Centre for Reproductive Medicine and Fertility Jessop Wing Tree Root Walk Sheffield S10 3SF

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1 Assisted Conception Unit Consultants: Prof William Ledger Mr Jonathan Skull (Clinical Head) Mr TC Li Mr Hany Lashen Clinical Nurse Specialist Anne Mowforth Scientific Staff Dr Karen Martin (Head of Embryology) Dr Allan Pacey (Head of Andrology) Rachel Cutting (Senior Embryologist) Business Support Manager Val Kitcheman Centre for Reproductive Medicine and Fertility Jessop Wing Tree Root Walk Sheffield S10 3SF EU Open Consultation on Draft Technical Requirements for Tissues and cells Response from: Assisted Conception Unit Centre for Reproductive Medicine and Fertility The Jessop Wing Sheffield Teaching Hospitals NHS Foundation Trust Sheffield S10 2SF 21 st June General Comments Directive 2004/23/EC was adopted to prevent the transmission of diseases by human tissues and cells, specifically applying to the donation, procurement, testing, processing, preservation, storage and distribution of human cells intended for the human application and of manufactured products derived from human tissues and cells intended for human applications. As the technical annex of the directive covers a wide range of applications some of the terminology and structure used in the document have questionable relevance to IVF clinics. From a historical view point IVF clinics have developed differently from tissue banks and therefore the implementation of the directive will be more complex and involve a greater working and financial burden on ART clinics. The directive is written biased towards tissue banks where the document can be more easily applied. Interpretation and application to the IVF unit will be much more difficult as no specific requirements have actually been detailed. A separate document with specific guidance for IVF units should be developed. IVF units are currently inspected by the HFEA and to impose further inspections on units would create time pressures on clinics. We feel that discussions between the EC and the HFEA may have been useful prior to creation of the document. Comments on specific sections Section 2.A.1 The Person Responsible in an IVF unit with respect to HFEA requirements may have different qualifications and experience to those outlined in Article 17 and may cause confusion within the IVF unit. A conflict of interest may arise between the two individuals to who is overall responsible for the unit as the EU directive remit for a person responsible is different to that of the HFEA. Reception: Results Line: Business Support Manager: Fax: Embryology Hospital Switchboard:

2 Section 2.A.3 As a unit we have currently started to implement ISO 9001, although supportive of a quality management system this does have financial and staffing implications. Initial costs have been covered through sponsorship but the unit will have to meet the ongoing financial costs of running ISO. Tissue banks may already have systems in place and have staff employed specifically for this work and therefore can employ the directive without difficulty. Section 2.A.5 With respect the term third party, it is unclear to how this relates to IVF procedures, is this the patient undergoing treatment, suppliers of consumables / services? This needs clearer definition. Section 2.C.2 In the definition section critical is defined as potentially having an effect on the quality and / or safety or having contact with cells and tissues. This is a broad definition and may be interpreted differently in different units. Validation has cost implications, as units will have to employ Validation consultants / companies to perform the work or purchase the necessary equipment to fulfil the requirements. The process of Validation is complex and in the definitions it is not clear whether all aspects of Validation, DQ, IQ, OQ and PQ will need to be covered and to what extent the unit will have to provide documented evidence. Costs will ultimately be passed on to either self-funding patients or to PCTs which may restrict the number of people having access to treatment. Section 2.C.6 Guidance is needed to determine what the documented requirements and specification should be for IVF products. Section 2.D.3 and 4 The requirement in a tissue bank is to protect the recipient from disease transmission as the tissue is not autologous. In the majority of cases IVF involves gametes received from the couple undergoing treatment and does not involve donation. IVF therefore is a different concept to tissue banking and therefore the processes involved in IVF should be considered separately. The document states that a less stringent environment may be acceptable in 4 cases. The two options that may be applicable to IVF are c and d. In option c, it states that if it can be demonstrated that the mode and route of application of the tissue or cell to the recipient implies a significantly lower risk of bacterial or fungal infection than cell and tissue transplantation a lower grade may be acceptable. The example given is insemination, clearer guidance is required as it is unclear - does this mean IUI treatments or the whole process of IVF. If this applies to IUI why is this not extended to embryo transfer and embryo culture? Clearer guidance is required to define what is acceptable and what defines a lower risk. In option d, a lower grade of air quality is acceptable if it is technically not possible to carry out a procedure in a grade A environment. This is open to different interpretation, for example is it possible to carry out ICSI in a flow cabinet; (The ICSI procedure in the majority of clinics is currently not carried out in a flow cabinet due to fears of external vibration

3 interfering with the delicate injection procedure) It is possible to carry out ICSI in a flow cabinet as demonstrated in our unit but does the equipment physically reduce the effectiveness of the cabinet. Does this clause mean that ICSI can be performed outside a cabinet or in a cabinet to try to attain grade A? If these two options are applied to IVF, the document still states that the environment is as close as possible to grade A, and documentation needs to be provided to demonstrate that it achieves the quality and safety required for the intended purpose. How is this quality and safety defined? Who defines this and how is this standardised? Clearer guidance is required to enable units to proceed in a standardised manner. Guidance is needed to whether continuous particle monitoring is required (eg for flow cabinets) We are currently in the process of upgrading our laboratories to near GMP standards which will meet the EU directive, we have been fortunate to secure funding for this but other units may have difficulty in funding projects similar to ours. Section 2.D.5 The document does not refer to what appropriate garments are. Section 2.D.8 The concept of quarantine / release is not applicable for autologous routine IVF. We agree the concept for donated material as far as technology applies (e.g. not feasible for donated oocytes due to the current ineffectiveness of storage). Section 2.F.2 Defining the required standards of safety and quality for embryos in an IVF treatment is different to stating if a tissue has met the agreed standards for release and donation. Defining quality of embryos (product) is subjective and may be influenced by environmental and genetic factors. Non conformances may be interpreted as situations such as a failed fertilisation, failed cleavage or failed thaw. Any non-compliance of the equipment during monitoring would be recorded but embryos cultured/exposed in this environment would still be replaced if their development was assessed as normal, unless there was evidence of an infection or the embryo failed to develop. To not replace any embryos that were cultured during a non-compliance would be unethical practice, although patients would be informed. An example of this would be if a flow hood failed to maintain grade A whilst the embryo was being manipulated it would be unethical not to proceed with the patient s treatment. Section 3.B Although fully supportive in improving standards within IVF clinics further guidance is required with respect to validation. This may be a new concept for IVF units and employing validation consultations will have financial implications for units. Section 4

4 Clearer guidance is required to enable clinics to determine what is a serious adverse event with respect to this directive and confusion may occur with the alert system complied by the HFEA. Only one system should exist. Annex 1 and 2 The forms designed for the reporting of serious adverse events are designed for use within tissue banks, more relevant forms should be designed for use within ART clinics. Only one form should be in existence to prevent duplication with HFEA s system. Conclusion Whilst parts of the documents such as the quality management system will be able to be implemented into IVF clinics to improve working practice, this will not be without implications for both the staff and financial status of units. The impact on clinics will vary and comprehensive guidance is required to enable units to meet requirements. The technical draft fails to do this and it still leaves many questions unanswered and parts open to individual interpretation.

5 This paper represents the views of its author on the subject. These views have not been adopted or in any way approved by the Commission and should not be relied upon as a statement of the Commission's or Health & Consumer Protection DG's views. The European Commission does not guarantee the accuracy of the data included in this paper, nor does it accept responsibility for any use made thereof.