Devine Guidance

IVDD Annex VI (EC Verification)

By Dr. Christopher Joseph Devine

Two takeaways this week are immensely important for device manufacturers: 1. Make sure maximum effort is exuded during the documenting and validation of the manufacturing processes, and 2. Manufacturers must take an active part in determining appropriate sample sizes for verification testing; do not let notified bodies make this decision without your input.

Annex VI (EC Verification) is all about the manufacturer or their EU authorized representative declaring that products covered by the Design Examination Certificate (DEC) actually meet the requirements of the IVDD. Dr. D guesses it only makes sense that products actually meet the requirements of the Directive. Who knew?

Dr. D also guesses that it may be correct to surmise if a notified body issues a DEC, then it is a realistic expectation for the manufacturer of devices to actually comply with the Directive. After all folks, what part of compliance is not being understood? The doctor recommends that instead of casting aspersions (look-it-up) and heaping maledictions (look-it-up) upon the notified bodies; try complying with the Directive. That being said, a few of the requirements delineated under Annex VI of the IVDD are as follows.

  • Make sure to establish policies, procedures, and protocols prior to commencing with the manufacturing process.
  • Make sure testing and controls are adequately defined.
  • Make sure to establish a post-market surveillance program.
  • Make sure the notified body performs the appropriate examination, including testing, of products.
  • Make sure the sample plans selected by the notified body are realistic and practical.
  • Make sure the CE mark is affixed onto the packaging of approved products.
  • Make sure manufacturing occurs in homogeneous batches.
Similar to the previous Annexes explored by Dr. D in his weekly diatribes known as Devine Guidance (DG), the requirements for compliance with Annex VI are pretty-straight forward and should be easy to comprehend. Then again, maybe not, as ambiguity in regulations can result in compliance issues. When in doubt, ask your notified body for guidance. Remember, you are paying them for the abuse (the doctor means support). Enjoy!
The IVDD – 98/79/EC
Annex VI – EC Verification
1. EC verification is the procedure whereby the manufacturer or his authorized representative ensures and declares that the products which have been subject to the procedure set out in section 4 conform to the type described in the EC type-examination certificate and meet the requirements of this Directive which apply to them.

2.1. The manufacturer must take all the measures necessary to ensure that the manufacturing process produces products which conform to the type described in the EC type-examination certificate and the requirements of the Directive which apply to them. Before the start of manufacture, the manufacturer must prepare documents defining the manufacturing process, in particular as regards sterilization and the suitability of starting materials, where necessary, and define the necessary testing procedures according to the state of the art. All the routine, pre-established provisions must be implemented to ensure homogeneous production and conformity of the products with the type described in the EC type-examination certificate and with the requirements of this Directive which apply to them.

2.2. To the extent that for certain aspects the final testing according to section 6.3 is not appropriate, adequate process testing, monitoring and control methods shall be established by the manufacturer with the approval of the notified body. The provisions of Annex IV, section 5, shall apply accordingly in relation to the abovementioned approved procedures.

3. The manufacturer must undertake to 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 and notification action as referred to in Annex III, section 5.
4. The notified body must carry out the appropriate examinations and tests taking account of section 2.2 in order to verify the conformity of the product with the requirements of the Directive either by examining and testing every product as specified in section 5 or by examining and testing products on a statistical basis as specified in section 6, as the manufacturer decides. When carrying out statistical verification according to section 6, the notified body has to decide when statistical procedures for lot-by-lot inspection or isolated lot inspection have to be applied. Such decision must be taken in consultation with the manufacturer.
In as far as the conduct of examinations and tests on a statistical basis is not appropriate, examinations and tests may be carried out on a random basis provided that such procedure in conjunction with the measures taken in accordance with section 2.2 ensures an equivalent level of conformity.
5. Verification by examination and testing of every product

5.1. Every product is examined individually and the appropriate tests defined in the relevant standard(s) referred to in Article 5 or equivalent tests must be carried out in order to verify the conformity of the products with the EC type described in the type-examination certificate and with the requirements of the Directive which apply to them.

5.2. The notified body must affix, or have affixed, its identification number to each approved product and must draw up a written certificate of conformity relating to the tests carried out.

6. Statistical verification

6.1. The manufacturer must present the manufactured products in the form of homogeneous batches.

6.2. One or more random samples, as necessary, are taken from each batch. The products which make up the sample are examined and the appropriate tests defined in the relevant standard(s) referred to in Article 5 or equivalent tests must be carried out to verify, where appropriate, the conformity of the products with the type described in the EC type-examination certificate and with the requirements of the Directive which apply to them in order to determine whether to accept or reject the batch.

6.3. Statistical control of products will be based on attributes and/or variables, entailing sampling schemes with operational characteristics which ensure a high level of safety and performance according to the state of the art. The sampling scheme will be established by the harmonized standards referred to in Article 5, taking account of the specific nature of the product categories in question.

6.4. If the batch is accepted, the notified body affixes, or has affixed its identification number to each product and draws up a written certificate of conformity relating to the tests carried out. All products in the batch may be put on the market except any in the sample which failed to conform.

If the batch is rejected the competent notified body must take appropriate measures to prevent the batch from being placed on the market. In the event of frequent rejection of batches, the notified body may suspend the statistical verification.

The manufacturer may, on the responsibility of the notified body, affix the notified body’s identification number during the manufacturing process.

What IVDD medical device manufacturers need to know
In regards to Annex VI, compliance commences with the documentation and validation of manufacturing processes. Device manufacturers must ensure that the all processes, including sterilization, and the materials used in construction for the device are capable of producing a quality product. Documentation prepared by the device manufacturer must support the claims of conformance to the Directive. In short, devices must be capable of producing accurate and repeatable results. Product testing requirements must be defined and documented considering the state-of-the-art of available technologies. Additionally, if complete final testing of a device is not practical, effective measures for process control (test, monitoring, and control) must be implemented.
Similar to the other Directives (e.g., 93/42/EEC), device manufacturers are required to establish, implement, and maintain a documented approach for post-market surveillance. It is extremely important for manufacturers to collect information from the users, including vigilance reporting data to assess overall device performance. The information collected needs to be used to drive overall device improvements, and if deemed appropriate, device corrections. Remember, if the device is deemed not to be effective, rest-assured, the Competent Authorities will soon be involved. Can you say “Recall?”  Oops, excuse the doctor, the correct term is “market withdraw.” Regardless, the device manufacturer will be out of the EU market.
Similar to other IVDD Annexes, the notified body is required to appropriately examine and test product to ensure conformity with the requirements of this Directive. It is up to the notified body to determine the statistical basis for which testing on product is to be performed. The good news is as the manufacturer you have input into the statistical rationale applied. Remember the notified bodies work for you and it does not hurt to remind them of this fact from time-to-time. Besides, device manufacturers are paying their notified bodies great sums of money to provide this type of device oversight and support.
Another responsibility of the notified body is to draw up certificates of conformity highlighting the testing performed. Remember, until the notified body has determined that product is acceptable and the DEC is created, the CE mark of conformity containing the notified body’s registration number cannot be affixed to product. 
Finally, device manufacturers are expected to manufacture products employing processes that support the creation of homogeneous lots. More good news, Dr. D cannot recall ever seeing manufacturer of IVDD products not employing a batch management system; and the doctor is an old guy. As previously stated, samples are removed from each lot for the purpose of conformance testing to ensure compliance with the IVDD. Sampling plans employed may be premised on attributes and/or variables data, as appropriate. The expectation is that testing be performed in accordance with established harmonized standards. Yes, Dr. D understands that employing harmonized standards is only recommended, but try telling that to your notified body.

Now for some bad news, if the samples extracted from a batch fail testing, the notified body will block the entry of the rejected batch from entering the EU market. The notified body will probably adjust their sampling plan as well. The moral of this story is quite simple, always manufactured devices that are safe and effective in their intended use; or in the case of IVDDs capable of producing accurate and repeatable results; otherwise, affixing the CE mark to product is always going to be problematic.  

What IVDD medical device manufacturers need to do
For starters (Dr. D broken record time), the processes employed by device manufacturers must be well-documented and validated. Regardless of how great a device design appears to be, if the device cannot be produced in mass, employing a processes that results in a device that is safe and effective in its intended use, there is no marketable device, nada, zip, nine, no, etc. Additionally, devices manufactured in compliance with the IVDD, must be capable of producing test results that are accurate and repeatable, 100 percent of the time, no exceptions.

Now the doctor is going to climb out onto that proverbial limb again this week and assume device manufacturers are prescribing to the philosophy of manufacturing in homogeneous batches.  If so good, if not what are you thinking? Regardless, the notified body is going to evaluate the device manufacturer’s approach to batch management to determine appropriate sample sizes for verification testing. Make sure, as a device manufacturer, you participate in the sample-size determination process up front; otherwise, you will be sorry.

Dr. D is now going to climb a little higher into the tree and climb out onto another limb by assuming device manufacturers have a post-market surveillance program. If not, then my question would be what are your notified body’s thinking? Sorry notified bodies. Finally, once the notified body has determined through the verification process that a device is acceptable to place onto the market, the last step is to affix the CE mark of conformity. However, if test results lead the notified body to the conclusion that a device batch is not suitable for entry into the EU market, do not pass go or collect $200. Instead, it’s back to the proverbial drawing board. Sorry but there are no Mulligans in medical device manufacturing.

Takeaways
Folks, the doctor is going to leave you with two takeaways this week that are immensely important for device manufacturers. Number one, make sure maximum effort is exuded during the documenting and validation of the manufacturing processes. Number two, since the manufacturer should be the most knowledgeable about their device design, manufacturing processes, methods for testing, and device performance parameters, they must take an active part in determining appropriate sample sizes for verification testing. Do not let the notified body make the sample-size decision without your input; otherwise, it could end up costing you in the long run.  

Until the next installment of DG, when Dr. D provides insight and guidance into complying with Annex VII (EC Declaration of Conformity) of the In Vitro Diagnostic Medical Device Directive, a.k.a., IVDD – cheers from Dr. D and best wishes for continued professional success.


References: 

  1. 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
  2. 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.
  3. Devine, C. (2011). Devine guidance for complying with the European medical device directive – MDD. Charleston, SC: Amazon.
  4. Devine, C. (2012). Devine Guidance series on complying with the IVDD. Published in The Medical Device Summit. 
  5. 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

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About The Author

Dr. Christopher Joseph Devine, President, Devine Guidance International