Guidance on the regulation of medical devices manufactured from or incorporating viable or non-viable animal tissue or their derivative(s): Overview

Introduction

There are potential risks associated with incorporating or using animal tissues or their derivatives in medical devices. The potential biological risks include bio-incompatibility and the transmission of pathogens to patients and health care providers. The zoonotic potential of bacterial, viral, fungal and parasitic pathogen contaminants has been demonstrated in many animal species.

Of particular concern is exposure to abnormally folded and aggregation-prone prion proteins (PrPTSE). These are believed to cause the following:

scrapie in sheep and goats
chronic wasting disease (CWD) in deer and elk
bovine spongiform encephalopathy (BSE) in cattle
transmissible spongiform encephalopathies (TSEs) in humans

Human prion diseases are fatal, neurodegenerative conditions marked by progressive dementia and other multifocal neurological signs. TSEs identified in humans include:

Creutzfeldt-Jakob disease (sporadic (sCJD)
familial (fCJD), iatrogenic (iCJD) and variant forms (vCJD))
kuru

There is strong epidemiologic and laboratory evidence for a causal association between BSE exposure and vCJD. There is also experimental evidence that TSE agents transmit between species (CDC, 2015). Observational data also shows that vCJD may be transmitted through blood transfusions (WHO, 2006).

The continued concern for potential prion contamination in humans stems from the clinical severity of the disease and confirmatory diagnoses that largely rely on post-mortem exams. Current ante-mortem immunoassay methods are not considered confirmatory.

The ISO 22442 standards highlight the importance of considering atypical BSE types (that is, H and L types) when addressing the safety of medical devices. The L type has shown a greater infection rate in test animals. In particular, any evaluation of intra-cranial devices should consider sporadic atypical BSE in the risk assessment.

Medical device biocompatibility is already considered and assessed as part of Class III and IV application reviews. However, given the potential for pathogen transmission from incorporating or using animal tissues or their derivatives, additional data requirements and a specialized review are a must.

These requirements are described in this guidance document.

Policy objectives

Additional supporting evidence is required to prepare new and amended medical device licence applications for Class III and IV devices that incorporate or are manufactured using viable and non-viable animal tissues or their derivatives. These are in accordance with the Medical Devices Regulations (Regulations).

Policy statements

Industry is required to submit the content described in this document along with the general data elements listed in paragraphs 32 (4) of the Regulations.

This guidance document should be read with the following guidance documents:

The biological safety data requirements referenced in this guidance document are adopted from risk-based approaches that have been developed and used by the following organizations:

Canadian Food Inspection Agency (CFIA)
World Organization for Animal Health (OIE)
International Conference on Harmonization (ICH)
International Organization for Standardization (ISO)

Despite measures taken by other jurisdictions to prevent, control or eradicate BSE and/or TSEs, their BSE risk status may change. To help maintain adequate risk control over animal tissues and their derivatives, we recommend that you routinely consult the OIE for current country BSE status.

Scope and application

The minimum biological safety data required for new and amended licence applications is determined by the device classification and the specific animal tissue(s) or derivative(s) used or incorporated. Data requirement categories are provided for guidance.

No additional data requirements/out of scope

Class II medical devices, including those that are intended for intact skin only, are not subject to a pre-market technical review. Additional biological data, unless requested, are also not required. Materials manufactured from human tissues or their derivatives, in vitro diagnostic devices and xenografts are also outside the scope of this guidance document.

Limited data requirements

Manufacturers must provide evidence of regulatory acceptance or compliance with established requirements for Class III or IV devices that:

incorporate animal tissues or derivatives that have been previously assessed and accepted by Health Canada (for example, tallow - previous medical device licence, heparin with DIN# issued) or
meet established pharmacopoeial or good manufacturing practice (GMP) requirements

Reduced data requirements

Some Class III devices incorporate or have been manufactured from animal materials that are considered to be lower risk. These include highly processed materials, such as those derived from hides, as well as those listed in Table 1.

A reduced suite of biological safety data may be submitted with the licence application, as outlined in the page on reduced data requirements for Class III devices.

Full data requirements

A full suite of biological safety data must be submitted with the licence application for a Class IV medical device (see Schedule 1, Special Rules, Rule 14(1) a) and b) of the Regulations) that is manufactured from or that incorporates:

human or animal cells or tissues or their derivatives
a product produced through the use of recombinant DNA technology

Table 1: Animal tissues and derivatives and the minimum treatment conditions that qualify for reduced data requirements
Animal tissue or derivative	Minimum treatment or condition
Amino acids^{Footnote 3}	Amino acids produced from hides and skins by processes that involve: material exposure to a pH of 1 to 2, followed by a pH of >11, followed by heat treatment at 140°C for 30 minutes at 3 bar post-production filtration of the AAs/peptides analysis of residual intact macromolecules that demonstrates compliance with appropriate limits and is based on validated and sensitive methods
Blood derivatives from ruminants (including serum)	Each batch of serum or plasma shall be traceable to the slaughterhouse, farms from which the animals are sourced and individual animals. Also, bovine blood shall be sourced from countries with minimal exposure to bovine spongiform encephalopathy (BSE) unless justified. Method of slaughter must also be known. Captive bolt stunning (with or without pithing), pneumatic stunning (with or without air injection) and some non-penetrative stunning methods can destroy the brain, cause CNS tissue embolism and disseminate higher infectivity tissues into the blood stream. As such, stunning methods must be described, unless the material is sourced from a country with a negligible BSE risk status. If blood and/or blood derivatives are sourced from countries with limited BSE exposure, a non-penetrative stunner or electro-narcosis shall be used for slaughtering animals over 12 months of age. The use of non-penetrative stunning shall be justified on the basis of a risk estimate of brain/cns tissue dissemination into the blood. Fetal bovine serum: obtained from fetuses harvested in abattoirs from healthy dams fit for human consumption, where the womb was completely removed. The blood shall be harvested in a dedicated space by cardiac puncture in a closed collection system using aseptic technique. New born calf serum: obtained from calves aged less than 20 days. Calf serum: obtained from calves aged less than 12 months. Donor bovine serum: can be derived from animals aged less than 36 months old, provided the BSE status of the herd is well defined and collection is done to avoid cross-contamination with higher-risk tissues.
Charcoal (animal)^{Footnote 3}	Regardless of the geographical region and nature of the tissue, these materials present a negligible TSE risk when prepared by carbonization at temperatures > 800°C.
Collagen, produced from bones	Manufacturing conditions specified for gelatin apply when collagen is derived from: countries with minimal exposure to BSE (interpreted as negligible risk) countries on the APHIS List or low-risk herds (defined in ISO 22442-2) and when obtained from animals fit for human consumption
Collagen, produced from hides and skins	This material does not present a significant TSE risk, provided there is no cross-contamination with potentially infected materials during procurement.
Gelatin derived from hides	When obtained from animals fit for human consumption, this material: is considered a safer source than bones is considered not to present a significant TSE risk Cross-contamination with potentially infected materials must be avoided during procurement. No other specific processing requirements are required.
Gelatin derived from bones	Bones shall be sourced from countries with minimal or limited exposure to BSE. Skulls and spinal cords shall be removed from the collected bones (source of specified risk material, SRM) from cattle of a specific age as defined in national legislation. Vertebrae shall be removed from the raw/starting materials from cattle of all ages from countries with limited exposure to BSE. Both acid and alkaline manufacturing methods described below have shown similar overall TSE inactivation/elimination potential. However, an additional alkaline treatment (pH 13 for 1 hour) further increases the effectiveness of the acid manufacturing process. Typical alkaline treatment involves degreasing finely crushed bones with hot water. This is to be followed by (in order): de-mineralization with HCl (4% min) at a pH of < 1.5 over 48 hours to produce ossein an alkaline treatment with saturated lime solution (pH ≥ 12.5) for at least 20 days Following concentration of gelatin, it is subjected to a flash heat treatment of 138°C to 140°C for 4 seconds. The acid process typically involves replacing the liming step with an overnight acid soak at pH < 4. The finishing steps are similar to the alkaline treatment. As part of the heat/pressure process, the dried, degreased and crushed bones are autoclaved with saturated steam at pressures > 3 bar and a minimum temperature of 133°C for at least 20 minute. This is, followed by an extraction of the protein with hot water.
Heparin, including crude forms	The materials must not be contaminated by either over-sulfated chondroitin sulfate (OSCS) or ruminant materials. A certificate of conformity with a recognized pharmacopeia (for example, USP, Ph. Eur., BP) supports material safety.
Milk and milk derivatives	Subject to national legislation, milk derivatives manufactured according to the conditions below present an acceptable TSE risk if: the milk is sourced from healthy animals under the same conditions as milk collected for human consumption and no other ruminant-derived materials, with the exception of calf rennet, are used to prepare such derivatives (for example, pancreatic enzyme digests of casein) Also, a risk assessment has been conducted on lactose and other whey derivatives. The assessment has determined that the TSE risk is negligible if the calf rennet is produced in accordance with that described in the assessment report.^{Footnote 1} ^{Footnote 2}
Peptone derivative of animal materials	Peptones are partial hydrolysates of protein, achieved by enzymatic or acid digestion. They are used in microbiological culture media to support the nutritional requirements of micro-organisms, which might be used as seed stocks. They are also used in industrial-scale fermentations for the production of human and veterinary medicinal products, including vaccines. Where gelatin is the source material, requirements for gelatine apply. Where casein is the source material, requirements for mild and milk derivatives apply. Where tissue of TSE-relevant animal species is the protein source material, the tissue must be sourced from animals fit for consumption with a maximum age of 30 months old for cattle from countries with a controlled BSE risk (Category B). The age of animals is of minimal concern for animals from countries with a negligible BSE risk (Category A).
Tallow3 derivatives, including glycerol and fatty acids	Tallow derivatives manufactured from tallow by processes at least as rigorous as those described below are thought to present acceptable TSE risk, regardless of the geographical origin and nature of the tissues from which the derivatives are derived. These processes include: trans-esterification or hydrolysis at not less than 200°C for not less than 20 minutes under pressure (glycerol, fatty acids and fatty acid esters production) saponification with 12 M NaOH (glycerol and soap production) in a batch process ≥ 95°C for ≥ 3 hours or in a continuous process ≥ 140°C under pressure for ≥ 8 minutes or equivalent distillation at 200°C
Wool and its derivatives, including lanolin and wool alcohols	When derived from healthy slaughtered animals declared "fit for human consumption", these materials are considered to present an acceptable TSE risk. This is only if the manufacturing process in relation to pH, temperature and duration of treatment meets at least 1 of the following stipulated processing conditions: treatment at pH ≥ 13 (initial; corresponding to NaOH concentration of ≥ 0.1M) at ≥ 60°C for at least 1 hour molecular distillation at ≥ 220°C under reduced pressure
Table 1 Footnote 1 EMEA. 2002. Risk and Regulatory Assessment of Lactose and Other Products Prepared Using Calf Rennet. Biotechnology Working Party Meeting 11-13 February 2002. Public Report. The European Agency for the Evaluation of Medicinal Products, Pre-authorization Evaluation of Medicines for Human Use. Doc.Ref.: EMEA/CPMP/BWP/337/02/Public/Final. Table 1 Return to footnote 1 referrer Table 1 Footnote 2 EMEA/410/01 Rev.3 — June 2011, Note for guidance on minimizing the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products adopted by the Committee for Proprietary Medicinal Products (CPMP) and by the Committee for Veterinary Medicinal Products (CVMP). Official Journal of the European Union 5.3.2011. Table 1 Return to footnote 2 referrer Table 1 Footnote 3 Amino acids, charcoal (animal) and tallow derivatives that are acceptable for TSE risk (Annex C) due to their processing and not their sourcing shall also be considered to have acceptable risk for viruses, bacteria, molds and yeasts, but are subject to proper storage conditions. Table 1 Return to footnote 3 referrer

Definitions

Collagen: A fibrous protein component of mammalian connective tissue.

Closed herd (replaces low-risk herd): A herd governed by SOPs that specify criteria restricting admission of new animals to ensure that all introduced animals are at the same or higher health standard, compared to the residents of the herd. There should also be a fully documented record of any animals kept within close proximity to the closed herd.

Derivative: A substance obtained from an animal material by a manufacturing process. Examples include hyaluronic acid, collagen, gelatin, monoclonal antibodies, chitosan and albumin that is involved directly in the manufacturing process of the medical device or is part of the final medical device).

Gelatin: A natural soluble protein (gelling or non-gelling) obtained by the partial hydrolysis of collagen produced from bones, hides, skins, tendons and sinews of animals.

Master cell bank (MCB): A collection of cells of uniform composition, derived from a single source and prepared under defined culture conditions. Working cell banks are derived from the MCB.

Device: An instrument, apparatus, contrivance or other similar article, or an in vitro reagent, including a component, part or accessory of any of them, that is manufactured, sold or represented for use in:

diagnosing, treating, mitigating or preventing a disease, disorder or abnormal physical state, or any of their symptoms, in humans or animals
restoring, modifying or correcting the body structure of humans or animals or the functioning of any part of the bodies of humans or animals
diagnosing pregnancy in humans or animals
caring for humans or animals during pregnancy or at or after the birth of the offspring, including caring for the offspring or
preventing conception in humans or animals

A device does not include an instrument, apparatus, contrivance or article, or a component, part or accessory of any of them, that does any of the above actions solely by pharmacological, immunological or metabolic means or solely by chemical means in or on the body of a human or animal.

Non-viable: No potential for metabolism or multiplication.

Prion (PrPTSE): Proteinaceous and infectious prion particle, which is the causative agent of TSEs.

Prohibited material: Defined in Part XIV S.162 in the Health of Animals Regulations as:

anything that is, or that contains any, protein that originated from a mammal, other than:
1. a porcine or equine
2. milk or products of milk
3. gelatin derived exclusively from hides or skins or products of gelatin derived exclusively from hides or skins
4. blood or products of blood or
5. rendered fats, derived from ruminants, that contain no more than 0.15% insoluble impurities or their products and
Prohibited material that has been treated in a manner approved by the Minister to inactivate the agents that cause transmissible spongiform encephalopathies is no longer prohibited material

sCJD: Sporadic Creutzfeldt-Jakob disease is attributed to a genetic polymorphism of the gene encoding endogenous normal prion protein (PRNP).

Tallow: The rendered form of fat, processed from animal fat (suet), which may also be derived from bones and offal.

TSE: Transmissible spongiform encephalopathies are transmissible and fatal neurodegenerative diseases.

vCJD: Variant Creutzfeldt-Jakob disease is a variant form of CJD, a human TSE that is distinguished from the sporadic form (sCJD).

Xenograft: The live cells, tissues and organs used in xenotransplant procedures.

Xeno-harvested: Material obtained from an animal species other than humans.

Xenotransplantation: The use of live cells, tissues or organs from a non-human animal source transplanted, infused or implanted into a human or used for ex vivo contact with human body fluids, cells, tissues or organs that are subsequently transplanted, infused or implanted into a human recipient. Excluded are live cells tissues or organs from a non-human animal source that, due to modification, manipulation or combination with other components, fall under the definition of a medical device.

Zoonosis: A disease or infection that is transmissible from vertebrate animals to humans.

Note about guidance documents in general

Guidance documents provide assistance to industry and health care professionals on how to comply with governing statutes and regulations. They also provide guidance to Health Canada staff on how mandates and objectives should be met fairly, consistently and effectively.

Guidance documents are administrative, not legal, instruments. This means that flexibility can be applied. However, to be acceptable, alternate approaches to the principles and practices described in this document must be supported by adequate justification. They should be discussed in advance with the relevant program area to avoid the possible finding that applicable statutory or regulatory requirements have not been met.

As always, Health Canada reserves the right to request information or material, or define conditions not specifically described in this document, to help us adequately assess the safety, efficacy or quality of a therapeutic product. We are committed to ensuring that such requests are justifiable and that decisions are clearly documented.

This document should be read along with the relevant sections of the Regulations and other applicable guidance documents.

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Date modified:: 2013-09-09

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