This post on the importance of using quality controls in a laboratory’s patient testing workflow provides an overview of the purpose and regulatory implications of using quality control materials. You will gain insight into the optimal solution of using third-party controls and In Vitro Diagnostic (IVD) labeled controls for your clinical testing scenarios.

When driving an automobile, it is necessary to perform preventative maintenance for the car to operate safely and efficiently. Similarly, when performing diagnostic testing, one must ensure that patient testing is done in an accurate and streamlined way. Thus, what steps can a laboratorian take to achieve such goals? The use of a reliable quality control program will lead the laboratory to a path for productive patient testing; this will not only ensure efficient laboratory workflow but also verify that the results are correct in deciphering clinical decision-making.

What is the purpose of performing quality control checks in the context of diagnostic testing? In essence, Quality Control (QC) in a clinical laboratory is used to detect deficiencies to reduce potential errors in a laboratory’s testing process before releasing a patient’s results. Thus, the use of defined quality control materials ensures that the results being reported are accurate and precise. How does implementation of the proper QC materials serve as a check of the laboratory workflow and what does this entail? An effective program of quality control includes the processes of sample acquisition (preanalytical), the testing process (analytical) and result reporting (postanalytical). These steps are listed in detail in Table 1 below:

Table 1

Considering the complexities surrounding the laboratory workflow, how does utilization of an appropriate quality control material reveal potential areas of incorrect or invalid results? Furthermore, what actions could prevent or reduce the risk of errors occurring during clinical testing? The laboratory must first decide on the frequency of inclusion of QC for each analyte under investigation, based on a risk assessment. The same is true for analytes that have pre-defined levels of positivity. The QC material must cover the range(s) of the analyte being tested. In this respect, QC may be customized for each specific test, instrument, or facility where clinical testing is occurring. In addition, it is essential that the laboratory monitor their quality control plan for any test or result deviations that prove unacceptable.

What do the regulatory/compliance agencies have to say about quality control frequency and levels of QC materials? As an example, let’s take a look at the Clinical and Laboratory Standards Institute (CLSI) standards. CLSI guideline EP23¹ states the following: “[F]frequency of QC procedures should also conform to applicable regulatory and accreditation requirements. Monitoring the measuring system at shorter intervals increases the likelihood that systematic errors are detected before incorrect results are reported or decreases the time before alerting the health care provider who might have received incorrect results…”. The College of American Pathologists (CAP) has a Microbiology Checklist, MIC.65200, that outlines the frequency of running QC for molecular- based tests and differentiates Quantitative vs. Qualitative tests.²   MIC.65200 also cites the possibility of a laboratory implementing an Individualized Quality Control Plan (IQCP) in which the frequency of QC testing can be adjusted based on performing a comprehensive risk assessment. The International Organization for Standardization (ISO) has a standard, ISO 15189, with information on requirements for quality and competence in clinical laboratories.³   While this standard does not describe specific frequencies for QC testing, it does allow clinical laboratories to tailor their QC based on the type of test, its criticality, and stability of the analytic process. ISO 15189 standard does require laboratories to subscribe to an External Quality Assessment (EQA) to help ensure the compatibility of test results as compared to a peer group.  In the US, EQA is referred to as Proficiency Testing (PT); more information about PT can be found in the publication by the Federal register entitled, “Clinical Laboratory Improvement Amendments of 1988 (CLIA) Proficiency Testing Regulations Related to Analytes and Acceptable Performance”.⁴

Like a Check Engine light for your laboratory, PT results can indicate impending problems

How does Proficiency Testing (PT) fit into the clinical laboratory testing workflow? PT samples are from an organization that provides pre-analyzed samples, with the end user blinded to the actual test result. Once the laboratory’s result is submitted to the PT agency, an end-user score is then calculated, based on a peer group consensus in comparison to other similar laboratories using the same or similar testing equipment. Thus, the use of PT ensures the accuracy, reliability, and consistency of patient test results. Ideally, PT samples are treated identically as patient specimens with the same preanalytical, analytical and postanalytical steps. A good PT program will ensure that the entire testing process is evaluated under routine operating conditions. Hence there is an advantage of using QC materials that mimic proficiency testing (and patient testing), as failure of QC may be a harbinger of larger issues that may affect the laboratory’s PT results—almost like a check engine light going off in your car.

For accurate clinical laboratory results, what is the best type of external or third-party quality control materials to be used? Should one use a control labeled In Vitro Diagnostic (IVD) or alternatively consider a Research Use Only (RUO) control in the context of laboratory patient testing? According to the FDA guidance document, “Distribution of an In Vitro Diagnostic Products Labeled for Research Use Only or Investigational Use Only”, RUO is defined as “IVD product currently under development and not approved for clinical diagnostic use… The term RUO refers to devices that are in the laboratory phase of development.” “During the research phase of development, the focus of manufacturer-initiated studies is typically to evaluate design, limited-scale performance, and issues such as usability of the test”.⁴  Similarly, in the EU MEDDEV 2.14/2 rev.1, RUO is identified as having “ no intended medical purpose or objective… .”⁵  In addition, RUO materials are not defined in the EU’s In Vitro Diagnostic Medical Devices Regulation (IVDR) and do not have any regulatory requirements.⁶  RUO labeled QC can be used in testing scenarios without any direct link to clinical or medical patient diagnostics. In the US, the FDA states that RUO materials must be labelled as ‘Not for use in diagnostic procedures.’”⁷

What are the key factors influencing purchasing decisions for third-party QC in clinical laboratories? The primary consideration is the compatibility of the materials with the existing patient testing workflow and laboratory instruments. It’s also important to assess the level of post-sales support and the shelf-life of the materials provided. Ideally, the QC materials should remain effective for a significant period. Other factors to consider include the long-term efficiency of the materials within the laboratory workflow and their ease of use for the end user. The vendor’s reputation and brand recognition play an essential role as well. Establishing a solid working relationship with a quality control vendor is critical for preventing shortages of QC materials. Since timing is a crucial aspect of QC, reliable product availability should be a top priority.

Once an efficient and user-friendly quality control scheme is implemented in the laboratory, it is necessary to perform a periodic review of the QC system. As part of the continuous improvement process, one may evaluate five major areas where errors can occur. Errors related to (1) sampling, (2) the operator, (3) the reagents, (4) the laboratory environment, and (5) the measuring system may be revealed. This is where the appropriate choice of QC materials and their use in the testing process is key. The critical components of preanalytical, analytical and postanalytical methods are addressed using a quality control material that follows the patient testing pathway. By closely monitoring your QC results, a laboratory may anticipate or even prevent errors in any of the above processes. Remember the old adage, inadequate quality control in, poor test results out!

Finally, what will the future of quality control in the clinical laboratory look like? It is all about creating a “smart lab” to improve efficiency and clinical testing quality. More than just LIS integration of QC results, Artificial Intelligence (AI) will take a lead role in quality control practices. AI would be able to monitor QC data in real-time to identify any non-compliance issues prior to affecting patient results. It would be able to proactively alert the end user on predictive maintenance based on QC performance trends. Due to AI’s ability to process large data sets, it can help troubleshoot inconsistencies or errors in QC results, improving overall laboratory test performance. Most importantly, AI via its automation capabilities can perform routine tasks, freeing up personnel to handle more complicated analyses. Other current AI related laboratory activities include molecular pattern recognition and genomic analysis as well as classification of disease subtypes.⁸ The future of AI in the clinical laboratory and quality control practices is still in its infancy.

Despite its potential to significantly change clinical diagnostics, AI will augment rather than eliminate QC. As AI technology advances, clinical laboratories must continue focusing on the basic principles of QC, including the timely supply of IVD controls that monitor the entire analytical process.  To enable increased automation, laboratories will need precision QC materials to detect problems early, before they can be repeated and amplified.

Partnering with QC Experts for Reliable Precision

Microbiologics is a company which can meet the QC challenges outlined above. What Microbiologics offers is a Quality Control IVD portfolio that encompasses products that have undergone a rigorous product development process that adheres to both FDA and IVDR requirements. An example is the Helix Elite™ Molecular Standards product line that has proven clinical and analytical performance. These products are manufactured to meet IVDR registration and FDA 510(k) clearance criteria and as such, are labeled as IVD. In contrast, third party RUO materials do not specify requirements for these development processes and may not meet the requirements as far as performance and regulatory adherence. RUO products are not to be used in laboratory diagnostic procedures, but in scientific investigations only. Many of Microbiologics quality controls have also been developed to be agnostic amongst various laboratory instruments.  This approach means that Microbiologics’ quality controls maintain their effectiveness and reliability across various instruments. Cross-platform compatibility enhances operational efficiency, reduces the need for instrument-specific adjustments, and provides laboratories with consistent, high-quality results. It allows labs to focus on their core work without being limited by the constraints of specific instrument types, ultimately improving workflow and reducing complexity. Lastly, as experts in QC, Microbiologics keep their customers front of mind, offering superior technical support that diagnostic laboratory professionals need to consistently deliver the accuracy patients deserve.

Guest Author:

Andrea Pierce, PhD, MBA AmpSci Consulting LLC [email protected]

Andrea is experienced in Medical & Scientific Affairs for the clinical diagnostics industry. She has developed FDA 510(k) and IVDR compliant Instruments and PCR-based assays. Andrea has served as the Subject Matter Expert for New Product Development and Quality teams related to FDA 21 CFR 820 and ISO 13485 standards, and is recognized for leadership in regulatory compliance, international market expansion, and clinical affairs.

Sources

1 Clinical and Laboratory Standards Institute.

https://clsi.org/standards/products/method-evaluation/documents/ep23/

2 The College of American Pathologists (CAP) Microbiology Checklist MIC.65200

https://documents-cloud.cap.org/appsuite/learning/LAP/TLTM/resources/checklists/2020/cl-mic.pdf

3 ISO Medical laboratories — Requirements for quality and competence https://www.iacld.com/UpFiles/Documents/2e096ce5-485b-4f22-b7be-e557fb7d06f8.pdf

4 The Federal Register: Department of Health and Human Services Centers for Medicare & Medicaid Services. Accessed Jan 14, 2025, https://www.federalregister.gov/d/2022-14513

5 European Commission. (2004, February). Guidance document – In vitro diagnostic medical devices – Research Use Only products – MEDDEV 2.14/2 rev.1. European Commission. Accessed Jan 14, 2025, https://ec.europa.eu/docsroom/documents/10292/attachments/1/translations

6 REGULATION (EU) 2017/746 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 5 April 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU

https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32017R0746

7 U.S. Department of Health and Human Services Food and Drug Administration Center for Devices and Radiological Health Office of In Vitro Diagnostic Device Evaluation and Safety “Distribution of In Vitro Diagnostic Products Labeled for Research Use Only or Investigational Use Only”

https://www.fda.gov/files/medical%20devices/published/Distribution-of-In-Vitro-Diagnostic-Products-Labeled-for-Research-Use-Only-or-Investigational-Use-Only—Guidance-for-Industry-and-FDA-Staff.pdf

8 Dias and Torkamani Genome Medicine (2019) 11:70 https://doi.org/10.1186/s13073-019-0689-8 https://genomemedicine.biomedcentral.com/counter/pdf/10.1186/s13073-019-0689-8.pdf