On March 1, 2016 the International Organization for Standardization published the new edition of the ISO 13485 standard. Previously updated in 2003, the revision places more emphasis on the quality management system throughout the supply chain and product lifecycle, as well as on device usability and postmarket surveillance requirements.

ISO 13485 was written to support medical device manufacturers in designing quality management systems that establish and maintain the effectiveness of their processes. It ensures the consistent design, development, production, installation, and delivery of medical devices that are safe for their intended purpose.

While the ISO 13485 is based on the ISO 9001 process model concepts of Plan, Do, Check, Act, it is adapted for a more rigorous regulatory environment. It is more prescriptive in nature and requires a more thoroughly documented quality management system.


  • Inclusion of risk-based approaches throughout the quality management system
  • Improved alignment with regulatory requirements, particularly for regulatory documentation.
  • Increased applicability to include all the organizations that are involved throughout the lifecycle and supply chain for the product.
  • Harmonization of the requirements for software validation for different software applications in different clauses of the standard.
  • Additional emphasis on validation of processes, particularly for production of sterile medical devices, and addition of requirements for validation of sterile barrier properties.
  • Enhanced focus on complaint handling and reporting to regulatory authorities in accordance with regulatory requirements, and consideration of post-market surveillance.
  • Better planning and documentation of the CAPA, and duly implementing the corrective action.


Organizations have until March 1, 2019 to transition to the new standard.  The coexistence of ISO 13485:2003 and ISO 13485:2016 over the next three years will provide the Medical device companies, certification bodies and regulators with some time to switch over to the new standard. After three years however, any existing certification issued to ISO 13485:2003 will not be valid.



Detailed Methods for Performing Extractables Testing of Materials

A recent article from the Parenteral Drug Association (PDA) Journal provides some of the best information we have found on methods to determine and characterize extractables. It is definitely suggested reading for anyone performing extractables testing, or hoping to better understand this type of materials testing.

From the Parenteral Drug Association Journal:

"Plastic and rubber materials are commonly encountered in medical devices and packaging/delivery systems for drug products. Characterizing the extractables from these materials is an important part of determining that they are suitable for use. In this study, five materials representative of plastics and rubbers used in packaging and medical devices were extracted by several means, and the extracts were analytically characterized to establish each material's profile of extracted organic compounds and trace element/metals. This information was utilized to make generalizations about the appropriateness of the test methods and the appropriate use of the test materials. "

Pacific BioLabs performs device extractables and ISO 10993-18 testing services.

Full article: Extractables Characterization for Five Materials of Construction Representative of Packaging Systems Used for Parenteral and Ophthalmic Drug Products

New FDA Expectations for Reusable Device Reprocessing Validations

In March of 2015, the FDA published a new guidance document titled, Reprocessing Medical Devices in Health Care Settings: Validation Methods and Labeling.  A draft guidance on the same subject had previously been issued and has been used by device manufacturers since 2011 as the leading document concerning FDA’s expectations for validating reprocessing procedures for reusable medical devices.   In terms of cleaning, disinfection and sterilization validations, the most notable modifications to the 2015 document are:

  1. A more inclusive recommendation to incorporate multiple full simulated soiling, cleaning, disinfection or sterilization cycles to assess the accumulation of soil over time. 

  2. Guidance for using the worst case “master device” to validate other devices in a product family.

  3. Emphasis on visual inspection.  Visual inspection of both external and internal surfaces should be performed. 

  4. A statement recommending that devices that become hot, such as powered hand pieces or electrosurgical instruments, be validated while hot to replicate clinical use.

  5. A recommendation that two quantitative test methods be used to test for the amount of residual soil.  The recommendation of two different methods was not present in the draft version of the document.

  6. A recommendation that the type of soil chosen be justified and if the soil deviates from FDA-recognized standards then the deviation should be justified.

  7. A more detailed recommendation of what is expected from the positive and negative controls.  The Negative Sample Control is the blank - the extraction fluid only.  The Negative Device Controls should be unsoiled and undergo the same cleaning and extraction as the test devices.  The Positive Sample Control is the extraction fluid with a known amount of soil at or slightly above the limit of quantitation.  The Positive Device Control is a device that is soiled with a known amount of soil.  The Positive Device Control is not cleaned and the soil is then extracted.  The amount of soil extracted should be equivalent to or slightly lower than the amount of soil placed on the device.  

  8. An emphasis on disassembly during the soil extraction steps in order to remove soil from difficult to access areas.

  9. A recommendation to demonstrate that cleaning solutions are not penetrating internal compartments that are not intended to come into contact with soil or fluids.

Many of the changes above had been prescribed by AAMI documents and had become standard practice within the industry, while other modifications are welcome clarifications that had not been addressed previously.  What is not included in the new guidance document is also noteworthy.  Previous communications with the FDA indicated that six reprocessing cycles would be recommended before testing for residual soil. Surprisingly, this recommendation was not included in the most recent guidance document.  The only advice given by the FDA guidance document is that the number of reprocessing cycles must be scientifically justified.

Six Full Soiling, Cleaning, and Disinfection Cycles May be Needed

Yet there is still some question as to what the FDA specifically requires. Recently, a Pacific BioLabs client contacted us for reprocessing services because the FDA had rejected the client’s disinfection validation. This validation had been performed at another contract lab, and did not incorporate repeated soiling, cleaning and disinfection cycles.  The FDA, upon review, asked this client to conduct six repetitive soiling, cleaning, and disinfection cycles.  Thus, even though the FDA did not stipulate in the most recent guidance document that six full soiling, cleaning, and disinfection repetitive cycles be conducted, it appears that the FDA is internally subscribing to the policy that reusable devices should undergo at least six full cycles.  

Pacific BioLabs performs validations of device cleaning and disinfection protocols and other medical device reuse studies.

Why Understanding Bioburden and Sterilziation is Key to Medical Device Development

Pacific BioLabs and Nutek (a contract sterilizer specializing in e-beam irradiation) work closely together to perform the microbiology and sterilization needed for medical device sterilization validation programs. In this presentation we share some of our knowledge and advice on how to ensure a successful validation, which is a key factor in a medical device development program.

Pacific BioLabs performs medical device testing including sterilization validation services

Evaluation of Immunogenicity and Allergic Reactions to Medical Device Materials and Combination Products

Collagen - an example of a biological material used as part of medical devices.

Collagen - an example of a biological material used as part of medical devices.

As devices become more complex, biocompatibility and material evaluations must necessarily become more complex and thorough as well. Allergic and immunogenic reactions are a serious safety concern not only for pharmaceuticals, but because of increasing device complexity, they are also an emerging concern for devices. In the past, evaluation of devices looked only at allergic potential (not at immunogenicity), and was done by looking for sensitization to the device itself. This testing - for a delayed-type of hypersensitivity in guinea pigs - is still required for all devices.

Complex and Novel Materials Require More In-Depth Testing

However, it has become more common to see devices comprised of engineered biomaterials (such as stents coated in collagen or using other biologically-derived scaffolds.)  Drug/device combination products pose novel immunogenicity safety concerns – for example, nano-particles often combine natural or synthetic polymers with drugs. Nano medicines such as liposomes, carbon nanotubes, dendrimers, and polymer conjugated proteins have physical, chemical, and biological properties that may attract the attention of the immune system.

These complex devices, and those containing novel materials (e.g., plastics, polymers, metals, ceramics, biological materials) or devices that are lacking adequate testing for immunotoxicity, should also be tested for additional immune responses.

It becomes important to evaluate immunogenicity because the results of an immunological response can be so serious. Immunological effects include inflammatory responses, immunosuppression, immunostimulation, or autoimmune responses.

Performing Immunogenicity Testing of Devices

Testing for immunogenicity may involve animal implantation studies followed by analysis of serum for changes in total circulating IgG, and/or antigen specific responses by ELISA.  Hemocompatibility testing should include measurement ofcomplement activation. This can be performed in vivo or in vitro.  Device material or extracts are incubated with specially handled human serum and then activated complement cascade proteins are measured by ELISA.   Alternatively, serum from animals implanted with the device can be tested for complement activation.  These bioanalytical tests provide information to manufacturers and regulators about the safety and biocompatibility of the product.

Pacific BioLabs performs immunogenicity testing, has an experienced staff, and is here to help in determining what may be needed for your device. It is important to identify early whether your device may need an immunogenicity evaluation, and to begin collecting this data along with your biocompatibility data to support your 510(k) or PMA submission.

Additional information can also be found at the FDA website, including a flow chart to determine whether immunotoxicity testing is necessary: