Medical Devices Manufactured Utilizing Tissues Or Cells Of Animal Origin

Introduction

Animal tissues and their derivatives are used in medical devices to provide functions that have advantages over non-animal materials.

The variety and amount of animal material in medical devices vary. These materials may form the bulk of the device (e.g., bovine/porcine heart valves, bone substitutes for dental or orthopedic applications, hemostatic devices), maybe product coatings or impregnating agents (e.g., collagen, gelatin, heparin), or may be used in the device manufacturing process (e.g., fat derivatives such as oleates and stearates, fetal calf serum, enzymes, media).

The use of this animal material has the risk of spreading infectious diseases if improperly collected, stored, or processed. (eg, prion diseases). Transmissible spongiform encephalopathy (TSE) is a prion disease that can affect the brain and nervous system of many animals, including cattle, sheep, goats, deer, elk, and mink. An outbreak of bovine spongiform encephalopathy (BSE), also known as “mad cow disease,” has prompted strict controls over the use of animal-derived material in medical devices because it infects humans, can cause brain inflammation, and can be fatal.

Examples of such Medical Devices are:

• Bovine / porcine heart valves
• Bone substitutes for use in dental applications.
• Collagen Injections
• Gelatin-sealed grafts

Specific requirements according to EU MDR

The EU MDR 2017/745 contains a section expressly devoted to the specifications for this kind of device in Chapter II of Annex I.

The regulation makes a distinction between:

• Devices utilizing derivatives of tissues or cells of human origin that are non-viable or are rendered non-viable; and
• Devices using animal tissues or cells that are viable or rendered non-viable;

For the first type of device, the specific applicable requirements can be summarized as follows:

• Directive 2004/23/EC applies to the donation, acquisition, and testing of tissues and cells used in the device.
• When processing tissues, special attention must be paid to the safety of the patient, user, or other person. , cells, and related derivatives. Special attention must be paid to viruses and other infectious pathogens and to the use of validated methods to eliminate possible sources of infection.
• The traceability system will be harmonized with the applicable Directive 2004/23/EC and Directive 2002/98/EC.

On the other hand, devices using tissues and cells of animal origin must meet the following requirements:

• Tissues and cells derived from animals, when possible and accounting for the type of animal, must come from animals that have undergone veterinary controls appropriate for the intended use of the tissues. Manufacturers are required to keep records of the animal’s geographic origins;
• Tissues, cells, and substances derived from animals, as well as their processing, preservation, testing, and handling, must all be done with patient safety, user safety, and other people’s safety in mind. Specifically, during the manufacturing process, safety concerns concerning viruses and other transmissible agents must be addressed by implementing validated methods of elimination or viral inactivation, unless doing so would cause unacceptable degradation that compromises the device’s clinical benefit.
• In such cases, special requirements are set for devices specified in Regulation (EU) No. 722/2012, the production of which uses tissues or cells of animal origin or their derivatives.

ISO 22442 – Medical devices containing animal materials

Medical devices that use materials or tissues obtained from animals belong to a significant class of devices and are subject to stringent regulations that fall within the ISO 22442 family of standards.

Of course, the regular procedures that apply to all devices still apply, including the risk management process, usability, and all requirements for validation activities (such as biocompatibility). To appropriately apply all of the basic requirements, however, particular standards are required for certain kinds of devices. In reality, certain risks must be taken into account when implementing risk management procedures, such as when it comes to contamination by bacteria, viruses, agents that cause transmissible spongiform encephalopathy (TSE), or anything else that could result in an unfavourable pyrogenic, immunologic, or toxicologic reaction.

The ISO 22442 set of standards, “Medical devices utilising animal tissues and their derivatives,” is aligned with and further clarified by the FDA guideline. Among the ISO standards in this series are:

The purpose of EN ISO 22442-1 is to offer guidelines and standards for risk management for the risks associated with medical devices that are produced using animal tissues or their derivatives, including:

• contamination by yeasts, molds, or bacteria
• contamination by viruses
• contamination by agents responsible for immunological, toxicological, or pyrogenic responses agents producing transmissible spongiform encephalopathies (TSE).

The purpose of EN ISO 22442-2 is to offer guidelines and regulations regarding:

• steps in the quality system processes
• people and instructions for locating, gathering, managing, storing, moving, and labeling tissues and animals

The purpose of EN ISO 22442-3 is to offer guidelines and regulations regarding:

• Review of the literature on the validation of the removal and/or inactivation of viruses and TSE agents during manufacturing; regular monitoring and control of crucial process parameters; and investigation of the removal and/or inactivation of viruses and TSE agents.

Risk assessment of devices containing animal tissues according to ISO 22442-1

In order to carry out an appropriate risk assessment, various aspects must be taken into account. For example, one must assess whether the Contact type between the body and the material comes from animal tissue. Duration of exposure, type of fluid exposed and other similar issues must be considered.

In addition, the types of materials that come into contact with or are contained in the medical device must be carefully analyzed. In this case, different factors must be analyzed, for example:

• Furthermore, the terms and circumstances of the device’s supply are crucial. Variations in the bioburden level of bacteria or other microorganisms in the tissues will be estimated according to the norm.
• Finally, it is important to assess whether any harmful residues have been left over from the production process. This should be thoroughly evaluated from a risk perspective.
• The residual risk acceptance stage, which must be completed at the level of each risk, is the next step in the traditional risk management approach.
• The acceptability of the associated risk for TSE (transmissible spongiform encephalopathy) must meet certain criteria.

Based on ISO 22442-1, TSE-related risks can be considered acceptable under the following conditions:

• The residual risk assessment shows that the TSE risks have been reduced as much as possible to an acceptable level
• In the context of a risk/benefit analysis, the medical benefit arising from the intended use of the device is judged to outweigh the residual risk estimate.

Finalizing the assessment of the overall risk acceptability is one of the last steps in the risk management process. After the risk management mechanisms have been put in place, this evaluation usually consists of assessing each remaining risk together with the anticipated medical benefit of the particular medical device.

Situations when there are still concerns associated with transmission agent contamination require special consideration. It will be determined whether to utilize: a) alternative materials with a better risk/benefit profile; or b) other goods with the same intended purpose under these circumstances.

References