A step-by-step approach may simplify the task of preparing technical documentation.
Despite the efforts of the European Device Manufacturers Association (EDMA; Brussels) and other European organizations to help clarify the most obscure requirements of the IVD Directive, several ambiguous portions still remain. In particular, the process involved in preparing proper technical documentation (TD) is not well defined, yet forms a fundamental step in the path toward applying for the CE mark.1
The term technical documentation has no formal definition in any of the IVD medical device directives or other European Union (EU) documents. However, IVD manufacturers are provided with direction in the Guide to the Implementation of Directives Based on the New Approach and the Global Approach, which states:
“The Technical Documentation is intended to provide information on the design, manufacture, and operation of the product. New Approach directives oblige the manufacturer to draw up technical documentation containing information to demonstrate the conformity of the product to the applicable requirements.” 2
Thus, in the TD, an IVD manufacturer should provide all information necessary to demonstrate its conformity with the IVD Directive. In addition, a manufacturer should provide data that is sufficient to demonstrate that the device will perform safely, and achieve the stated performance claims for its intended use.
While creating its TD, a manufacturer may find itself faced with the analysis and organization of a vast amount of complex information. The Coordination of Notified Bodies Medical Devices (NB-MED; Brussels) attempts to address this problem by proposing that the TD be divided into two parts.3 The first part should summarize the essential technical data that will be most useful in the conformity assessment procedures, and the second should contain more-detailed and comprehensive information.
The IVD Directive does not provide a formally approved or even a suggested format for a technical file. Each IVD manufacturer must determine and document the rationale for the content and format of its TD. The TD must be part of the manufacturer’s quality system and should be handled as a quality document. Thus, a suitable procedure for controlling and keeping the TD up to date must be established and described in the TD. The TD must also include a description of all record-retention policies. IVD manufacturers should also account for where the TD will be stored and how its various components will be maintained.
When deciding how to organize information in the TD, IVD manufacturers should consider that the documents may be submitted to a notified body, will be subject to internal data management, and must be made available to the competent authority, upon request. As a result, full traceability, from each IVD Directive requirement to an approved standard, must be clearly documented in the TD, not only for self-certification by a manufacturer, but also in case of third-party inspection.
This article will summarize all of the requirements stated in Annex III, section 2, of the IVD Directive, with the intent of providing the best possible interpretation and approach to fulfilling those requirements. This information should be useful both for companies that have not yet completed their TD and for those who want to modify their completed TD to avoid additional work that may be required if they are asked to submit their TD for review by the competent authorities.
|Figure 1. Manufacturers may use a grid format to list relevant essential requirements from the IVD Directive, the measures taken to meet these requirements, and the standards employed. Click to enlarge.|
Providing a general description of the product in the TD should not prove to be difficult. Manufacturers can satisfy this requirement by using the product’s instructions for use. However, the directive also requires that manufacturers describe all planned variants of an IVD. This requirement originated from Directive 93/42/EEC, and has been very difficult to interpret.4
In particular, no clarification has been given on what is meant by “variation,” or for how far the planning should have progressed for its mention in the TD to be required. When manufacturers have elected to follow the compliance process outlined in Annexes IV and V, they should discuss and agree on a common interpretation of this requirement with their notified body, and should do so early in the process of creating the TD.
When following the compliance process described in Annex III, IVD manufacturers may interpret the requirement for describing variants of their products on their own. Generally any decision they make will be acceptable when supported by a strong rationale.
When, in accordance with the last paragraph of Annex I, section 8.1, no instructions for use are provided with the finished device, a general description of the product should be kept on hand and made available upon request. Identifying key information that will provide a clear classification of the product and allow anyone who reads the TD to place the device into its appropriate context will simplify the process of meeting this requirement. Providing such information in the opening of the TD will prove useful if a notified body will be involved in reviewing the TD. In the case of a reportable incident, the competent authority will be able to quickly determine whether the instrument design or production had any relevance to the incident.
Design Information. The IVD Directive requires that IVD manufacturers include information on the design of their devices in the TD. The directive states:
Design information, including the determination of the characteristics of the basic materials, characteristics and limitation of the performance of the devices, methods of manufacture and, in cases of instruments, design, drawings, diagrams of components, sub-assemblies, circuits, etc. [should be described in the TD].
In Annex III, section 3, of the directive, product design is referred to repeatedly, despite the fact that a design dossier is not specifically required. However, in section 4.1 of Annex IV, the manufacturer is asked to submit to its chosen notified body “an application for examination of the design dossier relating to the device,” thereby requiring the creation and submission of a design dossier.
To fulfill this requirement, an IVD manufacturer should describe how its device has been designed, how it has been manufactured, and how it should perform. A selection of relevant documents should be extracted from the TD and included in the design dossier to enable the notified body to assess whether or not the device under consideration conforms to all pertinent design requirements of the directive.
Supplementary Descriptions. The IVD Directive requires that, when necessary, manufacturers provide descriptions and explanations that will be of use in understanding the functional characteristics of their devices. This information can take the form of drawings and diagrams that depict the operation of the device. Although this requirement appears to be very simple to fulfill, it is almost impossible to meet before consulting with a notified body or competent authority.
It is difficult to predict what description and explanation will meet the needs of the notified body or competent authority. Nevertheless, the type of information contained in a marketing brochure should be adequate for competent authorities to get a feel for the analyte detected and the technology employed. Ease of comprehension is a key concept in designing the TD. Not only for use in third-party expert review, but also as a common rule, the TD must be understandable, and all the information should be easily retrievable.
Quality System Documentation. Documenting the quality system should be a fairly easy task for any manufacturer that has a quality system in place that complies with an applicable standard like ISO 9000.5 However, such a quality system must be improved to satisfy the additional requirements of the directive.
Quality system TD generally includes the quality manual; the standard operational procedures; and the quality records (e.g., quality control data, production data, complaint-handling records, incident reporting, and field corrective actions). Manufacturers should make sure that quality records are placed under the control of one person who is responsible for carrying out quality-system-related activities, so that these records will be continually updated and modified, when necessary.
Characteristics of the Device
The processes involved in creating several features of an IVD must be clearly and thoroughly accounted for in the TD.
Sterilization. If procedures have been used to sterilize products, or to force them to maintain a microbiological state or state of cleanliness, then these procedures must be described in the TD. However, such documentation is only required when the labeling, instructions, or intended use of the product require or claim a specified state of cleanliness. Most IVDs are not claimed by their manufacturers to be sterile, with the exception of IVD systems that use culture media for microbiology. These systems are addressed in EN 12322: 1999/A1:2001.6
Controlled microbial conditions during manufacturing are commonly adopted to prevent the deterioration of active principle due to bacterial contamination. In addition, preservatives are widely used to prevent deterioration of the product after it has been opened. Manufacturers should note that documentation of these procedures is not required by the IVD Directive, unless the manufacturer wants to describe these conditions on the labeling or instructions for use. The specified microbiological state should be defined according to a harmonized norm that has been mandated for this purpose by the European Commission.
Substances of Human Origin. Under the IVD Directive, manufacturers of IVDs that incorporate human tissue or substances derived from such tissue into their devices must document both the origin of such tissue and the conditions under which it was collected. Manufacturers of recently developed products should be able to meet this requirement with ease. In fact, European importation rules for raw materials of human origin already require this information.
Creating documentation for older products that use human reagents that were characterized when such rules were not in force might be more problematic. In this case, manufacturers should create a declaration listing all available information concerning the material, including how it was originally selected and validated.7
Combination Devices. When manufacturers produce IVDs that are designed to work in combination with other devices, evidence must be provided demonstrating that when in combination with those other devices, the original device maintains specific performance characteristics. Although not specifically required by the directive, manufacturers of such combination devices should specify, by name and manufacturer, which product, reagent, or component should be paired with its device.
For example, if an instrument from one manufacturer should be used with reagents from another, then the instrument manufacturer’s TD must demonstrate compliance with each essential requirement for this combination of instrument and reagents. In addition, each claim included in the information for the user must be supported in the TD with data demonstrating the reliability of the claim.
Instructions for Use. Consumer information accompanying an IVD is subject to the same documentation control as any other quality document. Therefore, evidence that a system is in place through which the manufacturer will keep it up-to-date is implicitly required.
The latest revision of these documents should be made available upon request. During transposition, each member state will specify whether the labeling and instructions must include the local language of the state.
Annex I, section 8.3, requires that, in the case of devices containing dangerous substances, manufacturers must follow the labeling requirements of Directives 67/548/EEC and 88/379/EEC. These directives mandate that, when applicable, danger symbols must be applied to the labels. In addition, risk and safety statements must be translated into each local language that will be included in the instructions for use. Safety data sheets must also be included in the TD, and should be made available as a separate document, and eventually be included in the instructions for use.
Careful documentation of every examination and test involved in the design and manufacture of the IVD must be included in the TD.
Risk Analysis. Manufacturers must include in the TD the results of their risk analysis as well as a list of the standards from Article V of the directive that have been applied in the analysis. In the case that a standard does not exist or has not been used in full, each solution adopted for meeting the essential requirements must also be described in the TD.
When a risk analysis is carried out following standard EN 1441, a fairly long list of risks may be generated, depending on the complexity of the device.8 This list should be coupled with a list of countermeasures that have been or will be implemented when necessary. Manufacturers should note that after March 2004, it will be mandatory to follow the new standard for risk analysis, EN ISO 14971:2001.9
When a formal request for a review of the risk analysis has been sent by the competent authorities, they may decide that it will be adequate for manufacturers to merely present a declaration stating that the risk analysis has been performed. This declaration should include a summary of the tests carried out to establish the levels of the initial risks, the actions taken to reduce them, and the residual risk after countermeasures have been implemented.
The risk analysis is becoming an increasingly important resource used to support decisions concerning the device, both in Europe and elsewhere. With every modification to an IVD, its manufacturer should take into account the impact the modification could have on the initial risk analysis.
The risk analysis should be considered a dynamic document, reflecting all changes and new information generated once the device is placed on the market. The risk analysis should be used not only as a test of the finished device, but more importantly, as a vehicle for the collection of information related to the future development or improvement of similar products.
For devices that have been on the market for more than three years as of June 7, 2003, risk evaluations can be based on a complaint analysis. In this scenario, the device manufacturer should demonstrate that its complaint-handling system has been able to collect all relevant information arising from the experience of the device on the market.
If manufacturers choose to use a complaint analysis, the risk analysis should include statements regarding the history of the product on the market, including numbers of lots or kits released. Moreover, the ratio of the number of products that have received complaints to the total number of products distributed should be calculated and divided into complaint categories.
The categorization of complaints is an important step that should be followed by a classification of the risks identified by these complaints. Rationale should then be presented to support the fact that the potential risks that have been identified are acceptable. However, if the risks are not acceptable, the countermeasures that have been adopted to reduce them should be described and the acceptability of the residual risk should be documented.
Inspections. An additional area of documentation that manufacturers must cover is the results from the product design calculations and inspections of their product. In addition, the reasoning behind the selection of algorithms or methods used to conduct the inspections and formulate the design must be explained.
The design dossier of all Annex II, list A products must be presented to a notified body for inspection. Although the directive does not specify what should be contained in the design dossier, a notified-body inspector should be able to use the contents to assess whether the device conforms to each relevant and applicable design requirement of the directive.
One schematic approach to organizing the design dossier is to identify all sources that contributed to the design, whether they are the results of marketing analysis, R&D concepts, or manufacturing or regulatory constraints. All data that describe the fulfillment of each design input should then be documented, and the resulting design component should be described (e.g., claims in the instructions for use, product stability, performance characteristics, etc.).
Stability Studies. Obtaining the results of stability studies for older products could be a difficult task for manufacturers. The track record of these devices on the market cannot be used as evidence of their shelf life. Instead, the results of stability estimation from accelerated testing as well as experience gained with similar IVD reagents will be acceptable when included in the TD.
A reliable resource for stability testing recommendations is the “Stability testing of in vitro diagnostic reagents,” a standard in which statistical methods are described.10 Real-time testing is recommended, as accelerated stability testing does not always mimic the actual behavior of the device.
Manufacturers would be wise to perform multiple stability tests. In addition to performing stability tests that guarantee the performance of a device stored under ideal conditions, real-life conditions of the product, under both shipping and actual-use conditions, should be taken into account and examined.
Final Testing. All reports on internal and external testing of IVDs in their final, commercialized form must be included in the TD. These reports should include all research and development reports, quality control data, in-house testing, and verification testing of all performance characteristics that will be applicable to the finished device.
Some components of the TD are requirements that are particularly unique to the EU. Documentation of traceability and translation into multiple languages may prove to be new and daunting tasks for IVD manufacturers outside of the EU and within the EU alike.
Presenting Standards. In their TD, manufacturers must present a list of harmonized European standards that have been voluntarily selected and applied to fulfill the essential requirements of the IVD Directive. IVD manufacturers must demonstrate that the measurements, components, design, and performance of their product can be traced to these preexisting approved standards (see Figure 1). These standards have been specifically mandated by the European Commission and are, or will be, published in the Official Journal of the European Union. The standards are meant to support the essential requirements of the directive.
As an alternative to the EU’s harmonized standards, manufacturers may use the standards issued by the International Organization for Standardization (ISO; Geneva), those published by the National Committee for Clinical Laboratory Standards (NCCLS; Wayne, PA), FDA guidance, or the Common Technical Specifications (CTS). If a manufacturer has applied recognized standards, no further description (other than data demonstrating compliance with the respective standard) must be documented.
If a standard has not been applied, then the TD must include data demonstrating that the chosen procedure has been validated, and that its reliability is comparable to that of the standard, when one exists.
Each harmonized European standard contains an Annex ZA (informative). This annex contains supplementary information, and various clauses, which can be used as guidance for meeting traceability requirements. These clauses are intended to support requirements of the IVD Directive, but are not intended to be exhaustive, as other requirements may be applicable.
Reference Methods. The directive requires that IVD manufacturers include data sufficient to demonstrate that their devices meet the performance claims made in the TD. This performance evaluation data should be supported by a reference measurement system, when one is available.
Evidence used in the study that has been drawn from available literature, e.g., for normal ranges, should be critically validated in the study, and the validation should be documented. EN 13612 can aid manufacturers in fulfilling this requirement, because the standard defines the responsibilities of each entity that is involved in a performance evaluation study.11
The planning of the evaluation study should be documented in the TD. Once the experimental portion of the study has been completed, a report that includes a well-developed conclusion should to be written.
The calibration of any commercial test system should be traceable to a reference measurement system. In addition, the manufacturer’s in-house testing method must itself be traceable to a system of higher order, when available.
Full documentation of this traceability is an essential component of the TD. The documentation should include information on the reference methods and materials, known reference values, accuracy, and unit(s) of measurement.
When a reference method is not available, the guidance in prEN ISO 17511, paragraph 5.6, can be followed.12 This paragraph addresses attaining traceability in cases where neither an international-convention reference measurement protocol nor an international-convention calibrator is available. The standard describes how a manufacturer can establish its own reference calibrator.
Translation. The directive does not require manufacturers to prepare their TD in any specific language. Therefore, each manufacturer can determine for itself which translations it may require.
Some parts of the directive refer to documents used by operators at the production facility, so these parts of the TD should be kept in the primary language of the manufacturer. Selecting a language in which to write the TD is a decision that could be influenced by the language in which the notified body is able to work and communicate with the manufacturer.
A competent authority of a member state may request the presentation of the TD in its official language. In this case, relevant translations should then be made available in a timely manner.
When manufacturers are located outside of the European Community, the manufacturer’s authorized representative must be able to understand and explain its TD. In this case, a procedure should be created that will prescribe a procedure for communication between the IVD company and its representative.
Declaration of Conformity. Once the TD has been completed, the manufacturer or the authorized representative must draw up the EC declaration of conformity before the product is placed on the market. The EC declaration of conformity should identify the directives according to which it is issued, the manufacturer, the authorized representative, the notified body if applicable, the product identification and, where appropriate, a reference to harmonized standards.
|Antonella Fassio, MSc , is quality assurance and regulatory affairs manager at DiaSorin S.r.l. (Saluggia, VC, Italy). She can be contacted at antonella.fassio@
An IVD manufacturer must maintain its TD for at least five years after the final manufacture of its product. If the lifetime of a product, e.g., that of instruments, is normally longer than this period, the documentation should be maintained for at least the expected lifetime of the IVD. Manufacturers must remember that more-stringent requirements may result from legislation passed after the device has received the CE mark, and the TD must reflect these changes. Staying on top of vigilance requirements and staying aware of the postmarket experiences of other IVD manufacturers should enable manufacturers to maintain up-to-date and comprehensive TD.
1. “Directive 98/79EC of the European Parliament and of the Council of October 1998 on In Vitro Diagnostic Medical Devices,” Official Journal of the European Communities L 331 (1998): 1–37.
2. “Guide to the Implementation of Directives Based on the New Approach and the Global Approach, 2nd Rev.,” (Brussels: European Commission, 1999).
3. Recommendation NB-MED/2.5.1/Rec5 (Brussels: Coordination of Notified Bodies Medical Devices (NB-MED) on Council Directives 90/385/EEC, 93/42/EEC, and 98/79/EC, 2000).
4. “Council Directive 93/42/EEC of 14 June 1993 Concerning Medical Devices,” Official Journal of the European Communities L 169 (1993): 1–43.
5. Quality System: Medical Devices, Particular Requirements for the Application of EN ISO 9001:1994, EN 13485:2000 (revision of EN 46001:1996), (Brussels: European Committee for Standardization, 2002).
6. Medical Devices—Application of Risk Management to Medical Devices (ISO 14971: 2000), EN ISO 14971:2001 (Brussels: European Committee for Standardization, 2002).
7. Elimination or Reduction of Risk of Infection Related to In Vitro Diagnostic Reagents, EN 13641:2000 (Brussels: European Committee for Standardization, 2002).
8. Medical Devices: Risk Analysis, EN 1441: 1997 (Brussels: European Committee for Standardization, 1998).
9. In Vitro Diagnostic Medical Devices: Culture Media for Microbiology, Performance Criteria for Culture Media, EN 12322:1999/A1:2001 (Brussels: European Committee for Standardization, 2002).
10. Performance Evaluation of In Vitro Diagnostic Medical Devices, EN 13612:2002 (Brussels: European Committee for Standardization, 2002).
11. “Council Directive 67/548/EEC of 24 June 1967 on the Approximation of Laws, Regulations, and Administrative Provisions Relating to the Classification, Packaging, and Labeling of Dangerous Substances,” Official Journal of the European Communities P196 (1967): 1–98.
12. In Vitro Diagnostic Medical Devices: Measurements of Quantities in Samples of Biological Origin, Metrological Traceability of Values Assigned to Calibrators and Control Materials (ISO/DIS 17511:2000), prEN ISO 17511:2000 (Brussels: European Committee for Standardization 2000).
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