EFLM WG-Preanalytical phase opinion paper: local validation of blood collection tubes in clinical laboratories

Introduction

Preanalytical variability plays a crucial role in laboratory diagnostics [1]. Several lines of evidence, accumulated over the past decades, attest that most errors throughout the testing process emerge from manually intensive activities related to collection and management of biological samples [2]. The use of high quality blood collection devices is an aspect of utmost importance in routine laboratory practice, wherein inappropriate or even different sample containers may be a source of preanalytical bias, which can ultimately impact results of testing both in clinical and research settings [3]. It is also noteworthy that both the International Organization for Standardization (ISO) 9001:2008 and the ISO 15189:2012 certification and accreditation procedures include standards encompassing all laboratory activities, including preanalytical procedures, which should be standardized and monitored according to evidence-based practices.

Despite accumulating evidence about preanalytical quality assurance, selection and procurement of blood collection devices in healthcare facilities is often an underestimated issue. National, regional and local tenders are frequently plagued by policies, guided primarily by the price rather than by quality of devices. This is probably due to different factors, including the lack of knowledge of policymakers, hospital administrators and even laboratory managers about the importance of preanalytical quality and the phlebotomy process, as well as to the absence of reliable guidelines or recommendations on how to precisely assess the quality of blood collection devices around the globe.

Validation studies are crucial activities for generating reliable evidence that a novel instrument, method, reagent or device is fit for purpose and satisfies the particular requirements for its specific intended use [4]. In 2010, the Clinical and Laboratory Standards Institute (CLSI) released a specific GP-34A guideline, aiming to detail the procedures for validation and verification of tubes for venous or capillary blood specimen collection [5]. However, this document is mainly orientated towards validation of blood collection tubes from a manufacturer’s perspective to ensure that design goals and performance claims are met. With the awareness that a gap remains between manufacturers validation and clinical laboratories implementation, the Working Group for Preanalytical Phase (WG-PRE) of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) has drafted the present consensus document, which aims to provide a set of simple elements and criteria specifically for laboratory professionals, to verify whether the introduction of new blood collection tubes in clinical laboratories fulfills basic criteria of technical and clinical acceptability.

Operative definitions

In agreement with the CLSI guideline GP-34A [5], the “comparative tube” is defined as the blood collection tube currently used by the clinical laboratory, the “control tube” is defined as the blood collection tube that is to be introduced and replace the current. The “desirable quality specifications for bias” are conventionally derived from biological variation. The “validation” is finally defined according to the current ISO 9000:2005 specifications [6], as “confirmation, through the provision of objective evidence that the main requirements for a specific intended use or application have been fulfilled”.

Essential requisite for purchasing blood collection devices

Blood collection systems are considered as integrated in vitro diagnostic (IVD) medical devices and are thereby regulated by a number of national and supranational bodies and organizations such as the European Community (EC) or the US Food and Drug Administration (FDA) [7]. A key characteristic, highlighted by virtually all regulatory documents, is that the whole blood collection device (i.e. safety needle, butterfly needle, holder and blood tube) must be regarded as an integrated system. Therefore, the combination of the different parts must be safe and should not impair the performance of the individual components [8]. Manufacturers are responsible for assuring the full compatibility between the components of the system, to subside the risk of impairing the quality of testing and jeopardizing (both operator and patient) safety. Importantly, tenders allowing acquisition of devices from different manufacturers may end up with combinations that are not validated for clinical use. The manufacturers themselves also typically include specific claims in their product datasheets, stating that “devices (needles, single-use holders, safety devices) are designed to be used as a system of products, and the integration of other manufacturer’s products is solely the responsibility of the user”. However, according to the EFLM WG-PRE, it is outside the role and duty of laboratory professionals to perform a thoughtful validation study to establish whether or not an integrated system is safe and does not impair the quality of testing. Therefore, the possibility of using separate parts of the blood collection system obtained or purchased from different manufacturers is strongly discouraged by the EFLM WG-PRE except when the integration has been previously validated by the manufacturer(s) or by national or supranational regulation bodies.

Apart from research and development, tube manufacturers should be able to also demonstrate usability studies of their products following study subject recruitment according to Good Clinical Practice/International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (GCP/IHC) guidelines and independent Ethical Committee requests. Demonstration of ease of use, sustained plasma quality, perceived value compared to the comparative devices and potential performance risk should be included. User (named sites) feedback on collection, transport (foot, pneumatic tube, courier, etc.), reception and analysis results are especially valuable. The tubes/devices should also be analyzed by the manufacturer in different clinical settings, on major instrument platforms and investigated for potential test result bias and/or imprecision of analytes especially where this may be important for clinical decision making, including serum indices and analytes with known instability over time. The reasons for failures including missing and excluded data should be stated. For new suppliers evidence of factory capacity over time should also be supplied. The EFLM WG-PRE does however, also recommend that a laboratory performs a local validation of all new blood collection tubes (i.e. control tubes) estimating the potential bias and imprecision of test results compared to the previously used material (i.e. comparative tubes) to verify the manufactures claims. This approach has been proven by the constantly growing number of studies in all areas of diagnostic testing [9], [10], [11], [12], including molecular biology [13], [14].

The costs attributable to using an appropriate number of tubes for a local validation (as described in the following parts of this article) should be charged to the manufacturers participating in the tender. More specifically, the details of the validation process should be included in the tender specification, with a specific request to the manufacturers to supplement the laboratory with a number of tubes and cost of reagents that is sufficient to complete each part of the validation. Consideration should also be given to the process of submitting the validation to an Ethical committee and/or Institutional review board for approval (as for CLSI recommendations) [5]. Last but not least, the commission of a tender for purchasing blood collection devices should always include not less than one laboratory professional among the members (Table 1).

Validation of blood tubes

In the following sections of this article, the EFLM WG-PRE suggest a consensus protocol and some pertinent indicators that may be used for the local validation, both technical and clinical, of new (i.e. “control”) blood collection tubes, to be compared with the current system in use by the same laboratory (i.e. “comparative” blood tubes).

Conclusions

The validation of new laboratory equipment, instrumentation, methods and IVD devices by manufacturers and local users is a necessary part of clinical laboratory accreditation. Failure to comply with good manufacturing or good laboratory practices may have adverse consequences on operator and patient safety. Several lines of evidence now attest that the implementation of new blood collection devices, including blood tubes, may modify local practices and also influence the measured concentration of the analytes. Indeed, the selection and acquisition of systems for blood collection should be considered a critical aspect for assuring quality, safety and efficiency of the preanalytical phase of laboratory diagnostics and, therefore, of total testing process. This issue is expected to become even more important as long as innovative molecular biomarkers make it through the translational process, and are introduced into routine clinical practice [20], [21], as this emerging arena is particularly vulnerable to preanalytical issues [22], [23], [24].

Although the CLSI document GP34-A is an useful tool for verifying tubes for venous and capillary blood drawing, the real impact of blood collection tubes on local quality and safety of testing is often overlooked, and laboratory professionals often fail to recognize the need to accurately assess the reliability of new devices or perform continuous monitoring of ongoing performance [25]. Due to the fact that it is unfeasible for manufacturers to establish the impact of their devices on all instruments and reagents, the EFLM WG-PRE has drafted this consensus document with the aim of supporting laboratory professionals planning blood collection tube tenders and validating the devices before routine implementation. The laboratory professionals should also make sure that the tenders accurately and strictly define the responsibilities for validation experiments and the potential consequences in the case the validation outcome shows that tubes due not fulfill the expectations.