Guidance on regulating medical devices manufactured from or incorporating viable or non-viable animal tissue or their derivative(s): Full data requirements, Class IV devices

The following minimum additional biological safety data requirements must be included in new licence applications. This also applies to licence amendments in which animal tissues or their derivatives are introduced into the device for the first time.

These requirements are in place to demonstrate that viable and non-viable animal tissues incorporated or used in the manufacture of a medical device does not have a negative impact on its safety or effectiveness.

On this page

• Identifying materials
• Manufacturing information
• Biocompatibility
• Biological safety
• Risk assessment

Identifying materials

For a medical device that incorporates, or uses during manufacturing, any animal-derived materials or their derivatives, you must provide:

• the specific type (for example, part of the animal) and age of each animal tissue or derivative incorporated or used
• the originating animal species of the animal tissue or derivative incorporated or used
• the status (open or closed) of the herd or collection of organisms
• name and address of the supplier
• methods and conditions for transporting animal tissue (for example, refrigeration and quarantine)
• testing performed for permitting tissues to be further processed (for example, release criteria)

You must also provide the following signed certificates:

• animal country and residence of origin, or equivalent,* including BSE risk status of that country
• abattoir inspection demonstrating that:
• quality control processes and procedures are in place to prevent contamination or cross-contamination with potential infective tissues
• disinfection and/or decontamination procedures are in place in the event of contamination, or equivalent*
• full traceability to the slaughterhouse and to suppliers of processed animal materials
• veterinary inspection, which includes certification that the animals are fit for human consumption, or equivalent*

If sourcing from a species not intended for human consumption or where veterinary inspection may not be possible (cervids, mink, cat), you must also:

• provide a justification for the missing inspection and certification, relevant quality criteria for the material and
• demonstrate the materials are "safe"

* If signed certifications of the animal's country of origin, abattoir and veterinary inspection are not available when you submit your application, you may provide the following items as evidence:

• supplier checklists
• training activities
• verification testing and risk analysis (for example, audit reports)
• evidence of abattoir certification by regulatory inspections (for example, a list of government-inspected facilities)and
• export certificates for a representative lot of animal tissue or derivatives (for example, veterinarian-signed USDA FSIS Form)

Manufacturing information

As indicated in section 32(4) of the Medical Devices Regulations (Regulations), you must describe the potential for any manufacturing or processing activities to contribute to contamination.

The manufacturing information should give:

• details for collecting, handling, storing and transporting animal-derived materials
• test methods and acceptance criteria for assessing in-process and final production bioburden or sterility
• evidence of established systems for animals and tissue traceability and quality control processes
• procedures to prevent contamination with potential infectious/transmissible agents (for example, transmissible spongiform encephalopathies, or TSEs)
• disinfection and/or decontamination procedures if contamination occurs

You are to also provide a copy of the label for the (main) material container. The container must be labelled appropriately to avoid the possibility of cross-contamination and mix-up during transport and storage. The label must give details on the material and indicate both the collection date and location (for traceability).

Biocompatibility

Biocompatibility of the animal tissue or derivative (for example, pyrogenicity, immunogenicity and toxicity) is addressed as part of overall device biocompatibility.

For additional guidance, consult:

• ISO 10993 and its associated parts

Biological safety

Bacterial, fungal, yeast and parasitic pathogens

As indicated in section 32(4) of the Regulations, your device sterilization or related processes must adequately address bacterial, fungal, yeast and parasitic pathogen contamination risk. Class IV medical devices generally require a minimum sterilization assurance level (SAL) of 10-6.

For devices that incorporate or use animal tissues or their derivatives in their manufacture, you must demonstrate that the sterilization or related processes can inactivate the most resistant bacterial, fungal, yeast and parasitic pathogen bioburden to the minimum SAL. You must also show that the sterilization or related processes do not negatively impact the short- or long-term physical properties of the device or its safety or performance.

Viral pathogens

Viral contamination of many animal tissues and their derivatives is expected. However, their elimination and/or inactivation to an appropriate level must be demonstrated, as indicated in section 32(4) of the Regulations. Standardized principles, methods and risk management approaches are outlined in ISO 22442-2 and ISO 22442-3. They serve as the basis for assessing and managing viral contamination.

Two complementary approaches are suggested:

• sourcing animal tissues or their derivatives that have been demonstrated to be minimally contaminated and that carry a viral burden amenable to elimination or inactivation
• validation of a production process that can eliminate or inactivate the most resistant virus(es) expected to reside in the animal tissue or derivative

A literature review can also help:

• identify the most resistant viruses expected to reside in the chosen animal material or derivative
• inform the design of an inactivation or elimination validation study

If device sterilization is used to manage viral contamination, you must provide relevant validation data to show that the sterilization process can eliminate or inactivate the most resistant viral contaminants.

Products of biotechnology/expressed from cells

As indicated in section 32(4) of the Regulations, devices that are made of or incorporate materials expressed from animal cells must demonstrate:

• complete cell line characterization
• evidence that the cell line has been tested for the absence of undesirable viruses that may be infectious and/or pathogenic for humans

Some cell lines (for example, rodent) used to manufacture biological products express endogenous retroviruses, retrovirus particles or retrovirus-like particles may cause disease in humans. It's important to validate the capacity of the manufacturing process to remove or inactivate endogenous and non-endogenous viral contaminants from the master cell bank (MCB).

Each working cell bank (WCB), used as a starting cell substrate, must be tested directly or by analyzing cells at the in vitro cell age, initiated from the WCB. You must also provide a complete "profile" of the expressed materials and carrier. This profile should include:

• full physical, chemical and biochemical profile of the peptides or proteins by analyzing, including mapping, the expressed peptide or protein and/or carrier (if applicable), SDS-PAGE, cation exchange chromatography, 2D-gel electrophoresis and HPLC
• in vivo and in vitro device (materials) activity bioassays
• pharmacokinetics, biodistribution and stability of the expressed materials
• systemic effects of the expressed materials

For additional guidance, consult the:

• International Conference on Harmonisation (ICH) guideline on biotechnology products

Transmissible spongiform encephalopathies (TSEs)

Unlike viral pathogen risks, management of prion contamination and transmission risk is largely based on selective tissue sourcing. The current science does not allow for reliable interpretation of TSE removal and/or inactivation. However, if you make claims about the removal/inactivation of TSEs, you must provide the scientific rationale and complete details of these studies, as indicated in section 32(4) of the Regulations.

The standardized principles, methods and risk management approaches outlined in ISO 22442-2 serve as the basis for managing TSE contamination risk. All materials derived from ruminant sources (for example, cattle, sheep, goats, buffalo, deer, elk) must be identified and sourced from a country recognized by the World Organization for Animal Health (OIE) as having a negligible BSE risk status. Ruminant sources include cells that have been grown in media containing bovine-derived constituents (for example, fetal calf serum, bovine trypsin).

Ovine- and caprine-sourced materials must be from a country that is free of scrapie.

As indicated in section 32(4) of the Regulations, you must provide evidence that the manufacturing process minimizes the potential for prion contamination in sourcing materials (for example, an established, validated and maintained quality system). To do so, you must:

• identify the specific animal tissue or derivatives used
• identify the animal species, strain and age from which the material or derivatives are obtained
• declare that the animals are fit for human consumption
• provide quality assurances from the abattoir, including stunning procedures and practices that minimize cross-contamination with potentially infectious tissues, and any disinfection and/or decontamination procedures in the event of contamination
• indicate the TSE risk status of country or geographical region from which the material is sourced

You must also demonstrate:

• appropriate collection, preservation, handling, storage and transport procedures
• appropriate record-keeping practices
• the system used to trace animal and tissue sources

Evidence of additional risk reduction may include documentation that shows:

• animal tissues or derivatives were taken from ruminant animals not fed prohibited material (Health of Animals Regulations)
• animals belonged to a closed herd
• the ages of the animals were less than 6 months

Risk assessment

As indicated in section 32(4) of the Regulations, the incorporation or use of animal tissues or their derivatives in a medical device introduces risks of pathogen transmission. You must provide a risk assessment that addresses those risks.

For additional guidance, consult the risk assessment processes and methods described in:

• ISO 14971
• ISO 22442-1 (Annex C)

The following risk management items are required as applicable:

• a scientifically based justification for using animal tissue or derivatives
• a risk analysis describing hazards related to any pathogens known to contaminate the tissue or derivative
• the status (open or closed) of the herd or collection of organisms
• an assessment of risk mitigation strategies
• a comparison of the residual risk, along with the benefit of incorporating or using those tissues or derivatives in the device
• a system to identify changes in zoonotic status of the chosen source of animal materials, and consideration in the risk management evaluation