EU MDR Compliance

by | Jun 25, 2019 | Cleanroom News, Cleanroom Standards

Gearing Up for EU MDR

How cleanroom bioburden information can support biocompatibility assessments

In medical device manufacturing, low bioburden levels are essential. We address EU MDR compliance from a bioburden and biocompatibility perspective for sterile medical device packaging.

The EU Medical Device Regulation (EU MDR 2017/745), effective May 26, 2020 specifies regulatory changes focused on enhanced clinical data, improved feedback from post-market surveillance, and sets new expectations for technical file review by notified bodies. No medical devices are left untouched: Annex I, the General Safety and Performance Requirements, identifies the conditions that must be addressed for legacy devices (those devices CE marked under the current Medical Device Directives) to maintain CE mark for market in the EU. The update and changes in regulations address:

  • Reclassification of many devices to a higher risk class and a new classification for reusable surgical devices requiring notified body oversight
  • Requirements for clinical evidence including clinical evaluation and investigation
  • Increased requirements for risk management, labeling, usability, and a person responsible for regulatory compliance

As mentioned, the new classification rules in EU MDR resulted in the reclassification of some Class IIb devices to Class III medical devices. These classification changes means enhanced regulatory requirements and increased scrutiny on demonstration of biocompatibility which is especially true for the following new and clarified Class III designations:

  • Breast implants
  • Total and partial joint replacements
  • Spinal disc implants
  • Surgical mesh
  • Transient or short-term use devices in direct contact with the heart of central circulatory system
  • Non-invasive in vitro substances contacting human cells/tissues/organs pre-transplantation
  • Active implantable devices
  • Active devices that control, monitor, or affect active implantable devices
  • Active therapeutic devices incorporating diagnostic capabilities
  • Materials that may cause exposure to nanoparticles, whether by articulation and wear of the device

As a manufacturer, the majority of EU MDR readiness activities may be focused on bolstering clinical evidence and updating quality systems, especially for devices affected by reclassification. Remediation also means developing a regulatory strategy and ensuring technical documentation is in place. For reclassified devices listed above, biocompatibility assessments including biological evaluation per ISO 10993-1:2018 can be a priority. One often overlooked area of biocompatibility assessments is in device sterility and packaging.

We address two strategies for bioburden levels and environmental monitoring to assist in EU MDR remediation:

  1. Use cleanroom monitoring information and low bioburden levels to support biocompatibility assessments.
  2. Ensure technical files are updated with cleanroom environmental monitoring procedures and current reports.

Focusing on biocompatibility: Use bioburden levels to support the assessment

There is no hard and fast requirement that says a specific class of medical devices must be sterilized and packaged in a specific class of cleanroom. The requirement instead is that the production and sterilization environments must be controlled such that the medical devices are safe, effective, and meet sterility needs. For sterile devices, cleanroom requirements are determined by the manufacturer based on needs to achieve product and process validation, sterilization validation, and biocompatibility requirements. Most manufacturers opt for cleanrooms of ISO Class 7 and 8, though for relatively negligible increase in cost, improved sterility is provided by Class 7 with ≤10,000 particles/ft3 for particles ≥0.5μm. In essence, cleanroom bioburden and particulate count is selected so that devices meet bioburden requirements and sterility on a consistent basis.

With EU MDR taking a risk-based approach, low bioburden levels and environmental monitoring programs can play a crucial role in the biocompatibility assessment.  This is because validation of device sterilization is dependent upon the device’s pre-sterilization bioburden. If bioburden levels increase in the cleanroom, then the “validation of sterilization” is no longer valid. Compounding this is the fact that the cleanroom is really only as clean as materials, devices, equipment, personnel, etc. that are introduced.

What does this all mean?

  1. To maintain cleanroom bioburden levels, all sources of contamination must be controlled.
  2. Bioburden tests should be conducted just prior to products being sterilized, especially if the product was in storage.

Medical devices that require endotoxin-free or non-pyrogenic labels will require additional cleanroom monitoring for endotoxins which can often be introduced by water if used in any part of the manufacturing process. In deciding whether or not this level of testing is necessary, consider:

  • Is the device implanted or in contact with soft tissue or the circulatory system?
  • Is water used in the manufacturing process (milling, extrusion, cleaning)?

If the answer is yes to the questions above, endotoxin tests may be beneficial to support biocompatibility and minimize risk. In general, we recommend that cleanroom bioburden and endotoxin information (monitored on a regular basis) support the biocompatibility assessment as part of the risk-based biological evaluation per ISO 10993-1.

Update Technical File With Environmental Monitoring Procedures and Reports

Bolstering technical documentation with environmental monitoring information will provide additional confidence for low bioburden and sterility. If not already complete in the technical file, we suggest adding the following details on environmental monitoring of your sterile packaging facility. This can be accomplished by:

  • Supporting technical documentation with up-to-date cleanroom bioburden and particle count
  • Including environmental monitoring documentation of aseptic processing
  • Providing procedures and reports of physical and microbiological tests
  • Demonstrating sampling schedule (all devices covered by a certificate must be sampled over the validity period of the certificate)

This assumes the technical file already clearly identifies and describes design control process/plan, complete information/specifications, monitoring or product testing, and sites where design and manufacturing activities are performed. Other responsibilities of the manufacturer at this stage include providing a complete set of labels on the device and its packaging and the instructions for use in the languages accepted in the member states where the product is to be sold (not just English) and updating the device risk management documentation with biocompatibility assessment to include packaging and sterility information.

In conclusion

We recommend you leverage work you’ve already done maintain a sterile environment for packaging. Use bioburden and endotoxin data to support biocompatibility assessments and bolster the technical file with additional details on cleanroom environmental monitoring.

Where to go next?

Contact us for an assessment of your cleanroom and procedures with the goal of ensuring that bioburden and sterility requirements are met. We also offer turnkey medical device cleanroom design and construction services to provide the perfect levels of cleanliness for the manufacturing of medical devices and support the sterile packaging processes of these devices for your continued success!



Regulation (EU) 2017/745 on medical devices (MDR) and Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR) replace the three existing medical device Directives (93/42/EEC, 98/79/EC and 90/385/EEC) and came into force on 25 May 2017. The two new regulations will come into full application in May 2020 for medical devices and May 2022 for in vitro diagnostic medical devices, following a transition period to allow manufacturers, notified bodies and authorities to comply with the changes.

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