Trends in the Accreditation of Medical Laboratories by ISO 15189

Abstract

In areas such as transfusion, transplantation, and sports medicine, laboratory results are critical to the diagnosis of pathologies. In order to minimize intra- and interlaboratory variability of results, it is equally important to harmonize quality management and technical practices in the medical laboratory. To ensure the competence of medical laboratories, ISO 15189, 3rd edition, establishes international standards. A set of critical principles for effective management and control of technical specifications has been outlined in this document. December 2022 marked the publication of the fourth edition of this standard. An in-depth analysis of the ISO 15189 standard is presented in this chapter.

1. Introduction

The pivotal significance of laboratory results in healthcare is underscored by their contribution to 70% of clinical diagnoses [1]. This underscores the need for performance assessment techniques to ensure that these results are reported in alignment with their intended purpose. However, it is equally essential to maintain control over the entire technical environment and support infrastructure.

The quality and competency standards for medical laboratories are delineated in ISO 15189 “Medical laboratories - Requirements for quality and competence”, an International Organization for Standardization (ISO) standard [2]. ISO 15189 serves the dual purpose of establishing quality management systems (QMS) for medical laboratories and evaluating their competence. Moreover, third parties, including customers, regulatory bodies, and accreditation entities, employ these standards to affirm or acknowledge a laboratory’s competency.

As part of its standard life cycle, ISO standards necessitate a comprehensive review every 5 years. This review process falls under the purview of the Technical Committee ISO/TC 212, focusing on “Clinical laboratory testing and in vitro diagnostic test systems.” ISO 15189 is categorized in the International Classification for Standards (ICS) under 03.120.10, which pertains to quality management and quality assurance, and 11.100.01, encompassing laboratory medicine in general. The ICS framework functions as a structure for compiling international, regional, and national standards, along with other normative documents. It also serves as a basis for standing-order systems [3]. For detailed information on the revision cycle, please refer to [4].

The ISO 15189:2022 is a 76-page document. The current edition, which is the fourth, was published in December 2022, and it supersedes the third edition, which has since been withdrawn [5]. This chapter delves into the foundational principles of the present ISO 15189 editions, taking into consideration anticipated changes and emerging trends. The target audience for this chapter includes individuals with prior experience in ISO 15189 accreditation, including those who have been audited and auditors familiar with this standard.

2. Verbal forms

Drawing from our experience as auditors, we are often reminded of instances where requirements were mistakenly regarded as recommendations, and vice versa. It is of paramount importance to grasp the distinctions between what is mandated, suggested, or allowed in order to gain a comprehensive understanding of the standard and how it should be applied. This principle holds true not only for those being audited but also for auditors themselves, particularly internal auditors, who can sometimes introduce misconceptions when interpreting the standard. This applies to various fields, including management and technical. ISO 15189 employs specific verbal forms to convey these distinctions, and they are as follows:

• “shall” indicates a requirement;

• “should” indicates a recommendation;

• “may” indicates permission, and;

• “can” indicates a possibility or capability.

The ISO/IEC Directives, Part 2:2001, titled “Principles and rules for the structure and drafting of ISO and IEC documents,” outlines the fundamental principles governing the drafting of ISO and the International Electrotechnical Commission (IEC) documents. It also prescribes specific rules aimed at ensuring these documents are clear, precise, and unambiguous. These rules are not only essential for clarity but also for maintaining the effectiveness of each document in contributing to the cohesive and interconnected body of knowledge generated by ISO and IEC. In fact, this standard aligns with the principles governing the use of verbal expressions for provisions, as outlined in Section 7 of the ISO/IEC Directives ([6], Section 7).

3. Conceptual changes

3.1 Intended use/fitness for purpose

The updated ISO 15189 version includes the assessment of performance specifications based on the intended use of the method, whether it is for validation - harmonized methods; “commercial assays” - or verification - developed or modified methods - purposes. As a result, laboratories will be responsible for establishing the performance specifications, ideally drawing upon third-party peer-reviewed research. This methodology for assessing and ensuring precision in both (quantitative) measurements and (qualitative) examinations is of paramount importance for making accurate clinical decisions and subsequent actions.

Within the scope of intra-laboratory applications, it becomes imperative to take into account the guidelines provided by national accreditation agencies. These guidelines may even be obligatory for achieving recognition of ISO 15189 accreditation. Consider the example of glucose and its diverse applications, ranging from excluding diabetes, diagnosing diabetes, and ruling out hypoglycemia in emergency settings, to maintaining precise glycemic control in intensive care units. There are no systems with “pure” ISO 15189 accreditation, the system being a combination of other guidelines, in which the legal ones overlap.

To address these varied purposes, the laboratory should proactively consult the most current literature for state-of-the-art methodologies in the assessment of both quantitative, for example, using the Clinical and Laboratory Standards Institute (CLSI) EP15-A3 guideline [7], and qualitative assays, encompassing binary, unordered (nominal), and ordered (ordinal) categorizations, for example using CLSI EP12-A3 [8], Pereira [9], and Eurachem guide [10]. This literature selected is not only peer-reviewed papers but also regulation of in vitro diagnostic medical devices (IVD-MD) and inserts from manufacturers of this type of devices. In this step, it will be demonstrated whether the laboratory can achieve/replicate the required performance under its conditions, whether through regulation or that stated in the manufacturers’ inserts.

3.2 Risk-based decisions

Laboratory techniques come with inherent risks and opportunities, which are identified within the laboratory setting. The laboratory is required to respond to these identified risks. To address these risks, a proportional response is essential, taking into account their potential impact on laboratory test results and the safety of both patients and personnel. The principles of ISO 15189 and ISO 22367:2020 [11] closely align with the requirements for risk management. A risk-oriented approach is pervasive throughout the entire ISO 15189 document, particularly in Sections 5.6, titled “Risk management” and 8.5 “Actions to address risks and opportunities.”

In addition to establishing and implementing a management system for the laboratory, the laboratory director has the responsibility of applying risk management principles to all aspects of laboratory operations. By systematically identifying and addressing any risks that could affect patient care and identifying opportunities for improvement, the laboratory director ensures the seamless operation of laboratory activities. In cases where these processes are found to be ineffective, the laboratory director ensures that they are evaluated and, if necessary, modified and implemented effectively.

It is imperative to identify risks associated with emergencies or situations where laboratory activities are limited or unavailable. A coordinated strategy should be developed to enable the recovery of systems and the continuity of operations after a disruption. This involves the development of plans, procedures, and technical measures.

Throughout the pre-examination, examination, and post-examination processes, the laboratory must identify potential risks to patient care. As part of the risk assessment process, efforts are made to mitigate these risks where possible, and they are communicated to users most appropriately. The ongoing monitoring and evaluation of identified risks and the effectiveness of mitigation measures are critical to ascertain whether there is any potential harm to the patient.

Laboratory management bears the responsibility of developing, implementing, and maintaining processes for identifying risks that could harm patients in relation to examinations and activities. These processes are also tasked with devising actions to address the identified risks and opportunities.

Furthermore, this risk analysis process, established by the laboratory, leads to the definition and determination of immediate and long-term actions. Laboratories are obligated to rectify any non-conforming work, taking into account the likelihood of its recurrence in the future. In cases where there is a risk of harm to patients, examinations are halted, and reports are withheld to prevent such harm.

3.3 Leadership

Leadership involves the capacity of an individual, a group, or an organization to “lead,” exert influence or provide guidance to other individuals, teams, or entire organizations. Professionals, as a rule, do not like being forced to carry out specific and extraordinary tasks. On the other hand, maintaining competency matrices especially in complex techniques or with large teams can consume a considerable amount of time and effort. Leadership is influential but also influenced by the specific demands of the laboratory and the circumstances surrounding the risks of failure it faces. It must be clear that all activities, including support activities, always depend on a leadership policy.

4. Structure

4.1 Relationship with ISO/IEC 17025, ISO 9001, and ISO 15189:2012

The ISO 15189 structure is built upon ISO/IEC 17025:2017 [12], much like the previous versions. ISO 15189 aims to enhance patient well-being by instilling confidence in the quality and competence of medical laboratories. The 4th version can be viewed as less prescriptive in defining “what” is required and instead embraces a risk-based approach for determining “how” requirements are met, placing more emphasis on the interplay between different elements. This structure adheres to the principles outlined in the ISO Casco 1700 series for accreditation standards [13].

Similar to ISO/IEC 17025, ISO 15189 follows an input-output structure, aligning with ISO 9001 [14], which pertains to the QMS. This means that laboratories with QMS certification under ISO 9001 will undergo third-party audits for ISO 15189 accreditation, focusing primarily on technical requirements. The contemporary structure also addresses management responsibilities, with a focus on the flow of processes within the medical laboratory, encompassing recognized pre-analytical, analytical, and post-analytical phases.

A summary of the key changes and updates from ISO 15189:2012 to ISO 15189:2022 can be found below:

• Management requirements:

  • ISO 15189:2012 had a section on “Management Requirements” that covered various aspects of laboratory management.

  • ISO 15189:2022 introduces new sections, “Structural and governance requirements,” and “Requirements regarding patients,” which detail the structural organization and patient-related aspects of laboratory management.

  • The 2022 version places more emphasis on the “Requirements regarding patients” and “Advisory activities” (“Needs of users”) and includes information on “Objectives and policies,” “Structure and authority,” “Quality management,” and “Management system requirements.”

• Quality management system:

  • ISO 15189:2012 had sections on “Quality management system” and “Documentation requirements.”

  • ISO 15189:2022 introduces “Management system documentation” and specifies the documentation and control of management system documents.

  • The requirement for a “Quality manual” is marked as optional and is no longer mandatory in ISO 15189:2022.

• Service agreements:

  • In ISO 15189:2012, there were two sub-sections related to “Service agreements.”

  • In ISO 15189:2022, these are now merged in the section “Service agreements.”

• Evaluation and audits:

  • ISO 15189:2012 had sections on “Evaluation and audits.”

  • ISO 15189:2022 introduces a more structured approach with “Evaluations”, “Quality indicators” and “Internal audits.”

• Management review:

  • Both versions have sections on “Management review” but provide more details on the structure of this review in ISO 15189:2022.

• Technical requirements:

  • ISO 15189:2012 included sections on “Technical requirements.”

  • In ISO 15189:2022, these are categorized under “Resource requirements.”

• Personnel:

  • ISO 15189:2012 had sections regarding personnel qualifications, job descriptions, and staff performance reviews.

  • ISO 15189:2022 adds a section on “Competence requirements and provides more detailed information about “Continuing education and professional development.”

• Accommodation and environmental conditions:

  • These requirements remain mostly consistent between the two versions, with some slight reorganization and clarifications.

• Laboratory equipment, reagents, and consumables:

  • The sections about laboratory equipment, reagents, and consumables have been restructured, but the core requirements remain consistent.

• Pre-examination, examination, and post-examination processes:

  • ISO 15189:2022 revises the structure and organization of requirements related to pre-examination, examination, and post-examination processes.

  • While the core elements remain similar, the new version offers more clarity and detail.

• Laboratory information management:

  • ISO 15189:2022 includes new sections on “Downtime plans,” “Off-site management,” and “Continuity and emergency preparedness planning.”

• Annexes:

  • ISO 15189:2022 includes additional annexes, such as “Additional requirements for Point-of-Care Testing” and tables comparing the standard to ISO 9001:2015, ISO/IEC 17025:2017, and ISO 15189:2012.

In summary, ISO 15189:2022 builds upon the foundation of ISO 15189:2012, offering a more comprehensive and structured framework for quality management in medical laboratories. It places a greater emphasis on the needs of users, quality indicators, and external assessments, and provides additional guidance in various aspects of laboratory management and operations.

4.2 POCT integrates ISO 22870

The basis for point-of-care testing (POCT) requirements in the new ISO 15189 edition is a blend of the principles from the previous ISO 15189 version and ISO 22870:2016 [15]. Consequently, this edition incorporates ISO 22870 principles relevant to medical laboratories supporting POCT. Hospitals, clinics, or other ambulatory care healthcare facilities may conduct POCTs, aligning with ISO specifications.

An additional pertinent technical standard is ISO/TS 22583 [16], which offers guidance for supervisors and operators of POCT services conducted independently of medical laboratories’ oversight and support. As a result, ISO/TS 22583 can be seen as complementary to an ISO 15189 accreditation project.

Moreover, the technical specifications encompass several crucial elements that must be taken into account to ensure the safety and reliability of POCT results. In the ISO 15189:2022 context, POCT is treated as any other service provided by a medical laboratory, guided by the requirements and service level agreements, and tailored to the interaction with users based on medical needs.

4.3 Sampling is related to ISO/TS 20658

Starting from 2017, ISO/TS 20658:2017 [17] establishes a set of requirements and best practices for collecting, transporting, receiving, and handling samples intended for medical laboratory examinations. Within ISO 15189, sampling specifications retain their crucial role, incorporating the principles delineated in ISO/TS 20658. This technical specification serves as a valuable reference for sampling procedures.

The latest iteration of ISO 15189 now integrates specific requirements for the preparation and identification of suitable samples. These elements are essential components of the new sampling specifications. Additionally, the updated version introduces a risk-based assessment of criteria for accepting suboptimal samples, as well as acceptance and rejection criteria for sampling. So, it is essential to emphasize that the decision to reject a sample should never be “automatic” - it must be made with the patient’s best interests in mind, based on clinical data and prognosis.

4.4 Refers to ISO/TS 22367 on risk management

ISO 22367:2020, titled “Medical laboratories - Application of risk management to medical laboratories” [11], corresponds closely with the ISO 15189 criteria for risk management. The principles established in the med lab standard are harmonized with the risk management requirements. Medical laboratories are encouraged to utilize this document as a tool for recognizing and addressing risks associated with medical laboratory examinations, benefiting both patients and staff. A robust risk management process encompasses the identification, assessment, evaluation, control, and monitoring of risks.

In addition, this document sets forth stipulations encompassing all facets of medical laboratory examinations and services, spanning pre-examination and post-examination protocols, the examination process itself, and the accurate transmission of test results into electronic medical records. Furthermore, it includes various technical and managerial procedures relevant to the field.

4.5 Interrelationship between personnel

Every member of the medical laboratory staff is obligated to adhere to the guidelines that govern the medical laboratory. These guidelines outline their roles, authority, communication channels, and how they interact with others involved in managing, executing, or validating laboratory results.

5. Metrological traceability

ISO 15189 is firmly anchored to ISO 17511 [18], which centers on metrological traceability. This standard establishes the technical prerequisites and essential documentation for achieving metrological traceability for quantities gauged IVD-MD. The highest level of metrological traceability for human samples is attained through Reference Measurement Procedures (RMP) and Certified Reference Materials (CRM). However, these materials are not always available, being rare or integrated into kits. The traceability remains considered in the scenario where primary reference materials or reference methods are unavailable. So, traceability must always be ensured for the quality control material, even if metrological traceability is not possible. This traceability refers to the reference of the materials, such as the batch and expiration date. Note that “metrological traceability”, by definition in VIM, is only applicable to quantitative quantities, not qualitative properties, as true/false, positive/negative.

The new version also deals with commutability issues within the traceability chain. Comparatively, the new ISO 15189 requirements can be interpreted as more pragmatic and forward-thinking when contrasted with the previous version. They comprehensively link all elements concerning metrological traceability. In fact, measurement traceability mainly refers to verification, validation, measurement uncertainty, internal quality control, and external quality assessment of methods.

6. Performance assessment

The performance specifications for each examination method should be directly linked to its intended use and the influence it has on patient care. The laboratory establishes a verification procedure to confirm its competence in conducting examination methods before their implementation. Verification thus applies to all standardized assays or methods - referred to as “commercial” - which have been subject to extensive validation and evaluation by a notified body. This process involves ensuring that the necessary performance criteria, as defined by the manufacturer or the method itself, can be consistently met.

Otherwise, non-normalized assays or methods, such as laboratory-designed or developed methods, methods used outside their originally intended scope, and validated methods subsequently modified, are validated. This process is deeper and more extensive than the one called “verification”, as it involves more complex components. For example, establishment cutoff. In the med lab, it is associated with rare or reference tests.

By providing objective evidence based on performance characteristics, the test will confirm that the specific requirements for its intended use have been met. To ensure consistency in the validity of the results relevant to clinical decision-making, the laboratory shall conduct sufficient verification or validation of the examination method. Which characteristics are relevant? The ones that are relevant to the intended use.

7. Refers to ISO/TS 20914 on measurement uncertainty

In the 4th edition, the measurement unit (MU) [19, 20] will undergo a comparison with performance specifications, the results will be documented, and regularly reviewed. In the current edition, ISO/TS 20914 [21] establishes itself as a definitive best practice guide for handling measurement uncertainty. It is crucial to assess and manage measurement uncertainty in a manner that aligns with its intended purpose, and this principle is part of the ISO/TS. When reporting uncertainty internally, it is imperative to take into account several sources of uncertainty, which may include, but are not limited to, factors related to biological variation. It must be clear what the components of uncertainty are. If a “top-down” model [22] is used in computing, important literature references can also be shared with the total analytical error determination (measurement analogous to uncertainty), such as CLSI EP15. The difference between the approaches can be summarized as being due to the different combinations of sources, where bias is seen as a source of uncertainty through bias uncertainty and the combination follows the laws of variance combination.

In cases where it is not feasible or relevant to estimate the MU for examination procedures, the justification for excluding MU estimation should be documented. MU details will be provided to laboratory users upon request.

The consideration of MU during the verification or validation of a method is advisable. However, it is important to note that this recommendation is only mandatory if the medical laboratory deems it relevant to the assessment.

In examinations producing qualitative results, the assessment of MU in intermediate measurement steps or internal quality control results that generate quantitative data should also be extended to critical (high-risk) stages of the process [23, 24]. However, this reported recommendation is rarely put into practice. The reason is that there are other quality control practices regularly applied by laboratories with success. For further details on MU in med lab, see [25].

7.1 Internal quality control

The primary objective of internal quality control is to ensure the intended quality of the results. Internal quality control can be deemed as fulfilled, given that it is contingent on the release of the patient’s results. In the fourth edition, there is a novel proposal addressing trends and shifts, as well as the inclusion of a data generator for assessing measurement uncertainty, which represents a focus on long-term compliance.

7.2 External quality assessment

External quality assessment (EQA), also known as proficiency testing (PT), is essentially an interlaboratory comparison. In the fourth edition, there is the introduction of a target value and verification of trueness following current schemes. Whenever feasible, achieving metrological traceability to reference methods is encouraged. The target value may be determined based on consensus within a peer group. The notion of “commutable material” indicates that it responds to measurement methods similarly to patient specimens, emphasizing the necessity of commutability. In cases where a suitable EQA scheme is not available, an alternative approach should be considered. For an introduction to EQA see [26].

8. Discussion and conclusion

The present version of ISO 15189 does not require specific documented procedures. However, this should not be understood as “not documenting” but rather as a model open to different documentation approaches. In fact, a basis for documenting could be to follow a similar approach to the previous version, when we asked, “what to document?”. While the previous version is clear on the do (“do this, do that”), the new edition focuses on doing what is needed. While the technical aspects of performance assessment may have traditionally emphasized measurement-related criteria, the fourth edition has shifted its focus toward the medical significance of these criteria. For instance, the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) criteria take into account medical requirements, biological variation, and contemporary conditions. It also emphasizes the specific purpose of each measurement and the intended use of the test, be it for screening, clinical diagnosis, or other purposes. As a result, the present edition can be seen as providing fewer rigid guidelines and, in turn, will demand more thoughtful consideration, making it a more challenging endeavor to implement.

A recurring limitation found in prior editions is the standard’s potential to foster better alignment of practices, especially in the context of performance assessment. Nonetheless, we recognize that this limitation will persist in present and future versions, as it could potentially conflict with prevailing national regulations, which always take precedence over standard norms. An example of this lack of harmony is evident in the variation of acceptable error limits.