Annex I of the IVDD (98/79/EC) delineates the requirements for the designing, manufacturing, and packaging of devices that are safe and effective in their intended use. For the European Union (EU) it is all about the establishment of and compliance with Essential Requirements. 

 

Specifically, Annex I of the IVDD delineates device requirements needing to be considered to support conformance with essential requirements. Remember, the EU’s need for common ground in developing device regulations, applicable for all Member States, led to the instauration (look-it-up) of the three Medical Device Directives (IVDD, MDD and AIMDD). For this week’s guidance, the doctor will review and provide guidance on: (A) General Requirements; and (B) Design and Manufacturing Requirements, each containing salient components of Annex I. Enjoy!  

The full text of the IVDD – 98/79/EC Annex I – Essential Requirements can be viewed here.  

 

The first thing that device manufacturers need to know is that Annex I is broken down into two major sections: (A) General Requirements; and (B) Design and Manufacturing Requirements. As stated in this week’s introduction, Annex I really does flow down into one salient concept. Manufacturers of devices categorized as an IVDD must be designed, manufactured, and package in a manner that makes the device safe and effective in its intended use.

There are five salient concepts that device manufacturers must know and understand in regards to the General Requirements.

1. Devices must be designed, manufactured, and packaged (common theme in case you have not noticed) to be safe and effective in their intended use. This includes, when employed directly or indirectly, the health and safety of the patient, user, or other persons.
2. Risk must always be considered; and if the risk level is not deemed acceptable, mitigation activities must be pursued. If appropriate, the user must be informed of potential risks associated with the use of the device.
3. Devices must be designed and manufactured considering state-of-the-art technologies, including the need to achieve specific performance criteria. When calibrators are being designed and manufactured, the traceability of associated variables must be controlled and documented by procedure.
4. The device must remain safe and effective for the duration of its useful life, as specified by the manufacturer.
5. The device must be designed, manufactured, and packaged (common theme) in a manner that ensures the effectiveness of device performance in its intended use.

The design and manufacturing requirements are extremely prescriptive and do not allow for any proverbial wiggle room. Now granted the doctor believes there is definitely room for interpretation liberties; however, when in doubt, talk to your notified body. After all that is what you are paying them for, amongst other things. There are eight categories of deliverables that device manufacturers must have a good grasp of in support of establishing compliance with essential requirements. Dr. D will provide some insight into the not-so-obvious requirements and reinforce critical points associated with the obvious as the doctor dissects each requirement.

 

If the readers have not noticed the common theme throughout Annex I, the theme is the “design, manufacture, and packaging of devices that are safe and effective.” In regards to chemical and physical properties, manufacturers must ensure that the materials employed in the actual device construction are compatible and support device utilization for its intended purpose. How does one accomplish this? The answer is through the employment of an effective material testing program. Additionally, the device must be packaged to reduce the risk of leakage and contamination, as a result of transportation and/or storage activities. Remember, opening device packaging, only to find a damage device, is always a bad thing. Can you say vigilance report?

 

Since Dr. D is not a biologist, I am only comfortable in stating germs are bad things. That being said, (common theme – yes Dr. D sounds like a broken record) devices must be designed, manufactured, and packaged in a manner to reduce the potential for infection. When a device employs a biologic component, a donor screening program must be employed. The screening program better be comprised of more than just a questionnaire. Robust testing is also required. Devices packaged and labeled as STERILE” must remain “STERILE.” Who knew? Guess what? The sterilization process along with the packaging shall be validated. Packaging systems must be capable of protecting sterile and non-sterile product from damage. The doctor strongly recommends becoming familiar with EN ISO 11607-1:2009 and ISO 11607-2:2006.

 

If the IVDD is going to be used in combination with another device(s), it must be safe and effective in its application. Potential risks associated with exposure to other materials, chemicals, and gases must be identified and mitigated as appropriate. Additionally, risk factors associated with device ergonomics (including readability of measuring and monitoring scales), exposure to magnetic fields, electro-static discharge (ESD), humidity temperature, and electro-magnetic interference (EMI) must be evaluated and if deemed necessary, risk mitigation activities pursued. Devices must be designed and manufactured in such a manner so they do not explode or burst into flames? Once again, who knew? Finally, consideration in support of safe waste disposal is also a requirement. Device manufactures definitely do not want to have an IVDD burst into flames or explode while being placed into a disposal receptacle.

 

Devices with a measuring function must be designed and manufactured in a manner that ensures the measurement function actually works. Again, who knew? The expectation is that measurement accuracy and stability are fundamental requirements, with the manufacturer responsible for defining the accuracy limits. An extremely important point is that when actual values are provided, they must be provided in legal units in accordance with Council Directive 80/181/EEC. Dr. D strongly recommends reading this Directive. Just a watch-out, the EU likes to use the metric system. I know real-rocket science from Dr. D; however, 80/181/EEC enforces the use.

 

Users of IVDDs really do not like to have body parts glowing in the dark. That being said, devices must be designed, manufactured, and packaged to reduce the risk of exposure to radiation, if applicable. When a device is intended to emit radiation, the radiation levels must be able to be controlled and/or adjusted. Additionally, visual displays and audible warnings (e.g., warning, warning, warning, you are about to be nuked) must be employed. Finally, the Instructions for Use (IFU) or an operating manual (if applicable) must be extremely detailed in regards to the nature of the radiation, user personal-protection requirements, misuse warnings, and installation risks. 

 

Devices incorporating electronic-programmable systems (with or without software) must be reliable. Wow, again, who knew? The doctor is really loving Annex I. Devices falling into this category must be designed and manufactured to minimize risks associated with EMI, electrical shocks, mechanical failure (e.g., moving parts), thermal properties (excessive heat), vibration, noise, or terminals and connections to electricity, gas, or hydraulic/pneumatic energy supplies. In short, everything associated with a device counts in regards to risk. That is why EN ISO 14971:2009 is such an important document. Dr. D strongly suggests reading this standard on risk management.

 

Devices intended for self-testing must be designed and manufactured in a manner to facilitate self-testing by the user. In short, this means “simple and easy to use while obtaining accurate and repeatable results.” In fact, the Geico commercial theme, “It is so easy a caveman can do it” is probably appropriate for Annex I. Additionally, although a 100-page operating manual is probably not appropriate, an adequate IFU should be provided. By the way, do not forget the multi-language requirement.

 

First and foremost, the manufacturer is required to provide adequate labeling (combination of product label and IFU) for each device. It is highly recommended that manufacturers employ EN ISO 980:2008 for symbols. If the device contains a component that can be categorized as dangerous, then the appropriate danger/warning symbol must be employed (reference Directives 67/548/EEC and 88/379/EEC – must read Directives). As minimum, the following labeling information must be included and/or considered:

• Manufacturer Name and Address (outermost package label);
• EU Authorized Rep address (outermost package label);
• The term “STERILE” (if appropriate);
• Batch “LOT” and/or serial number (outermost package label);
• Use by date (outermost package label);
• Devices for performance evaluation only, must be labeled as such;
• A statement depicting the in-vitro use of a device;
• Special handling or environmental concerns;
• Warnings and precaution statements;
• Self-testing statement (if applicable); and
• Do not forget the CE Mark of registration from your notified body.

Additionally, if the intended use of the device is not obvious, the manufacturer must state the intended use either on the label or in the IFU. All devices and their components must be identified and traceable (as appropriate). The IFU must also contain specific requirements associated with the device performance parameters. Since the list is quite extensive 21-elements, Dr. D is not going to dive into all of them. However, a few of the key ones that really require attention are:

1. Storage conditions and shelf-life requirements;
2. Detailed description of the procedure;
3. The mathematical approach employed in the calculation of the analytical result(s);
4. Relevant user information (e.g., traceability of calibration device);
5. Information needed for proper device installation;
6. Reuse information;
7. Precaution statements; and 
8. Date of issue/revision of the IFU (extremely important).

As you can see from the physical length of Annex I and the length of Dr. D’s rants associated with this week’s guidance, the requirements for compliance are extensive. Manufacturer’s need to clearly understand the ramifications associated with failure to comply with Annex I and take the appropriate steps to ensure lapses in compliance never occur. The best advice the doctor can give is to ensure that adequate written procedures exist that support (common theme) the design, manufacture, and packaging of IVDDs. Dr. D also recommends employing Harmonized Standards. Yes, these standards are only recommended; however, a salient factor of the Directive is presumption of compliance with essential requirements. The regulatory gods in the EU have already established that if a device manufacturer employs Harmonized Standards, then a presumption of compliance exists (their sandbox, their rules). Regardless, the goal of any device manufacturer is to provide a finished device that is safe and effective in its intended use, period! Annex I, through the establishment of essential requirements, supports that goal.

 

Annex I is where the proverbial rubber meets the road for device manufacturers. A common theme (broken –record time) throughout Annex I is “designed, manufactured, and packaged” in a manner to support device safety and efficacy in its intended use. One of the ways to achieve device safety and efficacy is to ensure processes associated with device design, manufacturing (including all testing), and packaging are properly validated. 

 

Finally, device labeling for IVDDs is extremely important, especially when self-testing is the primary modality employed. Remember, as you prepare your technical file or design dossier device manufacturers should keep in close contact with their notified bodies. After all, they will be tasked with reviewing, and hopefully approving the device application. Besides, device manufacturers pay their notified bodies some significant coin, so they should take advantage of their notified body’s knowledge. 

 

Until the next installment of DG, when Dr. D provides insight and guidance into complying with Annex II (List of Devices referenced to in Article 9(2) and (3)) of the In Vitro Diagnostic Medical Device Directive, a.k.a., IVDD – cheers from Dr. D and best wishes for continued professional success.

 

1. Council Directive 67/548/EEC. (1967, June).  Council Directive 67/548/EEC of 27 June 1967 on the approximation of laws, regulations and administrative provisions relating to the classification, packaging and labeling of dangerous substances. Retrieve March 23, 2012, from http://eur-lex.europa.eu
2. Council Directive 80/181/EEC. (1979, December). Council Directive 80/181/EEC of 20 December 1979 on the approximation of the laws of the Member States relating to units of measurement and on the repeal of Directive 71/354/EEC. Retrieved March 23, 2012, from http://eur-lex.europa.eu
3. Council Directive 88/379/EEC. (1988, June).  Council Directive 88/379/EEC of 7 June 1988 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the classification, packaging and labeling of dangerous preparations. Retrieved March 23, 2012, from http://eur-lex.europoa.eu
4. Council Directive 90/385/EEC. (1990, June). Council Directive 90/385/EEC of 20 June 1990 on the approximation of the laws of the Member States relating to active implantable medical devices. Retrieved October 5, 2010, from http://ec.europa.eu
5. 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
6. 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.
7. Devine, C. (2011). Devine guidance for complying with the European medical device directive – MDD. Charleston, SC: Amazon.
8. Devine, C. (2012). Devine Guidance series on complying with the IVDD. Published in The Medical Device Summit. 
9. 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
10. EN 980:2008. (2010, May). Symbols for use in the labeling of medical devices. European Standard – Prepared by: Technical Committee CEN/CLC/TC 3.
11. EN ISO 11607-1:2009. (2010, March). Packaging for terminally sterilized medical devices – Part 1: Requirements for materials, sterile barrier systems and packaging systems. International Organization for Standardization.
12. EN ISO 11607-2:2006. (2006, July). Packaging for terminally sterilized medical devices – Part 2: Validation requirements for forming, sealing, and assembly processes. International Organization for Standardization.
13. EN ISO 14971:2009. (2010, March). Medical devices – application of risk management to medical devices (ISO 14971:2009).