The risk assessment of zoonoses
May 03 2023
and their legal requirements
The obligation of the legal manufacturer of medical devices to carry out specific risk management is set out in Chapter II of Annex I under the essential safety and performance requirements. In addition, the MDR stipulates that the following regulations and directives must also be applied to materials of animal origin:
- Regulation 722/2021 - Requirements for active implantable medical devices and medical devices manufactured using tissues of animal origin
- Regulation 1069/2009 - Hygiene requirements for animal by-products not intended for human consumption
- Commission Decision 2007/453 - Determination of the BSE status of Member States, third countries or regions thereof according to their BSE risk
In addition to the MDR, these regulations and directives also apply to materials of human origin. They apply not only to medical devices, but also to medicinal products:
- Regulation 2004/23 - Establishment of quality and safety standards for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells
- Directive 2002/98 - Setting standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components
- Directive 2001/83 - Creation of a Community code relating to medicinal products for human use
- Regulation 1394/2007 - Advanced therapy medicinal products
In addition, ICH guidelines and monographs of the European Pharmacopoeia are applicable.
Normative requirements
There are only normative requirements for medical devices with components of animal origin. In particular, the ISO 22442 series of standards must be applied. There is an obligation to take into account relevant publications and opinions of the European Commission, EFSA, WHO and WOAH (formerly OIE).
The 22442 series of standards describes in detail the risk assessment process to be applied to medical devices with components of animal origin. Therefore, the requirements for the safety of a medical device with components of animal origin and the instructions on how compliance with these requirements can be checked are briefly summarized below.
ISO 22442 Part 1: Application of risk management
The scope of Part 1 of ISO 22442 is the management of hazards that may arise from medical devices made from animal materials (MAO). These are in detail:
- Contamination with bacteria, fungi, yeasts, viruses, TSE agents, parasites and unclassified pathogenic agents
- Material responsible for biological incompatibilities
- Acceptance criteria for certain substances and materials
With reference to ISO 14971, Part 1 describes all aspects of special risk management for MAO:
Although the main focus of risk assessment and risk control is on viruses and TSE agents, you should also collect detailed data for the other transmissible agents (bacteria, yeast, fungi and parasites) and carry out a risk assessment and risk control based on this. As the pathogens and the infection status of the animals in the countries of origin can change and small changes in the process can have an impact on the residual risk, you should regularly check whether your risk assessment is up to date. Therefore, as required by the standard, you should set up a post-market surveillance system and a change control system and define how often a review of the risk assessment must be carried out.
The normative Annex C describes the specific requirements for these special MAOs: collagen, gelatine from bones and skin, bovine blood derivatives, tallow derivatives, animal charcoal, milk and milk derivatives, wool and wool derivatives and amino acids. The materials and requirements mentioned largely correspond to those in EMA/410/01 rev3. It is important to note that risk management in accordance with ISO 22442 must also be carried out for these products if the requirements are met by the medical device.
In addition, Part 1 summarizes the relevant information for TSE risk management. It should be noted that this information is also applicable to the risk management of all transmissible agents. Therefore, you should take care to obtain very detailed data on these requirements.
At the end, the decision-making process for the acceptability of the residual risk is presented in a final report. This includes weighing up the residual risk as defined in ISO 14971 and a risk-benefit analysis including a comparison with available alternatives.
ISO 22442-2: Controls on sourcing, material collection and handling.
The basic requirement according to ISO 22442-2 is complete documentation of the sourcing, collection, handling and manufacturing process, which is embedded in the quality assurance system according to ISO 13485 and is subject to continuous monitoring.
In addition, there are specific requirements for the quality management system for the use of MAO, which places particular emphasis on origin, health, hygiene, extraction, processing, storage, transportation, acceptance criteria, records and audits as well as on qualified personnel, including at suppliers and service providers. Proof of qualification must be part of your documentation. As a legal manufacturer of a medical device with components of animal origin, you are obliged to control the origin, collection and handling (including storage and transportation) and to provide the relevant evidence. You should therefore conclude quality agreements with suppliers / service providers to monitor compliance with the defined acceptance criteria, training of employees, pooling and traceability.
Furthermore, requirements for MAO of bovine origin are defined in Part 2. Comparable measures are also applicable to MAO of ovine or caprine origin. This concerns the assessment of the likelihood that the source material could be infected or contaminated with the BSE agent and the extent of infectivity. It is therefore essential to collect and keep available attestations and certificates relating to the following criteria:
- BSE status of the country of origin (according to WOAH and / or EFSA)
- Cross-contamination during extraction and pooling
- Status of the herd (e.g. low risk in closed herds)
- Animal age (e.g. < 3 years for cattle)
- Feeding regime / feeding history (e.g. feeding ban for animal products)
- Tissue infectivity (WHO tables from 2010 and latest literature, uncertainty factor)
ISO 22442-3: Validation of removal and / or inactivation of viruses and TSE agents ISO/TR 22442-4
Part 3 of ISO 22442 is only applicable to viruses and TSE pathogens. In summary, Part 3 describes the requirements for the
- Qualification of personnel, equipment and experimental systems
- Literature research (methodology, objective, data sources, selection, relevance, equivalence, quality, evaluation, conclusions, report)
- Implementation, application of removal and / or inactivation studies (virus selection, study design, cultivation of viruses and cells, calculation of the reduction to scale, calculation of the reduction factor, limits of the study or relevant TSE pathogens and tissue, inactivation / removal procedure, TSE model pathogen + spike, assay method, correlation of TSE and infectivity, influence of tissue, repetitions, assay variability, individual steps versus overall process)
- Validation procedures
- Preparation and review of the final report
- Routine monitoring and control of the effectiveness of the process.
The requirements for validation and literature research are also applicable to bacteria, yeast, fungi, parasites and other pathogens that are not further classified, as long as this is not regulated by other normative requirements (e.g. for the sterilization process). It must be ensured that all pathogens that may be transmissible to patients are recorded.
ISO/TR 22442-4 Principles for the removal and / or inactivation of TSE pathogens
Part 4 describes how validation tests for physico-chemical TSE inactivation methods should be designed and performed. Information on human tissue and TSEs is presented that can be applied analogously to other animal tissues.
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