CLINICAL ISSUES :: CONTROLS AND REAGENTS


proficiency testing (PT) and external quality assessment (EQA) programs, which provide assurance internally and externally that testing (and by extension, the reagents) taking place at your laboratory provides accurate and reliable results.


Managing lot-to-lot variation Unfortunately, it has been shown that even after a reagent lot has passed initial qualifications, there can still be sig- nificant lot-to-lot variation for “qualified” reagents.8


As


Algeciras-Schimnich (2014) explains, “Multiple factors can affect performance of a new reagent lot, including changes in a critical reagent material or in stability of the reagents, reagent damage during transportation or storage, or incorrect calibra- tion” When used in the clinical setting, these variations have potential to affect the results of previously validated assays.6


Characteristics of Lab Developed Tests (LDTs) Number of clinical labs in U.S.


267,000 Number of clinical labs using LDTs 12,000


Most common diagnostic areas for LDTs


Types of labs using LDTs Source: Pew Charitable Trusts5 The generally accepted way to deal with this lot-to-lot vari-


ability is to constantly evaluate assay performance as new lots of reagents are received. However, this continual re-evaluation process is time-consuming and comes with its own challenges and risks. For example, there are no mandated metrics for ensuring lot-to-lot quality, leading to wide variability in the number of sample tests run at any given lab and inconsistent testing methodologies. In addition, the decision to test with real patient samples or contrived controls is left to the individual lab.


Using quality management system CLSI has provided a guideline for user evaluation of between- lot reagent variation (CLSI, 2013) that should aid in evaluating lot-to-lot performance. Rigorous performance of these evalua- tions can help to establish a prediction of performance, creating trust between the clinical labs and their suppliers.9 This is not to say that once we have sourced a trusted sup-


plier and have assured ourselves of quality over time, we have completely absolved ourselves of responsibility. In fact, sourcing is just the beginning. We must all follow our own downstream quality processes including (but not limited to) incoming inspection, process control and chain-of-custody documentation. After all, there’s no point in establishing supplier quality if you can’t later tell which lot was used in a particular clinical test. Supplier quality goes hand-in-hand with our own quality


efforts and really is the only way to ensure quality over time. Where organizational size and bandwidth allows, the estab- lishment of a quality management System (QMS) should be considered, as the QMS will allow labs to efficiently focus on both internal and external indicators of quality. CLSI has provided several guidelines and standards to help


laboratories develop quality management systems.10 Sometimes living under a QMS can seem like a burden. We


trust ourselves; why should we have put up with the burden of QMS overhead to prove it to others? The answer is simple:


30 DECEMBER 2021 MLO-ONLINE.COM


molecular, including oncology and inherited diseases


academic medical centers, specialty labs, reference labs, large public health labs


we are suppliers to others, be-it elsewhere in the lab or to physicians and to the patients they care for. If we expect our own suppliers to adhere to a certain quality standard, so too should we hold ourselves accountable to at least the same standard, especially as we push forward into new territories like multi-quadrupole ICP-MS. As sensitivity increases, so too does the magnification of errors. Those depending on us must trust us, as we trust those that we depend on.


Trust is the key As with any relationship, there must be trust. When we purchase our controls and reagents, we must be able to trust that our vendor is giving us products of high quality. GMP and ISO certi- fications are excellent indicators of this quality. So too is the track record of the manufacturer. We must also trust ourselves. We must establish the practices, processes and protocols that make these quality-supplied products meaningful and worthwhile investments, lest that be our bad apple be inside the barrel.


REFERENCES


1. Lee M, Ji Q., Protein analysis using mass spectrometry: accelerating pro- tein biotherapeutics from lab to patient. Hoboken: Wiley. 2017.


2. Mayer A, Fraley K. 2021. The importance of quality critical reagents for the entire development lifecycle of a bioparmaceutical: a pharmacokinetic case study. Bioanalysis. 2021; 13(10): 817-827. doi: 10.4155/bio-2020-0253.


3. Gibson J. Does reagent quality play a role in reproducibility of experi- mental data? Medical Laboratory Observer. https://www.mlo-online.com/ management/qa-qc/article/21089049/does-reagent-quality-play-a-role-in- reproducibility-of-experimental-data. Published July 23, 2019. Accessed October 13, 2021.


4. U.S. Food & Drug Administration, 2018. Laboratory developed tests. https:// www.fda.gov/medical-devices/in-vitro-diagnostics/laboratory-developed- tests. Updated September 27, 2018. Accessed 28 October 28, 2021.


5. The role of lab-developed tests in the in vitro diagnostics market. Pew Charitable Trusts https://www.pewtrusts.org/en/research-and-analysis/ reports/2021/10/the-role-of-lab-developed-tests-in-the-in-vitro-diagnostics- market. Published October 22, 2021. Accessed October 28, 2021.


6. Algeciras-Schimnich A., 2014. Tackling reagent lot-to-lot verification in the clinical laboratory. Clinical Laboratory News. https://www.aacc.org/ cln/articles/2014/july/bench-matters. Published July 1, 2014. Accessed October 28, 2021.


7. Keen R. 2019. ISO 9001 Checklist. ISO 9000 vs ISO 9001: What’s the differ- ence. https://www.iso-9001-checklist.co.uk/ISO-9000-vs-ISO-9001-whats- the-difference.htm. Published July 27, 2019. Accessed October 18, 2021].


8. Staveline A, Riksheim B, Christensen N, Sandberg S. The importance of reagent lot registration in external quality assurance/proficiency testing schemes. Clin Chem. 2016 May;62(5):708-15. clinchem.2015.247585.


doi: 10.1373/


9. User evaluation of between-reagent lot variation, 1st Edition. CLSI. https:// clsi.org/standards/products/method-evaluation/documents/ep26/. Published September 13, 2013. Accessed October 28, 2021.


10.CLSI’s Quality Management System Resources. CLSI. https://clsi.org/stan- dards/products/quality-management-systems/. Accessed November 5, 2021.


Rudra Maharajh, MBA, is Senior Global Product Manager for Clinical Mass Spectrometry and Automated Mass Spectrometry Solutions at PerkinElmer. Prior to PerkinElmer, Rudra held various positions at Sciex and other organizations within the fiber-optic telecommunication space.


Arvind Kothandaraman, MBS, is Managing Director of Specialty Diagnostics at PerkinElmer. Prior to PerkinElmer, Arvind held positions at Thermo Fisher Scientific, BioReference Laboratories and Advanced Analytical Technologies.


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