by Hayden Skalski
Data integrity is of the utmost importance when testing and analyzing products and devices in the Quality Control (QC) laboratory. In an increasingly automated world, demands are also rising in the pharmaceutical and medical device industries for automated technologies. More often than not, newer technologies for QC testing in these industries come with better compliance to the regulations and features that make compliant testing easier for the analyst. It is vital to have instrumentation and products in QC labs that meet 21 CFR Part 11 compliance and remove the potential for human error by reducing steps which require analyst time. By removing some or the majority of hands-on time by an analyst, labs can further ensure that fewer errors will happen. And fewer errors mean fewer retests and better compliance.
Traditional bacterial endotoxins testing (BET) methods, including gel-clot assays and 96-well plates, are very manual and labor intensive. They require hours of training, excellent analyst technique, and fine attention to detail. Kinetic chromogenic and turbidimetric 96-well plate methods offer a step in the right direction in terms of moving towards a more automated assay with better data integrity compliance and quantitative results. However, even these more modern methods still leave ample room for improvement. Plate readers perform endotoxin analysis over time by measuring optical density or turbidity and returning the analysis to an endotoxin software platform. Human errors for these methods will be detected via the software/data analysis compared to gel clot. While kinetic chromogenic and turbidimetric technologies automate certain aspects of the assay, most platforms still rely on the lab analyst to manually create a standard curve, create a positive product control (PPC) for each sample in duplicate, and also add Limulus amoebocyte lysate (LAL) to each well. Standard curves are created for each assay, which means they are subject to analyst preparation and will have variability with each creation. Since endotoxin assays run on an inverse relationship between samples and the standard curve (meaning the amount of endotoxin recovered in a sample is back calculated to the standard curve), it is imperative to have an accurate curve each time.
Manual preparation of each standard curve presents the risk of generating a standard curve that is either too potent or too weak. This often comes down to simple dilution or pipetting errors by the analyst. Generating an overly potent curve will underestimate the amount of endotoxin that could potentially be in a product, giving a false negative result. On the contrary, generating a weak standard curve will overestimate endotoxin in a product, giving a false positive.
Implementing newer technologies and innovative products into QC labs can help further promote a company’s commitment to patient safety if the technologies are designed with the latest data integrity guidelines at the forefront. For example, kinetic chromogenic methods can be improved with technologies that reduce human error and offer more robust software. The Sievers Eclipse BET analyzer and microplate drastically reduce analyst hands-on time and decrease the potential for error, which in turn improves compliance. Each microplate has embedded Reference Standard Endotoxin (RSE) standards ranging from 50-0.005 EU/mL in triplicate and removes the variability of analysts having to generate a curve. PPCs are also embedded in duplicate, so analysts do not have to spike each product individually. The Eclipse is fully compliant with USP <85>, EP 2.6.14 and JP 4.01, while simultaneously checking each box for 21 CFR Part 11 compliance. Compared to traditional plate assays for 21 samples, the pipetting steps are reduced from 242 to less than 30. This reduces the risk for human error in pipetting mistakes, reduces the risk for repetitive injury, and decreases the time spent executing the test.
By removing so many aspects of human intervention, QC technologies can drastically improve data integrity. Software is also a major factor. The Eclipse software for endotoxin analysis offers a full 21 CFR Part 11 data integrity compliant package that includes ALCOA+ principles to help adhere to those guidelines. When an assay is running, it transmits data to the software every five seconds, so an analyst can check assay progress frequently throughout the test to analyze data in real time. The software also has a routine database backup and restore function, ensuring data will not be lost. If a disaster occurred or the system unexpectedly lost power, all data would be maintained in the secured database.
All aspects of data integrity in quality control testing – including bioburden, conductivity, TOC, and endotoxin – must be thoroughly thought through with patient safety at the forefront. If testing is compromised due to violations of data integrity, this puts the patient at risk. Pharma 4.0 is a great example of how integrating lab instrumentation with system software and connecting different testing platforms improves the effectiveness of lab analysts and makes their day-to-day lives easier. The concept of Pharma 4.0 ties in directly with data integrity by monitoring QC testing in real time and alerting the lab of errors or out-of-specification results.
Obtaining results in real time and being notified of failing tests allows the lab to act more promptly to address the error or failure and get to the root cause (taking the ‘right the first time’ approach) prior to completion of testing. Overall, this will reduce lead times and allow labs to get results faster and release product to market more efficiently. Platforms that offer integrated instrumentation and software, such as Sievers Instruments in the QC lab, provide an excellent starting point for achieving a Pharma 4.0 environment by incorporating more efficient and compliant testing solutions. These advancements in instrumentation for endotoxin, bioburden, TOC, and conductivity not only improve the quality of products and daily work lives of lab analysts, but ultimately the patient.
Author bio
Hayden Skalski is the Life Sciences Product Application Specialist for the Sievers Instruments product line, specializing in bacterial endotoxins testing (BET). Hayden has over 8 years of experience in the pharmaceutical industry and Quality Control Microbiology and has presented on numerous topics surrounding endotoxin testing.
Previously, Hayden held roles at Charles River Laboratories, Regeneron and Novartis, validating and executing method development protocols for endotoxin testing, providing customer support, troubleshooting and supporting high-volume product testing. Hayden has a B.S. from the University at Albany (SUNY) in Biology.
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