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Published: November 28, 2012
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A Modular Approach to Customizing IVD Instruments

By adopting a modular OEM approach, the rapid-test or private-label manufacturer can avoid investing in an R&D program that requires a time-to-market commitment.

By: Bernhard Gerstenecker, Michael Doumanas, and Klaus Haberstroh

Recently developed rapid tests provide significant improvements that increase the scope and reliability of these tests. The trend toward rapid tests that enable quantitative interpretation through an objective measurement creates market demand for

Figure 1: After an assay-specific method is completed, the accompanying file is downloaded to the reader.
Figure 1. After an assay-specific method is completed, the accompanying file is downloaded to the reader.

the development of corresponding reader systems and accompanying software. At the same time, rapid test manufacturers usually have neither the expertise in developing instrumentation nor the time and resources to start such a development from scratch. However, original equipment manufacturers (OEMs) offer solutions that are easily customizable, cost-effective, and available quickly.
Building a tailor-made instrument from scratch can be time consuming, expensive, and runs the risk of becoming an investment that fails to provide the highest return. It can easily take one to two years of work before a prototype instrument is available. Hardware and firmware, including the GUI and software, must be developed in accordance with the customer’s specifications. Necessary documentation must be prepared, which requires additional time and incurs additional costs. However, the time and costs prove to be worthwhile as the rapid test manufacturer receives a tailor-made instrument that’s market ready and that meets the users’ expectations.

Modular Customizing Approach

With a modular OEM approach, the rapid test manufacturer or private label manufacturer (PLM) benefits from the customization of an existing basic—i.e., generic—version of an instrument without risking investment in an R&D program requiring a time-to-market commitment.
Ideally, an instrument for processing rapid tests and its accompanying services should cover the following requirements, which translate into specific hardware (HW), firmware (FW), software (SW), and graphical user interface specifications (GUI).
1.    Flexible instrument programming by the PLM should be built in, enabling easy adaptation to various rapid tests (SW).
2.    The PLM should be able to purchase a tailor-made technological platform suitable for the many requirements of the PLM’s rapid tests (HW, SW, FW).
3.    Key corporate identity elements, such as corporate colors or the PLM’s corporate logo, must be visible on the instrument (HW).
4.    Reliable processing of rapid test readings—scanning, interpretation, reporting, and storing of the required data—is a vital part of the OEM solution (SW, FW).
5.    Connectivity is becoming an increasingly important requirement for a point-of-need (PON) instrument; corresponding interfaces must be included in the customized instrument (HW, FW).
6.    Documentation for the hardware and software must be provided with the instrument and must conform to legal requirements, including the appropriate (harmonized) standards.
7.    The instrument must be operable independent of a mains power supply (HW).
8.    The PON instrument must operate in stand-alone mode, i.e. independently of a PC (FW).
9.    The instrument should be portable and lightweight with a small footprint (HW).
10.    Lot-specific configuration should be introduced to the instrument at the user’s site by applying bar code or RFID technologies (HW, SW, FW, GUI).
11.    As the process owner, the PLM should have complete control over all aspects of the instrument (SW).
12.    The PLM must have a smooth transfer of the instrument from small-series to high-volume production (production transfer).
13.    The PLM must have high volume production potential at the OEM’s manufacturing site.
14.    The PLM requires reliable, long-term contracts as a basis for future business.

A Modular PON Solution

Qiagen’s ESEQuant Lateral Flow system is described here as an example of an up-to-date customizing solution for IVD instruments based on a modular approach. In 2010, Qiagen Lake Constance (formerly ESE GmbH) introduced an innovative modular PON lateral flow system, which is based on the requirements listed above. Several companies that develop rapid tests were involved in the specification of hardware and software and the subsequent validation of the various hardware and firmware prototypes. While the main hardware and firmware modules are generic and represent a consensus of customer needs, other features, such as corporate design elements, GUI, and the cassette holder, need to be customer-tailored during the design process.1
The rapid test manufacturer starts the customization process with a generic ESEQuant lateral flow reader and the corresponding software. The reader includes a generic GUI, which represents the consensus requirements of the rapid test

Figure 2. Flowchart of project management for a modular OEM approach.
Figure 2. Flowchart of project management for a modular OEM approach.

manufacturers who were involved in designing the workflow. The instrument is a fully functional device and includes important modules, such as a detector and mechanical parts taken from current serial production. The generic firmware is also fully developed. Use of components from serial production is the main benefit for the rapid test manufacturer.
The modular ESEQuant lateral flow system is an OEM business-to-business solution that enables rapid tests at the point of need. The system consists of the generic modules and customized components shown in Table I. The hardware of the main and basic component of the ESEQuant reader is strictly generic and enables immuno-chromatographic measurements at the PON. In addition to the reader, the system also comprises a software package for method development and data management and RFID/bar code technology.
The miniaturized detector is available in two basic variations, either for reflectometric measurements or fluorescence detection. While the reflectometric detector is generic, the fluorescence detector needs to be configured according to the fluorescence dye(s) used in the assay of the PLM. However, a set of off-the-shelf fluorescence detector configurations is available and allows R&D work to begin as early as possible.
In addition, the firmware controlling the reader’s basic functions is a generic module. As a starting point, the PLM starts the R&D work with a reader instrument containing a generic workflow. The GUI, which displays the workflow, provides features that represent the consensus requirements of IVD manufacturers. During establishment of the ESEQuant lateral flow system, several IVD manufacturers contributed their ideas and needs regarding the generic GUI. However, prior to the customization phase, the workflow provided by the GUI must be defined by the PLM. Usability requirements, human factors engineering issues, and risk management aspects need to be considered by the PLM for the design of an appropriate workflow.
The ESEQuant systems’ software module consists of Lateral Flow Studio software, which is strictly generic and serves as the reader development and management tool. On the other hand, end-user software solutions can be tailored to the specific requirements of the PLM, based on a standard version. Lateral Flow Studio software is a plug-and-play tool for R&D staff that enables generation of assay-specific method files, which contain all information and parameter settings to do the following:

1.    Introduce product name/article number and lot number of the test.
2.    Scan a given rapid test cassette after the defined incubation time.
3.    Identify reactivity in predefined areas—test line(s), control line(s).
4.    Process the data acquired from the scan.
5.    Calculate analyte concentration from a lot-specific
calibration curve.
6.    Interpret the test results using diagnostics.
7.    Report the diagnostic finding to the rapid test user.
After setting all necessary test parameters, the corresponding lot-specific assay method file is downloaded to the lateral flow reader.
Up to 15 bands per test strip can be processed independently, representing one parameter each. The PLM can choose from qualitative and quantitative interpretation of the assay based on various curve-fitting algorithms, such as four-parameter logistic function (Rodbard), logarithmic, exponential, or linear. In addition, the results of the different parameters on one test strip can be summarized in an overall result. The individual results, as well as the overall results, are displayed in the <REPORT> menu.

Table 1. The ESEQuant lateral flow system consists of the generic modules and customized components shown here.
Table I. The ESEQuant lateral flow system consists of the generic modules and customized components shown here.

During rapid test development, the lateral flow reader is connected to a PC via a USB interface. After completing an assay-specific method, the accompanying file is downloaded to the reader (Figure 1). The assay-specific instructions for the processing of a given rapid test are integrated into a corresponding section of the reader’s firmware. This allows the reader to work in stand-alone mode, independent of a computer and, because of its internal rechargeable power cells, also independent of an external power supply.
The reader can be updated while located at the user’s point-of-need site through 2-D bar code and RFID technologies (Figure 1). An assay- or lot-specific method file is generated and loaded into the Lateral Flow Explorer software. The PLM has to decide if only part of the information or the entire method information should be coded into the bar code or RFID chip for further processing. The coded information will be available either on the outer box label or, alternatively, as a label located directly on the test cassette. The integrity of data transfer is protected by checksums.
The PLM has full control of the lot-dependent assay method file. The entire information is protected from hacking or misuse by introducing the coded PLM name and/or the product name of a given assay.

Project Management for a Modular OEM Approach

Before discussing the details of a modular OEM approach, it’s important to clearly define the competencies and responsibilities of the co-operating parties, i.e., the OEM and the PLM.2
1. The OEM is the company that produces the finished device for a private label manufacturer but does not market the device under its name. By contrast, the private label manufacturer is considered the legal manufacturer of the device under the terms of medical device regulations in general because the OEM product is marketed under the name of the private label manufacturer.
2. The private label manufacturer is the OEM’s customer, who appears as the device manufacturer according to the Medical Device Directives (or legal manufacturer), but who doesn’t produce the device itself.
The project’s organization follows the procedure shown in the flowchart (Figure 2). Prior to starting an OEM project, the customer’s requirements are determined via a questionnaire. The main issues for the customizing process are:
1.    workflow, which is important for the graphical user interface;
2.    detector configuration;
3.    corporate colors of the instrument’s housing;
4.    corporate logo on the instrument’s housing and transport case.
The product requirements and needs of the PLM are translated by the OEM into functional product specifications. To ensure a streamlined and transparent project realization, it’s essential to fully define the customer’s needs at all levels. The requirements are documented in the OEM Development Agreement appendix, which is signed by the OEM and the PLM. In

Table 2. Types of technical documentation generated by the OEM.
Table II. Types of technical documentation generated by the OEM.

addition, milestone meetings for review of the project’s progress are scheduled.
Several iterative cycles of development activities and corresponding milestone reviews follow, leading to the realization of a prototype instrument that fulfills the customer’s needs. Formal verification of the prototype features against the customer’s requirements is performed by the OEM; the results are documented and the prototype instrument is released. It’s supplied to the PLM for subsequent validation under routine conditions for its intended application. The PLM is responsible for the validation processes; after successful validation, the prototype must be formally released in written form by the PLM for serial production.
After the PLM releases the prototype, a Supply Agreement is established regulating all aspects of postdevelopment activities and serial production, such as lead times, pricing, warranty, (minimal) order volume, or servicing. A quality plan will be established at the request of the customer, which describes the rights and responsibilities of the OEM and PLM, especially if an IVD medical device is being developed. The quality plan is of particular importance: it guarantees competent authorities or government agencies access to the technical documentation of the lateral flow reader that’s protected by the OEM’s intellectual property (IP).

Regulatory Aspects

Manufacturers of all classes of IVD medical devices must demonstrate conformity of the device with the “Essential Principles of Safety and Performance of Medical Devices.” Technical documentation needs to be prepared that explains how the device’s development, manufacturing, labeling, and marketing processes comply with these principles.
The Global Harmonization Task Force (GHTF) published several guidelines aimed at establishing globally harmonized standards on:
1. principle classification of in vitro diagnostic medical devices;3
2.    labeling of medical devices;4
3.    Summary Technical Documentation for Demonstrating Conformity to the Essential Principles of Safety and Performance of Medical Devices;5
4.    Principles of Conformity Assessment for In vitro Diagnostic Medical Devices6
5.    Essential Principles of Safety and Performance of Medical Devices7
Of particular interest to the OEM business is the GHTF standard GHTF/SG1/N011: 2008 of the Summary Technical Documentation. The OEM must generate technical documentation, the types of which are addressed in a highlighted section in Table II. The required content is relatively generic from a global point of view; however, specific requirements related to the national medical device law of a given country need to be considered, as well.
It’s the PLM’s responsibility to prepare the technical documentation of the customized lateral flow reader. But given the OEM’s knowledge and experience, it must support the PLM by preparing the documentation. However, the technical documentation requires information about the manufacturer, which includes the OEM’s protected IP. Therefore, the OEM prepares a detailed version of the technical documentation that contains this sensitive information. To allow government overview, a quality plan is implemented as described above.
The modular approach to customization of IVD instruments is beneficial to the PLM from the regulatory point of view. Apart from fluorescence detectors, the lateral flow reader hardware and the main parts of the firmware are generic; the corresponding technical documentation sections for the hardware and firmware are also generic, including design and manufacturing information, essential principles checklist, risk analysis, control summary, and product verification and validation. The firmware’s documentation covers the European Safety Class C and FDA’s High Level of Concern, allowing the PLM to use the customized reader for even the highest safety class rapid tests.
The advantage of this modular approach is that only the GUI, which represents the most important customized part of the instrument, needs to be introduced into the technical documentation individually and PLM-wise. While the OEM exclusively focuses on the verification description and the GUI validation processes, the PLM must address aspects around human factors engineering of the GUI and perform a formal risk analysis.

References

1. I Macfarlane, F Davis, “Building blocks for the point-of-care boom,” IVD Technology, January 2002.
2. ZLG/EK-Med Answers and Resolutions, “Conformity Assessment – Certification of OEM Devices,” 2007. Available online at http://www.tuvps.co.uk/uploads/images/1281516789545136220477/ZLG%20EKmed....
3. Global Harmonization Task Force, “Principles of In vitro Diagnostic Medical Devices Classification,” SG1-N45: 2008.
4. Global Harmonization Task Force, “Labeling for Medical Devices,” SG1-N43: 2005.
5. Global Harmonization Task Force, “Summary Technical Documentation (STED) for Demonstrating Conformity to the Essential Principles of Safety and Performance of In vitro Diagnostic Medical Devices,” SG1-N63: 2011.
6. Global Harmonization Task Force, “Principles of Conformity Assessment for In vitro Diagnostic Medical Devices,” SG1-N46: 2008.
7. Global Harmonization Task Force, “Essential Principles of Safety & Performance of Medical Devices,” SG1-N41: 2005.

Bernhard Gerstenecker, PhD, is senior scientist, head of the application laboratory, and responsible for market development PON instrumentation at Qiagen. He can be reached at bernhard.
gerstenecker@qiagen.com.

Michael Doumanas (MBA) is associate director strategic alliances & OEM PON global sales at Qiagen. He can be reached at michael.doumanas@qiagen.com.

Klaus Haberstroh is senior director and head of PON instrumentation at Qiagen. He can be reached at klaus.haberstroh@qiagen.com.


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