BEST PRACTICES ::QA/QC


Establishing expiry date for clinical diagnostic reagents


Alireza Ebrahim, PhD, Karl DeVore, BA, and Tim Fischer, MS P


roduct shelf life is an essential product performance require- ment that, along with other design


requirements, are used to determine the safety and efficacy of a clinical diagnos- tic reagent, whether they are made by a laboratory or commercially produced. Product shelf life can be determined following various domestic and inter- national guidance documents. In this article, we provide a high-level


overview of how product shelf life is de- termined and how accelerated stability studies can be used to estimate product shelf life. We also discuss some of the limitations and key considerations lab should consider before using an acceler- ated stability model to estimate shelf life for lab-developed reagents. The discussion also will help laboratory


employees understand how their suppliers determine the shelf life of products, which has the potential to impact test results.


Product expiration date Establishing the expiry date (expiration or shelf life) for in vitro diagnostic prod- ucts — such as reagent kits, calibrators, and quality controls — is a key quality and regulatory requirement for these products and is required by national and international regulatory agencies. Since laboratory developed tests (LDTs) may be subject to these design control requirements, laboratories also need to demonstrate that specified design requirements, such as shelf life and stability, are also met during the design verification process. (LDTs are assays that are intended for clinical use and are designed, manufactured, and used within a single laboratory.1


)


The expiration date shown on the product label, as well as the instructions for use (IFU), indicate that the product will perform as designed and was devel- oped to meet product design require- ments and user needs within the time period — from the manufacturing date to the expiration date (last day of use). There are several domestic and Eu- ropean standard and guidance docu- ments providing recommendations and direction on how to design and execute stability experiments to generate the necessary stability data, which could be used to establish shelf life at the recom- mended storage conditions for these products. For example, the Clinical and Laboratory Standards Institute (CLSI) documents for EP25-A2 and EN ISO 236403, provide guidance on the establish- ment and verification of shelf life stability claims for quantitative and qualitative in vitro diagnostic products. There are typically three questions that need to be answered for defining stability: 1) Which product characteristics/ metrics are considered key performance indicators? 2) What are the acceptance criteria or


changes for each characteristic/metric that can be tolerated? 3) What is the statistical confidence level required for analyzing stability results? Since each of these characteristics is different for various diagnostic reagents, it is not practical to provide a single pro- tocol that is appropriate for all diagnostic products. For example, the stability ac- ceptance criterion for a calibrator, quality control and a wash buffer of a reagent kit are very different and may vary from ±1% to ±20% of the initial value for the key measurement of these products. The appropriate sample size and statistical confidence level may also vary, depending on the intended use of the reagent. Appropriate statistical meth-


There are two methods for determining product expiration dates: real time stability studies and accelerated stability studies


36 JANUARY 2022 MLO-ONLINE.COM


odology (for example, detec- tion of outliers, determination of replicate runs, etc.) should be used to ensure that quality results are generated for shelf life stability determinations. Therefore, manufacturers of


diagnostic reagents, as well as laboratory professionals involved in development of reagents for LDTs, should establish standard operating procedures for performing stability studies consistent with guidance and standardization docu- ments, such as CLSI EP25-A and EN ISO 2346, and select and monitor physical, chemical, biological, or microbiological properties of the product in which their changes (for example, potency, activity, or concentration) impact the product shelf life and ultimately the safety and efficacy of the product.


Stability studies for shelf life determination


Expiry dates are assigned to in vitro diagnostic reagents, calibrators, quality controls, and other components by the manufacturer based on experimentally determined stability properties. Typi- cally, two approaches can be used to generate the stability data necessary to establish an expiration date for a diag- nostic reagent.


Real time stability studies can be done


by storing the reagent at its recommended storage temperature and regularly sam- pling and testing the reagent at defined timepoints and periods of time, typically 20% longer than the desired expiration date. For example, for a reagent with a desired shelf life of 1 year, the reagent may be tested weekly or monthly for 14 months (2 months past the desired shelf life). On the other hand, accelerated stability studies can be designed and performed at elevated temperatures compared to normal storage conditions for products, or the storage tem- perature on the product label, to observe changes in product performance, mainly stability, more rapidly than what would be seen under normal storage conditions. For example, a product with a storage temperature of 2-8°C, can be exposed to temperatures such as 35°C or 45°C to accelerate the degradation process. Since many diagnostic reagents have long shelf lives, in the order of 1 to 3 years, the shelf lives for these products are first es- timated with accelerated stability studies during the product development process, which usually take several weeks, and are later supported with real-time sta- bility studies that require several years.


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50