is the reason why reagents' batch number should be recorded and took into consideration during evaluation by the EQA provider, contacting to the manufacturer when batch effects are observed [20, 21]. In spite of previous limitations, this type of EQA allows to measure the quality of the results with respect to the method and the other laboratories in

Independent of sample commutability, previous analysis tools are not valid for semiquantitative measures or measures reported on a discontinuous scale or where dichotomous results

Ideally, and with the previously commented objective of laboratories' result harmonization, international EQA programs are recommended. However, they are a nonviable option for routine use because of their cost and complexity, being precisely the challenge for EQA providers to find new solutions and overcome limitations related with EQA design [16]. In the meantime, an alternative option that has been proposed [10] would be to organize a global EQA characterized by its remarkable design (validated commutable samples and assigned value by references) for a few representative laboratories from different countries. In a second

risky participation rate.

homogeneous and stable conditions.

material production to EQA samples would be achieved [19].

prominent.

the same group.

are provided for a continuous parameter [15].

**Figure 2.** EQA participation process.

The optimal EQA participation frequency has not already established, but targeted high-quality schemes with a proper number of samples are preferred instead of many schemes with a risky participation rate.

Quality of EQA programs depends on the properties of their design [16]. The use of validated commutable samples and the assigned value definition based on a reference measurement procedure or by comparison with a certified reference material makes an EQA program prominent.

An EQA sample is commutable when the result after the analysis by a variety of methods is equivalent to the result obtained from patient samples with the same amount of analytes. In other words, the results for different methods are comparable because there are no matrixrelated biases in commutable samples [17, 18]. However, commutability is not always possible since enough volume of EQA samples with relevant concentrations must be prepared in homogeneous and stable conditions.

Additionally, to use biological samples as reference material is necessary in their certification precise information about their characteristics (processing, purity, characterization, "fitness for purpose", homogeneity, stability) and about their original clinical, biological, and pathological diagnosis. Only in this way, application of ISO Guide 34 requirements for reference material production to EQA samples would be achieved [19].

If commutable samples are not available, it is not possible to evaluate method accuracy. In this sense, laboratories are evaluated and classified by groups of participants with the same method and expected matrix-related bias (peer groups) because comparison to the same assigned value is impracticable. The assigned value is the group mean or median after outliers' removal or by using robust statistical tools and deviation is calculated. It is worth mentioning that the uncertainty of the estimated assigned value would be larger in a small peer group than in a bigger one [13]. Another disadvantage is that peer group evaluation is made impossible to identify a poor performance result when all reagents from the participants are affected. This is the reason why reagents' batch number should be recorded and took into consideration during evaluation by the EQA provider, contacting to the manufacturer when batch effects are observed [20, 21]. In spite of previous limitations, this type of EQA allows to measure the quality of the results with respect to the method and the other laboratories in the same group.

Independent of sample commutability, previous analysis tools are not valid for semiquantitative measures or measures reported on a discontinuous scale or where dichotomous results are provided for a continuous parameter [15].

Ideally, and with the previously commented objective of laboratories' result harmonization, international EQA programs are recommended. However, they are a nonviable option for routine use because of their cost and complexity, being precisely the challenge for EQA providers to find new solutions and overcome limitations related with EQA design [16]. In the meantime, an alternative option that has been proposed [10] would be to organize a global EQA characterized by its remarkable design (validated commutable samples and assigned value by references) for a few representative laboratories from different countries. In a second

**Figure 2.** EQA participation process.

30 Quality Control in Laboratory

phase, these laboratories would participate in smaller national or regional programs with an optimal design as reference laboratories. In the frame of this initiative, results from EQA should be reviewed by a professional international advisory board to inquire the root causes for global deviations.

Quality improvement of the laboratory after EQA participation will be only possible if changes in the deviated processes are developed. As part of their educational, training, and helping responsibilities, EQA providers should support and collaborate with the laboratory in this phase.

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Proposed corrective actions must be documented and include the steps taken to find the cause of the deviation and to solve its consequences. As a troubleshooting tool for EQA concerning analytical performance, the Norwegian Clinical Chemistry EQA Program (NKK) has developed a flowchart with additional comments in collaboration with the External quality Control of diagnostic Assays and Tests (ECAT) Foundation [13]. It is a public instrument, only valid for quantitative analysis, which proposes actions to be initiated in the format of corrective and preventive action (CAPA) documentation or root cause analysis (RCA) after deviation identification by EQA. Four points are considered in the flowchart and associated comments: the potential cause of deviation, the corresponding responsibility for this cause, a brief, and,

The previous points are classified according to the consecutive steps in the EQA participation

• Pre-survey issues: unrelated to the laboratory. Unfortunately, sample reanalysis is

• Sample receipt or handling: derived from incorrect address information, misunderstanding of EQA provider instructions, bad integrity of the EQA sample, or lack of records.

• Test performance: new or old causes that made necessary to identify who, when, and how, to look at the internal quality control data (IQC), and to look for systematic deviations from

• Data handling by EQA provider: these errors are due to the statistical procedure, their

To sum up (**Figure 3**), the procedure to integrate the EQA results in the QMS of the laboratory

**a.** To collect information about who, when, and how in relation with EQA participation,

**2.** Initiating documented corrective and preventive (whenever possible) actions

finally, a detailed explanation about the proposed actions.

• Transcription errors: the most frequent cause.

different participations over time.

**b.** To find the cause of deviation

**5.** Revision of EQA program selection

**3.** Monitoring of actions taken

• Report and interpretation.

**1.** Report interpretation

identification by the laboratory being difficult.

IQC data, and previous and global EQA results

**4.** New analysis of a stored aliquot left of the EQA sample

process:

is [16]:

necessary.

A particular case of testing is the point-of-care (POC) technologies, which has the very prominent advantage of increasing the populations' access to diagnoses through introduction of a decentralized model. However, from the EQA program's point of view, POC analytical performance increases in the same manner the design difficulty: many EQA samples are necessary for multiple testing points, where nonspecialized staff is available with a poor and delayed participation [12]. To deal with this situation, connected devices to a central database for POC technologies have been developed to establish an efficient and on time EQA workflow. Sent EQA samples are distinguished thanks to specific IDs, obtaining a cheaper, fewer errors and simplified EQA approach for each step by means of direct data collection and analysis [22].

To be clear, EQA participation does not improve directly the quality, but it identifies and monitors poor performance issues. So, it is very important that a proactive participation is implemented in the laboratory [9], being recommended that an EQA manager is available.

The laboratory must choose an EQA organizer in function of the EQA designs offered and the own quality assurance or supporting needs of the laboratory. This selective process should be justified and documented. The choice is easier when proficiency testing with a regulatory purpose is imposed. EQA providers with professional committees and accredited laboratories are preferable. With this objective, EQA provider must inform about EQA programs' designs and especially about analytical performance specifications used in each case. This information will allow the comparison between different EQA programs, as harmonization of analytical performance specifications for the same analyte has not been achieved yet.

A proactive attitude by the laboratory is also necessary, even mandatory in the case of accreditation, for proper and timely EQA report revision. Reports from EQA providers are often used as a quality follow-up tool by auditors. Laboratory staff should know the laboratory's EQA analytical performance results by means of formal communications [9].

Three kinds of reports should be available [15]:


A very important supporting element for the evaluation in the reports, and required by international standards, is graphical representations. Graphs are also powerful tools to show combined information from a variety of analysis with different samples, time points, or other relevant variables.

Quality improvement of the laboratory after EQA participation will be only possible if changes in the deviated processes are developed. As part of their educational, training, and helping responsibilities, EQA providers should support and collaborate with the laboratory in this phase.

Proposed corrective actions must be documented and include the steps taken to find the cause of the deviation and to solve its consequences. As a troubleshooting tool for EQA concerning analytical performance, the Norwegian Clinical Chemistry EQA Program (NKK) has developed a flowchart with additional comments in collaboration with the External quality Control of diagnostic Assays and Tests (ECAT) Foundation [13]. It is a public instrument, only valid for quantitative analysis, which proposes actions to be initiated in the format of corrective and preventive action (CAPA) documentation or root cause analysis (RCA) after deviation identification by EQA. Four points are considered in the flowchart and associated comments: the potential cause of deviation, the corresponding responsibility for this cause, a brief, and, finally, a detailed explanation about the proposed actions.

The previous points are classified according to the consecutive steps in the EQA participation process:


phase, these laboratories would participate in smaller national or regional programs with an optimal design as reference laboratories. In the frame of this initiative, results from EQA should be reviewed by a professional international advisory board to inquire the root causes

A particular case of testing is the point-of-care (POC) technologies, which has the very prominent advantage of increasing the populations' access to diagnoses through introduction of a decentralized model. However, from the EQA program's point of view, POC analytical performance increases in the same manner the design difficulty: many EQA samples are necessary for multiple testing points, where nonspecialized staff is available with a poor and delayed participation [12]. To deal with this situation, connected devices to a central database for POC technologies have been developed to establish an efficient and on time EQA workflow. Sent EQA samples are distinguished thanks to specific IDs, obtaining a cheaper, fewer errors and simplified EQA approach for each step by means of direct data collection and analysis [22].

To be clear, EQA participation does not improve directly the quality, but it identifies and monitors poor performance issues. So, it is very important that a proactive participation is implemented in the laboratory [9], being recommended that an EQA manager is available.

The laboratory must choose an EQA organizer in function of the EQA designs offered and the own quality assurance or supporting needs of the laboratory. This selective process should be justified and documented. The choice is easier when proficiency testing with a regulatory purpose is imposed. EQA providers with professional committees and accredited laboratories are preferable. With this objective, EQA provider must inform about EQA programs' designs and especially about analytical performance specifications used in each case. This information will allow the comparison between different EQA programs, as harmonization of analytical

A proactive attitude by the laboratory is also necessary, even mandatory in the case of accreditation, for proper and timely EQA report revision. Reports from EQA providers are often used as a quality follow-up tool by auditors. Laboratory staff should know the laboratory's

• A confidential and clear individual report for each laboratory, also for outliers, including its deviation regarding the assigned value and usually the acceptance limits. In addition, reports may contain the number and origin of the participants and their distribution of results to allow comparison between them and even the laboratory's performance history.

• Summary reports at the end of each scheme or program with global and anonymized infor-

• Periodic reports can be published as well to highlight the most significant results found.

A very important supporting element for the evaluation in the reports, and required by international standards, is graphical representations. Graphs are also powerful tools to show combined information from a variety of analysis with different samples, time points, or other

performance specifications for the same analyte has not been achieved yet.

EQA analytical performance results by means of formal communications [9].

mation about analytical performance variation for different analyses.

Three kinds of reports should be available [15]:

relevant variables.

for global deviations.

32 Quality Control in Laboratory

To sum up (**Figure 3**), the procedure to integrate the EQA results in the QMS of the laboratory is [16]:

	- **a.** To collect information about who, when, and how in relation with EQA participation, IQC data, and previous and global EQA results
	- **b.** To find the cause of deviation

management system (QMS) mentioned at the beginning of this chapter of fulfillment user requirements and satisfaction [24]. The design of such programs should be developed care-

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Clinical laboratories' activities are based on evidences derived from research [10]. Biobanks are singular laboratories that provide samples for research. Differences between biobanks in preanalytical and processing methods for the same kind of samples may impact research results [25]. Therefore, EQA process provides an opportunity for harmonization in the biobanking field as well. With a main educational purpose, the International Society for Biological and Environmental Repositories (ISBER) have developed an EQA program focused on sample processing and testing [26] that represents a very important part of a biobank quality manage-

[1] World Health Organization. Quality Management System in the Laboratory: Manual;

[2] Rafael J, Mateo C. Quality Trends. 2009. Available from: http://qualitytrends.squalitas.

[3] Jane Keathley MS. QMS: A model for laboratory services GP26-A4. Labmedicine. 2012;

[4] Vives J, Oliver-Vila I, Pla A. Quality compliance in the shift from cell transplantation to cell therapy in non-pharma environments. Cytotherapy. 2015;**17**(8):1009-1014. Epub

[5] Honsa JD, McIntyre DA. ISO 17025: Practical benefits of implementing a quality system.

[6] Valeria (28 de marzo de 2011). Normas ISO para Laboratorios. Available from: http:// vrconsultora.blogspot.com.es/2011/03/normas-iso-para-laboratorios.html.[Accessed:

[7] Schneider F, Maurer C, Friedberg RC. International Organization for Standardization (ISO) 15189. Annals of Laboratory Medicine. 2017;**37**(5):365-370 Epub 2017/06/24

Journal of AOAC International. 2003;**86**(5):1038-1044 Epub 2003/11/25

fully to obtain useful information.

Verónica Valdivieso-Gómez and Rocío Aguilar-Quesada\*

Andalusian Public Health System Biobank, Granada, Spain

\*Address all correspondence to: rocio.aguilar.quesada@juntadeandalucia.es

ment system.

**Author details**

**References**

2016

**43**(1):26

2015/03/15

2017-10-18]

com [Accessed: 2017-10-17]

**Figure 3.** Procedure to integrate the EQA results in the QMS of the laboratory.

Although EQA has been usually applied to analytical performance, the EQA process should meet in the same manner the pre-analytical phases. Several efforts have been conducted trying to cover them, with three types of pre-analytical EQA schemes being categorized [23]:


Pre-analytical EQA schemes are more difficult to standardize, but it is worth progressing in this sense because these phases are more prone to errors.

Furthermore, the requesting and reporting diagnostic phases should also be covered by EQA programs due to two main reasons: high rate of errors associated and the definition of quality management system (QMS) mentioned at the beginning of this chapter of fulfillment user requirements and satisfaction [24]. The design of such programs should be developed carefully to obtain useful information.

Clinical laboratories' activities are based on evidences derived from research [10]. Biobanks are singular laboratories that provide samples for research. Differences between biobanks in preanalytical and processing methods for the same kind of samples may impact research results [25]. Therefore, EQA process provides an opportunity for harmonization in the biobanking field as well. With a main educational purpose, the International Society for Biological and Environmental Repositories (ISBER) have developed an EQA program focused on sample processing and testing [26] that represents a very important part of a biobank quality management system.
