In many regards, the readers familiar with 93/42/EEC (the MDD) will see stark similarities between some of the requirements. After all, Dr. D believes the requirements are premised on common sense.
However, with any regulation there will always be multitudinous (look-it-up) interpretations of requirements. Even the notified bodies occasional differ in their interpretation of requirements. Wait a minute Dr. D, you are telling us that there may be varying opinions on regulatory requirements? Who knew?
All kidding aside, you can take it to the bank (not the European Databank) that notified bodies occasional have differences of opinion in regards to regulatory compliance. Remember – their sandbox, their rules; so device manufacturers must work closely with their notified bodies, enough said. In this week’s DG adventure, the doctor will dissect Annex III and hopefully, provide some useful guidance for the readers. Enjoy.
1. The EC declaration of conformity is the procedure whereby the manufacturer or his authorized representative who fulfills the obligations imposed by section 2 to 5 and additionally, in the case of devices for self-testing, the obligations imposed by section 6, ensures and declares that the products concerned meet the provisions of this Directive which apply to them. The manufacturer must affix the CE marking in accordance with Article 16.2. The manufacturer must prepare the technical documentation described in section 3 and ensure that the manufacturing process follows the principles of quality assurance as set out in section 4.3. The technical documentation must allow assessment of the conformity of the product with the requirements of the Directive. It must include in particular:
— a general description of the product, including any variants planned,— the documentation of the quality system,— 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 the case of instruments, design drawings, diagrams of components, subassemblies, circuits, etc.,— in the case of devices containing tissues of human origin or substances derived from such tissue, information on the origin of such material and on the conditions in which it was collected,— the descriptions and explanations necessary to understand the above mentioned characteristics, drawings and diagrams and the operation of the product,— the results of the risk analysis and, where appropriate, a list of the standards referred to in Article 5, applied in full or in part, and descriptions of the solutions adopted to meet the essential requirements of the Directive if the standards referred to in Article 5 have not been applied in full,— in the case of sterile products or products with a special microbiological state or state of cleanliness, a description of the procedures used,— the results of the design calculations and of the inspections carried out, etc.,— if the device is to be combined with other device(s) in order to operate as intended, proof must be provided that it conforms to the essential requirements when combined with any such device(s) having the characteristics specified by the manufacturer,— the test reports,— adequate performance evaluation data showing the performances claimed by the manufacturer and supported by a reference measurement system (when available), with information on the reference methods, the reference materials, the known reference values, the accuracy and measurement units used; such data should originate from studies in a clinical or other appropriate environment or result from relevant biographical references,— the labels and instructions for use,— the results of stability studies.
4. The manufacturer shall take necessary measures to ensure that the manufacturing process follows the principles of quality assurance as appropriate for the products manufactured. The system shall address:
— the organizational structure and responsibilities,— the manufacturing processes and systematic quality control of production,— the means to monitor the performance of the quality system.
5. The manufacturer shall institute and keep up to date a systematic procedure to review experience gained from devices in the post-production phase and to implement appropriate means to apply any necessary corrective actions, taking account of the nature and risks in relation to the product. He shall notify the competent authorities of the following incidents immediately on learning of them:
(i) any malfunction, failure or deterioration in the characteristics and/or performance of a device, as well as any inadequacy in the labeling or the instructions for use which, directly or indirectly, might lead to, or might have led to, the death of a patient or user or other persons or to a serious deterioration in his or their state of health;(ii) any technical or medical reason connected with the characteristics or the performance of a device for the reasons referred to in subparagraph (i) leading to systematic recall of devices of the same type by the manufacturer.
6. For devices for self-testing the manufacturer shall lodge an application for examination of the design with a notified body.
6.1. The application shall enable the design of the device to be understood and shall enable conformity with the design-related requirements of the directive to be assessed. It shall include:
— test reports including, where appropriate, results of studies carried out with lay persons,— data showing the handling suitability of the device in view of its intended purpose for self-testing,— the information to be provided with the device on its label and its instructions for use.
6.2. The notified body shall examine the application and, if the design conforms to the relevant provisions of this Directive shall issue the applicant with an EC design-examination certificate. The notified body may require the application to be completed by further tests or proof to allow assessment of conformity with the design-related requirements of the Directive. The certificate shall contain the conclusions of the examination, the conditions of validity, the data needed for identification of the approved design and, where appropriate, a description of the intended purpose of the product.6.3. The applicant shall inform the notified body which issued the EC design examination certificate of any significant change made to the approved design. Changes to the approved design must receive further approval from the notified body which issued the EC design-examination certificate wherever the changes could affect conformity with the essential requirements of the Directive or with the conditions prescribed for use of the product. This additional approval shall take the form of a supplement to the EC design-examination.
1. Not wanting to state the obvious but obliged to do so, Annex III is broken down into six sections. Sections 1 through 5 are generic to all products, and Section 6 is dedicated to devices categorized as self-testing. Successful adherence to Annex III, along with general compliance of the IVDD, will result in a device manufacturer being granted permission to affix the prized CE mark onto product packaging. In fact, affixation of the CE mark is a salient requirement of the Directive.
2. The next step in working toward compliance with Annex III is the collection of technical documentation needed to assess product conformance; and the development of manufacturing processes premised on the adherence to generally accepted quality principles. Can you say technical file? Section 3 of Annex III delineates the specific requirements in regards to technical documentation and documentation content. Section 4 delineates expectations in regards to acceptable manufacturing processes.
3. So what does Annex III require in regards to technical documentation? The technical documentation requirements delineated within Annex III are quite prescriptive. That being said, Dr. D strongly suggests complying with all of the requirements applicable to your IVDD products. As a minimum:
- Product description;
- Planned product line-extensions;
- Design information (device characteristics, materials, device performance boundaries, method of manufacturing, verification activities, validation activities, drawing, and associated design-relevant documentation);
- Incorporation of human tissue, including source (if applicable);
- Risk analysis and application of risk assessment tools (use EN ISO 14971:2009);
- Sterilization method (if applicable);
- Special microbiological state (if applicable);
- Product cleanliness;
- Results of design calculations;
- Results of inspections;
- If use in conjunction with another device (combination);
- Test reports;
- Performance evaluation data;
- Product labeling;
- Product Instructions for Use (IFU); and
- The results of stability studies; must be considered and if applicable included in the technical documentation package (the doctor prefers the term Technical File).
4. The manufacturer must ensure that manufacturing of IVDD product occurs in an appropriate environment. In fact, the IVDD is very specific in stating “that the manufacturing process follows principles of quality assurance.” What in the heck does that mean Dr. D? Basically, the regulatory gods in the EU do not want IVDD product being manufactured in someone’s basement, garage, work shed, or similar uncontrolled environment. The Directive delineates the requirement for manufacturing to occur in a facility that has:
- A recognizable organizational structure with roles and responsibilities that are clearly defined;
- Approved manufacturing processes (ensure they are validated);
- A systemic approach to quality control to ensure production continuously manufactures compliant product that is safe and effective in its intended use; and
- The deployment of effective tools to gage the ongoing performance of the quality management system (QMS).
In short, although not stated, the doctor strongly recommends that device manufacturers have a recognized and compliant QMS to support manufacturing operations. In the EU, ISO 13485:2003 is the vehicle used to establish the QMS.
5. As a minimum, device manufacturers are expected to establish an effective approach (that means written procedure) for pursuing post-market surveillance activities? Why? The response is eloquently simple, because the Competent Authorities want to know product performance issues, resulting in death or injury or potential death or injury to their citizens, are occurring within the borders of Member States. Can you say vigilance report? Additionally, device manufacturers are expected to glean information learned from post-production activities and pursue corrective action(s) when opportunities for improvement present themselves. As for reporting to Competent Authorities, device manufacturers are required to report:
- Device malfunctions, failures and degradation in device performance;
- Labeling or IFU issues that may result in death or a “serious deterioration” in the health of a patient or user (directly or indirectly); and
- Product recall(s) (Dr. D’s favorite 6-letter word) when device problems depicted in the first two bulleted points necessitate a recall be pursued.
6. Devices designed and intended for use as self-testing, require a formal review “design examination” by the manufacturer’s notified body. Can you say I better start collecting the necessary data for the submission ASAP? The entire process begins (providing the device manufacturer is compliant with all aspects of the IVDD, including a functioning QMS) with the completion of the application process. There must be sufficient data presented so the notified body can perform a reasonable assessment of the device. For example:
- Test reports;
- Studies performed, specifically with lay persons (code for potential users);
- Data depicting device handling and suitability for its intended use;
- Label information; and
- IFU; must be submitted to the notified body as part of the application process.
Remember, the CE mark of registration actually belongs to the notified body. Providing the device manufacturer complies with all of the regulatory requirements; and promptly pays all monies due their notified body; they get to affix the notified body’s CE mark to their product.
- Since Annex III is titled “EC Declaration of Conformity,” make sure your CJO completes and signs the DoC.
- Device manufacturers must collect technical documentation to support the application process.
- Devices must be manufactured in a facility with some evidence of a QMS in place.
- Some devices will require a DEC. The DEC is issued by the notified body upon the successful completion of the application process.
- Do not forget to affix the rented CE mark to the outermost device package, once authorization to do so is received from your notified body.
- Council Directive 93/42/EEC. (1993, June). Council Directive 93/42/EEC concerning medical devices. Retrieved December 21, 2010, from http://eur-lex.europa.eu
- Devine, C. (2009, July). Exploring the effectiveness of defensive-receiving inspection for medical device manufacturers: a mixed method study. Published doctoral dissertation. Northcentral University. Prescott Valley, AZ.
- Devine, C. (2011). Devine guidance for complying with the European medical device directive – MDD. Charleston, SC: Amazon.
- Devine, C. (2012). Devine Guidance series on complying with the IVDD. Published in The Medical Device Summit.
- Directive 98/79/EC. (1998, October). Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on in vitro diagnostic medical devices. Retrieved September 12, 2011, from http://eur-lex.europa.eu
- EN ISO 14971:2009. (2010, March). Medical devices – application of risk management to medical devices (ISO 14971:2009).
- ISO 13485:2003. (2004, February). Medical devices – quality management systems – requirements for regulatory purposes (ISO 13485:2003).