Medical laboratories- ISO 15189

Laboratories are responsible for delivering an average of 300,000 tests every working day in support of the nation’s health services. From blood tests to biopsies covering diagnosis or the ability to monitor treatment progress, medical labs provide the vital test results that inform treatment decisions and health outcomes.

ISO 15189 accreditation underpins confidence in the quality of medical laboratories through a process that verifies their integrity, impartiality and competence.  Assessments under UKAS accreditation ensure labs meet the relevant requirements including the operation of a quality management system and the ability to demonstrate that specific activities are performed within the criteria set out in the relevant standard.

Medical laboratories can be accredited to ISO 15189, Medical laboratories – Particular requirements for quality and competence, to demonstrate the quality and reliability of their services. ISO 15189 was developed with the participation of the medical, scientific, and clinical community, and it contains requirements for diagnostic labs to demonstrate competence to deliver timely, accurate, and reliable results.

Based on ISO/IEC 17025, General requirements for the competence of testing and calibration laboratories, and ISO 9001, Quality management systems – Requirements, ISO 15189 includes five additional criteria for medical laboratories 

• Providing advice on the type of sample and testing that may be required.
• Interacting with clinical staff with the laboratory responsible for the quality of service to clinicians referring patient samples for testing.
• Providing opinions on results of testing relative to diagnosis and patient care.
• Collecting samples or providing information on collection procedures, sample containers, and sample volumes.

• Ethical practice.

Why is ISO 15189 important?

MARCH 17TH, 2021 BY JONPAYNE

Competence in any field is crucial, but it’s even more pertinent in the medical sphere where the patient’s system is compromised by disease or injury. ISO 15189 is a mark of confidence awarded to medical laboratories – an accreditation that proves you are dedicated to delivering a proficient and quality service across all aspects of your operation.

With 300,000 tests performed every working day of the year and around 95% of clinical pathways relying on patients having access to pathology services, it’s clear that medical laboratories sit at the heart of a fully-functional modern society. Becoming ISO 15189 accredited will verify three key components of a laboratory: your integrity, impartiality and capabilities. Here’s a little bit more about this crucial ISO standard.

What is ISO 15189?

ISO 15189:2012 is an international standard for medical laboratories. Laboratory accreditation helps labs develop quality management systems, assesses their competence and ensures they are functioning in line with industry and legal standards.

As part of your ISO 15189 accreditation process, you will create a document that explains how your laboratory can work to conform to each requirement to a high standard of quality. This handy document will provide each member of your team with instructions for performing the tasks to an ISO-accredited standard.

Who needs ISO 15189?

Laboratory testing is incredibly important in the delivery of information-based healthcare outcomes – this is incredibly important in a world where decisions need to be driven by facts, science and data. Any medical laboratory that wants to deliver clinically relevant results that meet the highest ethical standards should become ISO 15189 accredited.

Is ISO 15189 mandatory?

ISO 15189 accreditation is not mandatory in every jurisdiction, but it’s worth checking your local regulations. Nevertheless, the importance of laboratory accreditation should never be overlooked, especially when you are dealing with public health.

As part of your accreditation process, you will get your organization up-to-date with all the complex legal requirements that a medical laboratory must adhere to. With the ISO’s culture of continuous improvement, any changes to law or regulation will be implemented as part of your ongoing commitment to best practice.

What are the benefits of ISO 15189 accreditation?

There are many reasons why ISO 15189 is important – here are some of the numerous benefits it offers to medical laboratories.

Risk reduction

When you structure your operation around best practice, your systems will be more rigorous. Planning for and identifying any potential risks will help massively reduce them – especially in laboratories that deal with sensitive information, complicated equipment and matters pertaining to people’s health.

Cost-saving

By assuring results are technically valid, your laboratory will save costs associated with retesting. There will also be other cost-saving measures implemented across the standard as your efficiency increases.

Improved team morale

The standard works to reduce staff mistakes and other preventable errors. Your staff motivation won’t only be improved by their demonstration of better performance, but also by you recognizing and promoting your staff’s technical competence.

Legally compliant

By implementing legislation and industry standards into your medical laboratory, ISO 15189 assures that your clinical services are safe, reliable and of good value. This conveys trust to stakeholders and decision-makers who recognize and appreciate the commitment. Legal challenges will be less likely and, if they do occur, you can ensure the framework will support you.

Continual improvement

Best practices won’t start and end with your ISO 15189 certification: through integrating this framework into the core of what you do, you will develop additional programs over time. The framework acts as a tool for measuring quality improvements and continually supporting consistency.

Globally recognized

Being a globally recognized standard not only has reputational benefits. For ISO 15189, global recognition is particularly pertinent. A series of Multilateral Mutual Recognition Arrangements within the International Laboratory Accreditation Cooperation (ILAC) means that laboratories accredited to ISO 15189 will have their certificates and test reports accepted in over 80 countries around the world. This way, your work can benefit medical health not just in your country, but all over the globe.

ISO 15189 accreditation involves an independent assessment of the medical laboratory that includes an examination of personnel qualifications and competence, equipment, reagents and supplies, quality assurance, and analytical, pre-analytical, and post-analytical factors. Qualified assessors conduct a thorough evaluation of all factors affecting the production of test data.

To ensure continued compliance, accredited medical laboratories are regularly re-assessed to ensure they maintain their technical expertise. They are also required to participate in proficiency testing programs (EQAs).

This diagram outlines the ANAB medical lab accreditation process:

ISO 15189 technical requirements are applied for personnel, accommodation and environmental conditions, laboratory equipment, reagents, and consumables, pre-examination processes, examination processes, ensuring the quality of testing processes results, post-examination processes, reporting of results, the release of results, and laboratory information management. Table 1 summarizes these stipulations.

 Table 1: Summary of ISO 15189 specifications

Sub-chapters 5.3, 5.5, and 5.6 require specifications for which there is not a harmonization of practices – note that all the results are recorded, and its traceability is assumed:

a) 5.3.1.4 Equipment calibration and metrological traceability

The medical laboratory participates in programs to calibrate and verification of trueness, i.e., to determine and verify bias (systematic error analysis) defined as “the difference between the expectation of the test results and an accepted reference value” (2.18 of [9]). Measurement Precision (random error analysis) is also measured and verified. It is defined as “the dispersion of independent results of measurements obtained under specific conditions, is expressed such as standard deviation or coefficient of variation”(2.15 of [9]). Preferably, traceable metrological materials should be used. When these materials are not available, or their use is not significant to the estimate accuracy, alternative materials could be used. See for a more in-depth discussion see [10-12].

b) 5.5 Examination processes require:

• 5.5.1.1 Selection of examination procedure: New tests are selected on the basis of clinical purpose (intended use, fit for purpose). For instance, a screening test selection in a blood bank should assure that a method with high diagnostic sensitivity [13] is chosen to minimize the residual risk (2.29 of [14]) of post-transfusion infection. ISO 15189does not recommend any approach to select a new test. Usually, it is based on a literature review using validation cases of state-of-the-art methods.
• 5.5.1.2 Verification of examination procedure: All tests used without modification – “non-waived” tests – are verified using performance information data available from the manufacturer. The verification shall confirm with evidence that the laboratory performance claims have been met. The calculations are based on experimental data. The methodology is presented in guidelines CLSI EP15-A3 [15] for quantitative tests or CLSI EP12-A2 [16] for qualitative tests.
  
• 5.5.1.3 Validation of examination procedure:  Modified (“waved”) or “in-house” tests require a more complex validation process. Also, “standard methods used outside their intended scope” shall be validated. Again, these tests are validated according to the clinical test purpose/intended use/impact of the result on the clinical decision. Therefore, the specifications, such as the allowable total error, allowable diagnostic sensitivity or allowable diagnostic specificity are selected accordingly. ISO 15189 does not state any specific statistical approach for method validation, and it does not state any goals/targets/claims. As with verification of non-modified tests, experimental data is involved with validation of modified tests. The methodology is as complex as needed, and it is identical to what is required to the manufacturer in the validation phase. CLSI guidelines referred to in 5.5.1.2 can also be used, but further studies are needed. For example, the calculation of a clinical decision point based on representative samples of the population.
  
• 5.5.1.4 Measurement uncertainty of measured quantity values: This requirement is just for tests expressing quantitative results, as suggested by the subtitle. For qualitative results, measurement uncertainty cannot be computed. Even if the qualitative results are expressed on an ordinal scale according to cutoff, its determination is optional. ISO 15189 does not recommend a methodology to calculate measurement uncertainty. However, since ISO is a member of the working groups of the Guide to the uncertainty of measurement (GUM) [17] and the Vocabulary of international metrology (VIM) [9], it is presumed that an “Uncertainty approach” ([17]) model is mandatory. Empirical models should be used, preferably using data from the validation of the examination procedure phase. It is not recommended the use of external quality assessment (EQA)/proficiency of testing (PT) data as a primary source due to the heterogeneity of the results [18]. However, the EQA/PT is probably the most common model in medical laboratories with tests accreditated to ISO 15189. It does not comply with the standard since usually, this determination is not according to the results’ intended use (clause 5.5.1.4 of [1]). ISO 15189 2nd edition required that measurement uncertainty is determined when its result was “relevant” and “possible” (5.6.2 of [4]) “Relevant” could be interpreted as when the outcome has a significant clinical value, and “possible” synonymous of the availability of a mathematical model. One such model available to labs is the total analytical error based on the “Error Approach” (also documented as Traditional Approach or True Value Approach). Measurement uncertainty is an additional model that is part of the evaluation of the quality of the reported result, which could be applied to any measurement. Target uncertainty must be defined, which can be very complex. See [19] for further details. Measurement uncertainty implementation has not been widely successful in medical laboratories, even after 23 years since GUM was published, such as demonstrated by the Westgard QC 2015 survey [20]. Note that the measurement uncertainty evaluation can be interpreted as redundancy of verification and validation, just differing due to the use of the “Uncertainty Approach.” For further details about models to determine measurement uncertainty in medical laboratories see [21].

c) 5.6 Ensuring quality of examination results

• Internal quality control: Design of internal quality control scheme is encouraged and implied, but no approach is recommended. Most of the methods used in labs are applications of the “Westgard Rules,” however just using a multirule QC approach does not automatically fulfill the principles [22], and around the world the practice of QC is not harmonized. An alternative to the Levey-Jennings charts could be used, such as the exponentially weighted moving average (EWMA) chart (9.2 of [23]). Nevertheless, the practical suggestion is to use statistical QC based on the Sigma-metrics [24] principally because it relates the determined total error with the allowable total error. The allowable total error is equivalent to the error that does not significantly contribute to incorrect clinical decisions. For a depth discussion on this issue, please see [25].
  
•  External quality assessment: Medical laboratories shall participate in programs for EQA/PT and shall provide evidence of corrective actions when results are out of control. For instance, when a result is out of acceptable group requirements. There are no specific recommended approaches. The use of the EQA/PT approach is sometimes misunderstood, because some calculations based on this data may be inconsistent. For example, EQA/PT could be an unreliable source for estimates of bias if the peer group’s results have a large discrepancy.

Figure 2 represents the steps from the test selection to the reported results. The accomplishment of the examination and post-examination phases are dependent on the pre-examination stage.

Frequently-Asked Questions about ISO 15189

Which books are suggested to support the ISO 15189 quality management system?

Principally two publications: David Burnett, Ph.D. “A Practical guide to ISO 15189 in laboratory medicine” (2013), and James Westgard, Ph.D. and Sten Westgard, M.Sc. “Basic quality management systems” (2014).

Which references can support ISO 15189 specifications on examination and post-examination activities?

a) Method selection

See Westgard QC lesson no. 20 Selecting a method to validate and Basic method validation 3^rd ed. (2008) book

b) Method verification and validation

Precision:

-Detection limit: See Westgard QC lesson no. 29 The detection limit experiment, Basic method validation 3^rd ed. (2008) book, and CLSI EP17

-Precision components: See Westgard QC lesson no. 22 The replication experiment, Basic method validation 3^rd ed. (2008) book, and CLSI EP15 (also EP5, EP9, and EP19)

-Bias: Proportional and constant bias: See Westgard QC lesson no. 23 The comparison of methods experiment, Basic method validation 3^rd ed. (2008) book, and CLSI EP15 (also EP9 and EP10)

– Bias: Drift and carryover: See Basic method validation 3^rd ed. (2008) book, and CLSI EP10

– Bias: Linearity: See Westgard QC lesson no. 26 The linearity or reportable range experiment, Basic method validation 3^rd ed. (2008) book, and CLSI EP6 and EP10

– Bias: Interferences: See Westgard QC lesson no. 27 Interference and recovery experiments, Basic method validation 3^rd ed. (2008) book, and CLSI EP7 and EP14

-Total error: See Westgard QC lesson no. 23 The comparison of methods experiment, Basic method validation 3^rd ed. (2008) book, and CLSI EP21

-Qualitative assays: See Westgard QC essay Basic validation of qualitative tests, Statistical methods in diagnostic medicine. 2nd ed. (2011) book, and CLSI EP12 and EP24

b) Measurement uncertainty

-Modular approach: See Westgard QC essay Time to engage in MU, GUM, EURACHEM QUAM books, and CLSI EP29

-Empirical approach: S: See Westgard QC essay The Hitch-hiker’s guide to MU in clinical laboratories, Uncertainty of Measurement in Medical Laboratories chapter, EURACHEM QUAM, NordTest TR 537, and EURACHEM Target Uncertainty books, and CLSI EP29

c) Internal quality control

See Westgard QC lesson no. 74 Best practices for “Westgard rules”, Six Sigma quality design and control 2^nd ed. (2006) book, and CLSI C24

d) External quality assessment/proficiency testing

See Westgard QC Quality Requirements, Six Sigma quality design and control 2^nd ed. (2006) book, and CLSI GP27

e) Reference intervals

See Westgard QC essay FAQ in reference intervals and biological variation, Statistical bases of reference values in laboratory medicine (1995) book, and CLSI C28

f) Risk management

See Westgard QC Risk management essays, Six Sigma risk analysis (2011) book, and CLSI EP18 and EP23.Which software intended to the medical laboratory is available?

For the validation of examination, procedures are suggested Medcalc (MedCalc Software bvba), EP Evaluator (Data Innovations), and Analyse-it (Analyse-it Software, Ltd.). Dietmar Stöckl, Ph.D. offers a huge number of spreadsheets helpful to validation at STT Consulting. For measurement, uncertainty calculated is recommended by the MUKit (SYKE). This is a freeware based on [26]. For IQC there are many software programsavailable, some based on Web services. For an IQC statistical design based on Sigma-metrics is the legacy EZ Rules (Westgard QC), but also Bio-Rad’s Westgard Advisor.

Is there some guideline based on audit requirements (4.13)?

Yes, ISO 19011:2018 [28] “is intended to apply to a broad range of potential users.” It is the recommendation to support the audits, including the documented procedure. Part 4 of these series will is oriented to audit requirements [13].

Is there some guideline to support safety specifications (5.2)?

Yes, ISO 15190:2003 [29] is the complementary standard to ISO 15189. Part 5 of these series is based on safety requirements.

What is happening with ISO 15189 implementation from a global perspective?

Currently, ISO 15189 is obligatory in Australia and Latvia. Since 2011 all new French medical laboratories must be accredited. All other public or private laboratories in France must be accredited after November 1, 2016, on at least 50% of the tests, 70% in 2018, and 100% in 2020. In the Netherlands, the CCKL accreditation has been changing to the ISO 15189 at the direction of the Dutch ‘Raad voor Accreditatie’ (RvA) after January 1st, 2018. Thus, the implementation case of ISO 15189 at a global perspective could be designated as unsuccessful, which is different from what is happening with ISO/IEC 17015 in other fields. On a harmonization perspective of good laboratory practices, this is a major concern.

Summary

Acreditation according to ISO 15180 has several advantages.

The pros could be summed up as:

• The only global standard for the accreditation of medical laboratory results;
• Based on good laboratory practices;
• Focus on technical specifications in the medical laboratory; – Process approach matching the pre-analytical, analytical, and post-analytical phases;
• Oriented to support accurate clinical decisions;
• Identification and traceability information of the different phases of the medical laboratory process;
• Monitoring and measuring of devices that significantly contribute to the trueness and uncertainty of the reported results;
• Training and competency assessment of the staff which is critical to good management and good laboratory practices, and;
• Infrastructure to correctly support operating practices.

Nevertheless, there are a few cons to ISO 15189:

• The accreditation is expensive when compared to the ISO 9001 certification;
• Its value is not well understood by the physician and the customers of clinical decisions;
• It is not used by most of the medical laboratory agencies as the standard to accreditation;
• It requires auditors with an advanced matrix of skills;
• It does not require sustainability;
• The specifications sometimes are too generic or abstract;
• It does not standardize critical practices such as the validation, measurement uncertainty, IQC and EQA/PT of examination procedures, and;
• The safety specifications are basic.

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