Commission Directive 2003/32/EC (repealed)Dangos y teitl llawn

ANNEX U.K.

1. RISK ANALYSIS AND RISK MANAGEMENT U.K.

1.1. Justification for the use of animal tissues or derivatives U.K.

The manufacturer must justify, on the basis of his overall risk analysis and risk management strategy for a specific medical device, the decision to use animal tissues or derivatives, referred to in Article 1, (specifying animal species and tissues) taking into account the expected clinical benefit, potential residual risk and suitable alternatives.

1.2. Assessment procedure U.K.

In order to ensure a high level of protection for patients or users, the manufacturer of devices utilising animal tissues or derivatives referred to in point 1.1 must implement an appropriate and well documented risk analysis and risk management strategy, to address all relevant relating aspects to TSE. He must identify the hazards associated with those tissues or derivatives, establish documentation on measures taken to minimise the risk of transmission and demonstrate the acceptability of the residual risk associated with the device utilising such tissues or derivatives, taking into account the intended use and the benefit of the device.

The safety of a device, in terms of its potential for passing on a transmissible agent, is dependent on all the factors described in points 1.2.1 to 1.2.7, which must be analysed, evaluated and managed. These measures in combination determine the device safety.

There are two key steps that must be considered.

These are:

• selecting starting materials (tissues or derivatives) considered appropriate regarding their potential contamination with transmissible agents (see 1.2.1, 1.2.2 and 1.2.3) taking into account further processing,

• applying a production process to remove or inactivate transmissible agents on controlled sourced tissues or derivatives (see 1.2.4).

Furthermore, the characteristics of the device and its intended use must be taken into account (see 1.2.5, 1.2.6 and 1.2.7).

In performing the risk analysis and risk management strategy, due consideration must be given to opinions adopted by the relevant scientific committees, and where appropriate to the opinions of the Committee for Proprietary Medicinal Products CPMP, the references of which have been published in the Official Journal of the European Union.

1.2.1. Animals as a source of material U.K.

The TSE risk is related to the source species, strains and nature of the starting tissue. As the accumulation of TSE infectivity occurs over an incubation period of several years, sourcing from young healthy animals is considered to be a factor reducing the risk. Risk animals such as fallen stock, emergency slaughtered and TSE suspected animals must be excluded.

1.2.2. Geographical sourcing U.K.

Pending the classification of countries according to the BSE status in Regulation (EC) No 999/2001 of the European Parliament and of the Council of 22 May 2001 laying down rules for the prevention, control and eradication of certain transmissible spongiform encephalopathies(1), the Geographical BSE risk (GBR) is used when assessing the risk of the source country. The GBR is a qualitative indicator of the likelihood of the presence of one or more cattle being infected with BSE, pre-clinically as well as clinically, at a given point in time, in a country. Where presence is confirmed, the GBR gives an indication of the level of infection as specified in the table below.

GBR level	Presence of one or more cattle clinically or pre-clinically infected with the BSE agent in a geographical region/country
I	Highly unlikely
II	Unlikely but not excluded
III	Likely but not confirmed or confirmed, at a lower level
IV	Confirmed, at a higher level

Certain factors influence the geographical risk of BSE infection associated with the use of raw tissues or derivatives from individual countries. These factors are defined in Article 2.3.13.2, point 1) of the International Animal Health Code of the OIE (Office International des Épizooties), which is available at web-site www.oie.int/eng/normes/Mcode/A_00067.htm

The Scientific Steering Committee has made an assessment of Geographical BSE Risk (GBR) of several third countries and Member States, and will continue to do so for all the countries, which applied for BSE status categorisation, taking the main OIE factors into account.

1.2.3. Nature of starting tissue U.K.

The manufacturer must take into account the classification of the hazards relating to different type of starting tissue. Sourcing of animal tissue must be subject to control and individual inspection by a veterinarian and the animal carcass must be certified as fit for human consumption.

The manufacturer must ensure that no risk of cross-contamination occurs at the time of slaughtering.

The manufacturer must not source animal tissue or derivatives classified as potentially high TSE infectivity, unless sourcing of these materials is necessary in exceptional circumstances, taking into account the important benefit for the patient and the absence of an alternative starting tissue.

In addition, the provisions in Regulation (EC) No 1774/2002 of the European Parliament and of the Council of 3 October 2002 laying down health rules concerning animal by-products not intended for human consumption must be applied.

1.2.3.1. Sheep and goats U.K.

A classification of infectivity in tissues for sheep and goats has been established based on actual knowledge on the basis of the titres of transmissible agents in tissues and body fluids from naturally infected sheep and goats with clinical scrapie. A table was presented in the Scientific Steering Committee (SSC) opinion of 22-23 July 1999 on ‘The policy of breeding and genotyping of sheep’, (as an annex)(2) and further updated in the opinion of the SSC — TSE infectivity distributed in ruminant tissues state of knowledge December 2001 — adopted 10-11 January 2002(3).

The classification may be reviewed in the light of new scientific evidence (for example using relevant opinions from the Scientific Committees, the Committee for Proprietary Medicinal Products CPMP and Commission Measures regulating the use of material presenting risks as regards TSE). A review of the references to relevant documents/opinions will be published in the Official Journal of the European Union and will be listed after a Commission Decision has been taken.

1.2.3.2. Cattle U.K.

The list of specified risk material (SRM) laid down in Regulation (EC) No 999/2001 shall be considered as potentially high TSE infective.

1.2.4. Inactivation or removal of transmissible agents U.K.

1.2.4.1. For devices which cannot withstand an inactivation/elimination process without undergoing unacceptable degradation, the manufacturer must rely principally on the control of sourcing. U.K.

1.2.4.2. For other devices, if claims are made by the manufacturer for the ability of manufacturing processes to remove or inactivate transmissible agents, these will have to be substantiated by appropriate documentation. U.K.

Relevant information from an appropriate scientific literature search and analysis can be used to support inactivation/elimination factors, where the specific processes referred to the literature are comparable to those used for the device. This search and analysis should also cover the available scientific opinions that may have been adopted by a EU Scientific Committee. These opinions shall serve as a reference, in cases where there are conflicting opinions.

When the literature search failed to substantiate the claims, the manufacturer must set up a specific inactivation and/or elimination study on a scientific basis and the following need to be considered:

• the identified hazard associated with the tissue,

• identification of the relevant model agents,

• rationale for the choice of the particular combinations of model agents,

• identification of stage chosen to eliminate and/or inactivate the transmissible agents,

• calculation of the reduction factors.

A final report must identify manufacturing parameters and limits that are critical to the effectiveness of the inactivation or elimination process.

Appropriate documented procedures must be applied to ensure that the validated processing parameters are applied during routine manufacture.

1.2.5. Quantities of animal starting tissues or derivatives required to produce one unit of the medical device U.K.

The manufacturer must evaluate the quantity of raw tissues or derivatives of animal origin required to produce a single unit of the medical device. Where a purification process is involved, the manufacturer must assess whether it may have the potential to concentrate levels of transmissible agents present in the animal starting tissues or derivatives.

1.2.6. Tissues or derivatives of animal origin coming into contact with the patients and users U.K.

The manufacturer must consider:

(i)

the quantity of animal tissues or derivatives;

(ii)

the contact area: its surface, type (e.g. skin, mucous tissue, brain) and condition (e.g. healthy or damaged);

(iii)

the type of the tissues or derivatives coming into contact with the patients and/or users; and

(iv)

how long the device is intended to remain in contact with the body (including bioresorption effect).

The number of medical devices that could be used in a given procedure shall be taken into account.

1.2.7. Route of administration U.K.

The manufacturer must take into account the route of administration recommended in the product information, from the highest risk down to the lowest.

1.3. Review of the assessment U.K.

The manufacturer must establish and maintain a systematic procedure to review information gained about their medical device or similar devices in the post-production phase. The information must be evaluated for possible relevance to safety, especially:

(a)

if previously unrecognised hazards are detected;

(b)

if the estimated risk arising from a hazard is no longer acceptable;

(c)

if the original assessment is otherwise invalidated.

If any of the above apply, the results of the evaluation shall be fed back as an input to the risk management process.

In the light of this new information, a review of the appropriate risk management measures for the device must be considered (including rationale for choosing an animal tissue or derivative). If there is a potential that the residual risk or its acceptability has changed, the impact on previously implemented risk control measures must be re-evaluated and justified.

The results of this evaluation must be documented.

2. EVALUATION OF CLASS III MEDICAL DEVICES BY NOTIFIED BODIES U.K.

For devices falling into Class III under rule 17(4) of Annex IX to Directive 93/42/EEC, manufacturers must provide to the notified bodies referred to in Article 4 of this Directive all relevant information to allow evaluation of their current risk analysis and risk management strategy. Any new information on TSE risk, collected by the manufacturer and relevant for their devices must be sent to the notified body for information.

Any change in relation to processes of sourcing, collection, handling and inactivation/elimination and that could modify the result of the manufacturer's risk management dossier must be transmitted to the notified body for the purpose of an additional approval prior to its implementation.

(1)

OJ L 147, 31.5.2001, p. 1.

(2)

Available on the website of the Commission

http://europa.eu.int/comm/food/fs/sc/ssc/outcome_en.html.

(3)

Available on the website of the Commission

http://europa.eu.int/comm/food/fs/sc/ssc/outcome_en.html.

(4)

All medical devices utilising animal tissue or derivatives rendered non-viable except devices intended to come into contact with intact skin only.