CLINICAL ISSUES :: CONTROLS AND REAGENTS
Controls and reagents as the ‘X-Factor’ in modern labs
By Rudra Maharajh, MBA, and Arvind Kothandaraman, MBS D
iscussions of laboratory innovations are oftentimes focused on automation and the other advanced technologies that optimize and accelerate the work of scientists. Controls
and reagents, however, play an equally important role – if not more so – in the modern clinical lab. Every researcher will tell you a story of the time that “one bad apple ruined the barrel.” While the so-called bad apples can take many forms (prac- tices, procedures and so on), failing controls and reagents are sometimes the hardest and costliest to identify wasting time and resources for products that should arrive with implicit trust in quality.1 Researchers have well characterized the impacts of inferior
materials when used in development activities for biopharma- ceuticals, which at this point are well understood processes.2 Now imagine the impact of poor-quality controls or reagents when used in post-development activities such as those found in the clinical laboratory setting, especially those involving new or emerging technologies like multi-quadrupole ICP-MS (Inductively coupled Mass Spectrometry). If you don’t know what a good result looks like, how do you know when you have a bad result? Here, the importance of being able to trust your controls and reagents is amplified significantly.
Controlling the controls and rating the reagents Finding a trusted controls provider may be less intimidating than finding a reagents provider, as there are several estab- lished brands that have become the de-facto standard for most applications. However, the search for full reagent kits becomes more complicated as there are vendors that offer products for sale with unknown quality, untraceable source materials. and potentially suspect manufacturing processes. Even within regu- lated markets, we cannot always be sure of ongoing quality: a quick search of the U.S. Food and Drug Administration’s (FDA) Medical Device Recalls database shows multiple reagents recalls every year. In these regulated environments, how do we ensure that we are acquiring the highest quality products possible?
Gibson (2019) points out that sourcing reagents from Good Manufacturing Practice (GMP) facilities “ensures a standard that minimizes variation during assay or drug development and, ultimately, an introduction into the clinical setting. (GMP) covers all aspects of production, including the location, starting resources, equipment and staff training.”3 Now consider the largely unregulated world of research use
only (RUO) reagents. These RUO reagents are often used in sce- narios where labs choose to develop and validate-for-purpose their own internally lab developed tests (LDTs). According to the FDA (2018), “While the uses of an LDT are often the same as the uses of FDA-cleared or approved in vitro diagnostic tests, some labs may choose to offer their own test.” The FDA also notes that accurate in vitro diagnostic tests ensure that “patients and healthcare providers do not seek unnecessary treatments, delay needed treatments, or become exposed to inappropriate therapies.”4 As we move to new technologies and new approaches to
clinical testing, such as mass spectrometry, LDTs may become more common,5
causing the impact that reagent quality has
on test results to become more pronounced. However, the regulations surrounding LDTs don’t mirror
those of FDA-approved tests, even though they may be used in similar situations: “As LDTs have grown in use and com- plexity, FDA regulations have not kept pace. Instead, LDTs are principally regulated by CMS (the Centers for Medicare & Medicaid Services) under separate regulations known as Clinical Laboratory Improvement Amendments (CLIA). CLIA oversight focuses on laboratory operations and staff training but does not assess the validity of individual tests in a lab”5 Inaccuracies in LDTs may be caused by invalid/incomplete methodologies but can equally be caused by poor-quality reagents or controls.6 As is the case with regulated reagents, manufacturing facili-
ties that operate under GMP and carry a minimum of ISO:9001 certifications are important thresholds for maintaining quality for reagents used in LDTs. Because standards such as ISO:9001 require continuous review and both internal and external audits, confidence in suppliers holding such certifications is increased.7 As we move to clinical testing in which LTDs may become
more common — and explore the use of more and more sensitive analytical techniques and instrumentation, such as multi-quad- rupole ICP-MS systems that offer PPT levels of sensitivity— it becomes increasingly important that we source our reagents from sources that treat RUO reagents with a high level of care.
Ensuring quality over time How do we establish the quality of sourced reagents? Do we head to Google and put our faith in the first reagent manu- facturer that appears in the search results? Do we phone a friend, or perhaps rely on past experiences? Compounding this conundrum is the knowledge that as we move forward with new and emerging technologies, the list of references and experi- ences can shorten significantly. The first step: establishing initial trust in a vendor. To do so, labs should implement both
Poor quality in reagents or controls can impact test results 28 DECEMBER 2021
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