Lie elk cont Maker ened Implementation of the EU Tissues and Cells Directives EU rules on quality and safety standards for tissues and cells are laid out in three directives, but the member states have implemented them in rather different ways. Christa Schréder and Matthias Wilken look at how Germany has gone about it, while Lubomir Arseniev and Tatyana Benisheva-Dimitrova examine the situation in Bulgaria. In March 2004, the European Parliament and the Council established Directive 2004/23/EC for setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells in the European Union’. This was followed in 2006 by two commission directives (Directive 2006/17/EC2 and Directive 2006/86/ EC) in order to further define technical requirements in accordance with the principles of Directive 2004/23/EC. Directive 2004/23/EC and the commission directives have only recently been transposed. into national law in all the EU member states. Furthermore, those member states that had earlier transposed the directive(s) have to some extent chosen different approaches to their implementation in national law. The European Commission's health & consumer protection directorate-general has produced a table showing responses regarding the situation in the member states and in Norway, Iceland and Liechtenstein as of 8 February 20074, This was done on the basis of a questionnaire sent to the authorities in preparation for the first meeting of competent authorities on tissues and cells, which the commission organised in February 2007 in order to exchange experiences with the transposition of the directives into national laws. ‘his article is the first of two for RA] Pharma that will look at the way the three directives have been transposed and implemented in the various member states. This first article examines the situation in Germany and Bulgaria. The second, to be published in a future issue, will examine the situation in France and the UK. Germany Implementation of the directives In Germany, the directives were implemented into national law by legislation on human tissue and cells that was passed on 24 May 2007 by the Bundestag (German national parliament) and on 6 July 2087 by the Bundesrat (Federal Council). The Human Tissues and Cells Act (Gewebegeset2) ‘came into force on 1 August 2007. ‘The Human Tissues and Cells Act is an omnibus bill and is based on the legal framework for human tissues and cell, as well as the German Medicines Act (AMG®) with its implementing rules, the German Transplantation Act (TPG?) and the German Transfusion Act (TRG). The rules for quality and safety requirements for donation facilities and tissue establishments are inthe TPG, and the legal authorisation requirements for human tissue and cell harvesting are in the AMG. Ethical questions concerning human tissue and cell harvesting, such as information and consent of donors or their relatives, are now addressed in the TPG. Human tissues and cells are almost completely subject to the rules of the AMG; exceptions are tissues and cells that are removed from a person as part of a single treatment procedure in order to re-transplant them, Cornea and germ cells used for fertilisation are, however, subject to the AMG (Section 2, No 3, para 8; Section 4a, para 2). The AMG stipulates the conditions required to ensure the quality and safety of medicinal Products, as well as the use of human tissue and cells as medicinal products. Other legal rules concerning human tissue and cells apply too, one of which is Section 17 of the TPG. Non- industrially manufactured and sufficiently well known tissue and cell preparations, such as heart valves and bones, are subject to a trade embargo under the TPG. Authorisation for marketing human tissue and cell preparations Arecent edition tothe AMG is Section 21, which contains new regulations for the authorisation of ‘well known human tissue and cells that have been processed using common techniques and 1 Chita Schroder scenic ana regultry alan, advanced therapy matical produ ae sue preparations, athe PrulEeteh neat Langen Germany (chop 3) Mathie Wilken isha of drug inultny sans Eaope st he Garman Phanmacruilidueyasciton te PL Bern en de, Lbomit Ameen quali person, hes of podton {a production developmen of te Crone Grup ans siete conether a he Medic Univers School, Hane (bir ‘Sseievdeyone le) Tatyana Benishevs:Dimirova ease poten of Gr aslatry ais nthe Fay of Ps Hen st ‘he Medial Unversy Sota enschevsWByshoo com). © Informa UK Le 2008 \wwitaipharms.com cscossamaust RAJ Pharma June 2008 363 The directives have only recently been transposed into national aw i all the EU member states Germany's Human Tissues and Cells Act is ‘an omnibus bill, based ‘on the legal frametoork for human tissues andRegulatory Feature Authorisation ruainty dats with the examination of the product's suitability and safely ‘The authorities in charge are not obliged to inspect the harvesting establishment in the ‘non-member state Among other things, the German Transplantation Act regulates the quality control of the harvested tissue and cells rot been manufactured by industrial methods. For example, heart valves, corneas, bones and skin, as well as allogeneic or autologous bone marrow and peripheral blood progenitor cells for haematological transplantation, fall into this category. These regulations also apply to human tissue and cell preparations that are produced by means of a new process but are nonetheless still ‘comparable to those produced using the usual processes ‘Authorisation according fo Section 21a AMG mainly deals with the examination of the product's suitability and safety It is possible to submit documents in support of the application, in particular those concerning scientific experience in the field of application. Only when this, authorisation has been granted will it be permitted to distribute the abovementioned human tissues and cells on the German market. In comparison to the standard marketing authorisation for medicinal products, a somewhat simplified authorisation procedure utilising the EU-CTD (common technical document) is proposed by the competent national German authority (Paul- Ehslich-Institut ~ PED, Import of human tissues and cells A certificate issued by the PEIis required forall tissue and cell preparations that are tobe distributed in a member state of the EU or the European Economic Area when importing them into Germany for the first time. However, the exact procedure has not yet been clarified; it may be established in similar way toa national authorisation by using a simplified marketing authorisation procedure via the EU-CTD. Tissue and cell preparations have to meet the requirements of the AMG and its regulations. Should the certificate from the country of origin turn out to be of the same standard, the PEI will accept it (Section 21a, 9, AMG). In addition, the law allows for a simplified import permit for known tissue and cell preparations such as heart valves imported to Germany from non-EU/EEA member states Section 72b AMG). Either the importer has to provide a certificate from its own authorities showing that the tissues and cells are manufactured in accordance with professional standards similar to those in Germany, or else the local German authorities in charge (inthis case, the regional commission) have to assure themselves on site that the standards of “good professional practice” are followed. In eeither case, the authorities in charge are not obliged to inspect the harvesting establishment in the non-member state, for example when the importer is well known. If neither a certificate nor ‘an inspection is possible, the responsible authority is allowed to certify that the import is in the interest of the public. When medicines are imported for ditect or immediate use, eg bone marrow ‘or blood stem cells, the import restrictions according to Section 72, 2 AMG have to be considered. Reporting serious events and serious adverse reactions ‘The holder of a permit or an authorisation must inform the PEI of any suspected incidents, such ‘as damage during manufacture, and any suspected severe adverse reactions in patients or donors. Serious incidents and reactions to unlicensed and unauthorised tissue or cell preparations even if they are only suspected ~ must be reported to the local authority in charge (the regional commission), Transitional provisions ‘A number of transitional provisions were put in place concerning applications. Applications for permission to remove, prepare or process (Section 20b, 1 or 2 or Section 20c, 1 AMG) and ‘manufacture (Section 13, 1 AMG) had to be made by 1 October 2007. Only when the decision on the ‘application had been made could the tissue cells or preparations thereof be placed on the market Applications for authorisation according to Section 21a, 1 AMG had to be submited to the PEI by. 1 February 2008, while applications for a registration approval permit (Section 21, 1 AMG) must bbe made to the PEI by 30 September 2008 ‘Any manufacturing permits and authorisations previously granted are unaffected by these transitional provisions. Requirements of the Transplantation Act Since 1997, the Transplantation Act (TPG) has covered issues relating to organ donors and donations. Harvesting of an organ is not permissible without the consent of the donor or a close relative. The TPG regulates the following: quality control of the harvested tissue and cells; he related documentation and its preparation; traceability from the donor to the recipient and vice versa; the storage period; and the reporting of serious events and serious adverse reactions via hospitals, Section 8f of TPG stipulates the need for a register of tissue and cell establishments. The German Institute for Medical Documentation and Information (DIMD)) keeps a record of these. Although blood is considered to be an organ, the TPG does not apply to blood, blood components or blood products. Instead, the Transfusion Act (TG) applies. 3G4 June 2008 RAJ Pharma memeneon wonraipharma.com © Informa UK Ld 2008Under-age bone marrow donors Persons who are of full age (18 years or over) and able to give their informed consent may donate ‘bone marrow to another person for the treatment of a severe illness, after obtaining all the relevant facts and agreeing to the bone marrow harvesting procedure. The donor has to be considered suitable by a doctor. The Tissue and Cells Act allows under-age bone marrow donation under very tight restrictions, and only when itis for first-degree relatives (je children donating to parents or siblings) Priority of organ donation over tissue/cell extraction ‘The legislator has specifically granted organ donation priority over tissue and cell donation. The reason for this isto avoid any chance of competition occurring between free organ donation and the often commercially run tissue and cell harvesting, Tissue/cells embargo The Tissue and Cells Act restricts commercalisation in tems of the procurement of and trade in tissue and cell products. Non-industrially manufactured and sufficiently well known tissue and cell preparations, such as heart valves and bones, are subject to a strict trade embargo under the Transplantation Act However, only allogeneic preparations fall under this restriction, which means that autologous and allogeneic bone marrow, for example, have diferent status Another exception to the rule is medicinal products, which have to obtain a marketing authorisation according to Section 21 AMG. In addition, celL-based medicinal products in terms ‘of Section 4, 20 do not fll under the trade embargo. Neither do the costs and medical expenses incurred in organ procurement, transportation and preservation and in quality control testing in ‘order to prevent infection or other disease transmission. Implementation of the directives The first national Bulgarian regulation in the field of organ, tissue and cell procurement, donation and use was initially established in the national health law in the mid-1970s, In September 2003, a dedicated law on the transplantation of organs, tissues and cells (the Transplantation Lav) was passed by the Bulgarian parliament and entered into force on 1 January 2004. To transpose the EU directives into national law, the Bulgarian Transplantation Law was amended, with the last amendments coming into force on 1 January 2007 ‘The Transplantation Law regulates all issues in the areas concerned apart from the following: blood donation and transfusion of blood and blood components; assisted reproduction; autologous transplantation performed within the same invasive procedure; and implantation of artificial organs and tissues. Blood transfusion-related issues are covered by the law on blood, blood donation and blood transfusion (the Transfusion Law), which was first issued on 21 November 2003 and last amended in April 2007 (the amended version came into force on 11 August 2007), With these amendments, responsibility for supervision and conttol was given to the Bulgarian Drug Agency (BDA), the national regulatory authority in the field of medicinal products and medical devices! Assisted reproduction is addressed by Patt III, Atticles 129-136, of the Health Law that was last amended in November 2007 (State Gazette (SG) No 95, which came into force on 1 January 2008). Under the transplantation and drug legislation, the Executive Agency for Transplantation (Transplantation Agency or LAT) was given responsibility for control and supervision’2., The IAT was established pursuant to the provisions of the Transplantation Law as the national authority in charge of all the issues covered by this law in the areas of procurement, harvesting, expertise, processing, preservation, storage, transportation and distribution of human ‘organs, tissues and cells. The IAT is also the body where all activities and results are recorded and the corresponding data are stored in registries The detailed provisions on technical requirements and financing are regulated in by-laws (ordinances) Table 1 shows all Bulgarian ordinances promulgated before Bulgaria's accession to the EU, while Table 2 lists the ordinances following accession. Taree of these ordinances (No 17 of 27 May 2004, No 4 of 31 January 2008 and No 29 of 27 June 2007) have no corresponding documents in the Regulatory Feature The Tissue and Cells Act restricts commercialsation in terms of the procurement of and trade in tissue and cell products ‘Th transpose the EU directives into law, the last amendments to the Bulgarian ‘Transplantation Law cme into force om 1 January 2007 Responsibility for supervision and control twas given to the Bulgarian Drug Agency © Informa UK L10 2008 suveraipharma.com === RAJ Pharma June 2000 365EU because they cover mainly local requirements and provisions. The ordinances published before 2007 show the work that was done in this field before Before 2007, ten Bulgaria's accession to the EU. Before 2007, ten ordinances were in place dealing with general and ‘ordinances were in place asic requirements in the field of transplantation, dealing with general and ‘After 2007, the by-laws are mainly related to standards, ingpections and surveillance. basic requirements in the ‘Feld of transplantation (SG) stipulating the requirements for procurement, harvesting, processing, labelling, preservation and distribution of organs, tissue and cells in order of publication before ‘No 12 of 15 April 2006 relating tothe conditions and rules for SG No 39, 12 May 2008 the disposal of organs, issues and cells Which may not be used for transplantation for medical reasons, fr other medical, diagnostic and scientific medical purposes initially no (eetospectvely Direetive 2004/23/EC) ‘No 13 0f15 April 2004 | relating tothe criteria forthe quality of | inialy no SG No 39,12 May 2004 tissues and cells subject to international | (retrospectively ‘exchange for the needs of the Republic of | Directive 2004/23/50) Bulgaria ‘No 14 of 15 April 2004 Felting tthe medical criteria and male for | Guide to efety and SG No 39,12 May 2004 the detection of death quality assurance for the transplantation of ‘organ, tissues and ells Grd edition, Council of Europe Publishing) [No 15 0f 20 April 2004 relating to the conditions and rules for the | no (partially EMEA. After 2007, the by-laws} SG.No38, 12 May 2004 tse of animal organs tissues and els for | documents on are mainly related to transplantation senotraneplantaton) Standards, inspections 917 of 7 May 2004 ‘elating ta the conditions and rules no «and surveillance 5c No 56,29 june 2004, | forthe inclusion of persons who need amended by No 21 of3 May | transplantation of ogans inthe ofc 2007 register of IAT and relating to the selection SGN039,15 May 2007 _| ofthe recipient of organs, issues and cells 8G No, 2 uly 2004 participation of healthcare establishments | (etrespectively ! in the international exchange of tissues and | Directive 2004/23/8C) | calle [hoa7cta sopcmber ine | roatng tothe cndions and vastorthe | no SG No 88,8 October 2004, | harvesting of embryonic organs and tissues famended No, 12 October | as well as of somatic, placental and amnion 2004 Cells fr transplantation | Nod of January 2005 | relating to the definition of diseases for | no | SG No13,8Febriary 2005, | the treatment of which the Ministry of i amended No 65,10 August | Health finances activites of harvesting and i 2007 transplantation of issues and cells { SG No 54,1 July 2005, procedures fr aceditatonofheatnare | (partially Diseive amended No 67,18 August | establishments 2004/28/C) 1 2006 j eens enemy ane persue For medicinal products manufactured from human organs, tissues and cells, the Law on Medicinal Products in Human Medicine (the so-called Drug Law) applies", The Drug Law was substantially amended according to the current European requirements (such as Directive 2001/83/EC as amencled, Regulation EC No 726/2004, Directive 2005/28/EC, Directive 2003/94/EC, etc) and ‘was issued de nov in April 20078, BGG June 2008 RAY Pharma semen ‘wwwfaiphaema.comArticle 4 of the Drug Law (LMPHM) states: “Where a product simultaneously fulfils the characteristics of both a medicinal product and another product regulated by another law, the provisions of this law shall apply,” clearly showing that it takes precedence over any other laws in this field that may also be relevant, ‘This ensures the adequate safety and quality of products that may fall under more than one legislative provision Authorisation for distributing human tissue and cell preparations Permission for the operation of tissue establishments is covered in the chapter on “additional provisions’ in the Transplantation Law according to the amendments of the Health Law and the Law on Healthcare Establishments! The procedure for intial and regular inspections is defined in Ordinance No 4 of 19 February 2007. Additionally, an accreditation procedure for tissue establishments is required and regulated by the provisions of by-law No 18 of 20 June 2005. Most of the other requirements of Directive 2006/86/EC are introduced into Bulgarian legislation by the Transplantation Law itself and are additionally specified by the by-laws in Table 1 ‘The involvement of the BDA in the procedure where appropriate seems reasonable, since a Grade A environment (as defined in the current European Guide to Good Manufacturing Practice (GMP), Annex 1, and Directive 2003/94/EC) — with a background environment appropriate for the processing of the tissue or cell concerned but atleast equivalent to GMP Grade D in terms of particles and microbial counts — is required in some instances. The BDA is the competent national regulatory authority for medicinal products and is experienced enough in this field to provide the corresponding certification. Ifthe IAT and the BDA could conduct joint inspections, this would have a synergistic positive effect on the safety and quality of tissue and cells. Bulgaria, in particular through the IAT, is participating in the European Union Standards and ‘Training in the Inspection of Tissue Establishments (EUSTITE) project, which is co-funded by the European Commission and intended to further increase the quality of inspections in Bulgaria”. ‘The primary objective of the EUSTITE project is stated to be the optimisation and harmonisation of the standards and methods applied by the inspecting and accreditation competent authorities, for tissue procurement and tissue establishments within the EU. ‘A secondary objective is to generate common systems for definition, classification and reporting of adverse events and reactions that are consistent with similar systems in other parts of the world, Import/export of human tissues and cells Oficial permission from the minister of health based on a written proposal by the director of the IAT is essential for import and export activities (Article 36 of the Transplantation Law). Tissues and cells may be subject to international exchange (export) only after national demand is satisfied (Article 37), ‘The respective by-law was issued by the health and finance ministries as early as June 2004. It states that a product may only be exported when the recipient is a nationally approved and registered tissue establishment. The tissues and cells have to be harvested, preserved and transported according to the Bulgarian Transplantation Law and have to comply with current ‘medicinal standards and the standards and rules ofthe corresponding recipient country. They also have to be recorded in the official register of the IAT. ‘Theimportoftissuesand cellsis similarly strictly regulated, by Article 38of the Transplantation Law. A restriction is in fore, allowing only the import of tissue and cell preparations for which there is a high demand, where safety and efficacy are proven, and no local production facilities are available. Similarly, the institutions providing tissue or cell preparations for import have tobe approved and registered tissue establishments in the exporting country. Imported tissues and cells have to comply with the provisions of by-law No 13 of 15 April 2004 (see Table 1. Reporting severe adverse reactions and events Under Articles 39 and 39a of the Bulgarian Transplantation Law, tissue establishments have to inform the IAT of all their activities in the procurement, harvesting, expertise, processing, labelling, preservation, transport and distribution of tissue and cells on an annual reporting basis. Under Article 11, Section 5, points 15 and 16 of the law, the IAT reports every three years to the European Commission all information gathered about activities in Bulgaria aimed at popularising. and stimulating voluntary and unpaid donation of tissue and cells, as well as activities in the areas of quality and safety assurance, harvesting, processing, preparation, labelling, controls and. inspections. Permission for the operation of tissue establishments is covered in the chapter on “additional provisions” in the Transplantation Low The objective of EUSTITE isthe optimisation and harmonisation ofthe standards and methods applied by the inspecting and accraitation competent authorities for tissue procurement and tissue establishments in the EU ‘The import of tissues and cells is strictly regulated under the Transplantation LawRegulatory Feature The peri from observing an adverse ‘event or reaction until final reporting is set at ten days The Bulgarien ‘Transplantation Law also covers the m of tissue and cell products commercialsot ‘There are no special provisions in Bulgarian legislation as yet swith respect (0 the mavsufacturing of tissues In case of severe adverse reactions or severe adverse events, as defined by European legislation, the notification procedure requires prompt action (Article 15b). Briefly, the nominated and officially registered responsible person ~ similar to the qualified person in the Drug Law in the area of pharmacovigilance (as referred to in Directive 2004/23/EC and Article 15g of the Transplantation Law) ~ has to be immediately informed by the person who identifies a severe adverse event or reaction, The responsible person is then obliged to inform the senior management of the tissue or healthcare establishment, the IAT andl all contracted tissue or healthcare establishments which have anything to do with the donor, recipient or the tissue or cell batch involved. Within three days, an expert committee at the establishment must provide an analysis and take corrective measures. The IAT must be informed of the final decision within seven days. Altogether, the period from observing the adverse event or reaction until the final reporting, as ‘well as for the introduction of measures to avoid and or solve the problem, is set atten days. This, information should be kept for at least 30 years. These issues are regulated in by-law No 10 of 30 March 2007 and are in full compliance with Directives 2004/23/EC and 2006/86/EC (ee Table 2). Based on the requirements of the Community (Article 7 and Annex V, parts A and B of Directive 2006/86/EC), an annual report on notifications of serious adverse reactions and events received by the corresponding competent authority (in this case the LAT) must be submitted to the commission by 30 June of the following year, ‘A summary of these reports has to be provided by the commission to the competent authorities ofthe member states, which in turn must forward it to the tissue establishments. These issues are regulated in by-law No 10 of 30 March 2007 and are in full compliance with the above- ‘mentioned directive (see Table 2). The future will show how all these reports influence the current procedures and requirements. Further requirements of the Transplantation Law ‘As mentioned above, all activities inthe field of organ. tissue and cell transplantation are subject to the Transplantation Law. The selection of either deceased or living donors, as well as all measures for their safety and for the safety and quality of the harvested organs, tissues and ces, are covered in Chapter II Sections 1 and 2 (Articles 18-29). Bulgaria has similar provisions to Germany for living donors under the age of 18, Section 3 (Article 30) deals with embryonic or foetal organs, tissues and cells, and Section 4 (Article 31) with organs, tissues and cells of animal origin Regulations on the clinical use of organs, tissues and cells are laid down in Chapter IV (Antcles 32:35). This chapter needs to be further developed to take account of further EU requirements in this field ‘The Bulgarian Transplantation Law also covers the commercialisation of tissue and cell products. It strictly prohibits trade in organs, tissues and cells pursuant to Article 5, as well as prohibiting commercial advertising or dissemination of information with the aim of providing a financial benefit asset out in Article 6. Only organs, tissues and cells that may not be transplanted for medical reasons may be made available for other medical, diagnostic and scientific/ medical purposes (Article 7), a8 also defined in by-law No 12 of 15 April 2008 Noiinformation on the donor recipient may be communicated thatwouldallow unauthorised identification (Article 8). However, Article 15, paragraph 2, permits tissue establishments to provide tissues and cells for the manufacture of medicinal products. The latter fall within the scope of the Drug Law and so require a marketing authorisation, and the holder of such authorisation. ‘may engage in relevant trading activities. Failing to observe these rules can draw steep fines of up to BGN 2 million (US81.6 milion) and can result in prosecution (Chapter VII, Articles 40-44). With respect to the manufacturing of tissues, there are no special provisions in Bulgarian legislation as yet. The quality and technical requirements for the donation, procurement and testing of tissues and cells, as well as the requirements for the qualification, training and health status of staff, are in line with Directive 2004/23/EC and Directives 2006/17/EC and 2006/86/EC respectively. Hovrever, in some areas ther is still a lack of consistency between the Bulgarian by-laws and the EU legislation. For example, the inspection and approval of premises ~ as with all other tasks is under the supervision ofthe JAT. In the transplantation legislation, there are no requirements relating to GMP inspectors’ knowledge and qualifications. So, while there isa need for improvement in some areas relating to manufacturing, Bulgaria has made a serious effort in the field of transplantation, with specific laws and regulations laying. down the main requirements inthis field. BEB June 2008 RAY Pharma — meme wewrapnarma.com © Informa UK tts 2008Reg ‘Table 2, Bulgarian by-laws promulgated in the State Gazette (SG) stipulating the requirements for procurement, harvesting, processing, labelling, preservation and distribution of organs, tissue and cells in order of publication after Bulgaria joined the EU Bylaw number end dete | Subject mater | Retowance 1 EU documents ‘Rhuepubtaaton “in Site Nod of 9 Febray 2007 | raling othe Condor andes tor | Dicive 204725760 Among ote things, SG N01 2a 2007 | inspectors atte ctalshmentsby. | Gulls one fhe bylaws coer | we Inopecionof tue and | nepecions of hence calprosienentand tance | eocmnet ccolchmens (i editor, fusnt | No.of Nava 2007 | foresablshing medialsendaristor | Gudevo aay ana | SCNow, 1sMarch | tapi cfenars sue and cols | quality ecureertorthe | | 2007, amended No 65, 10 transplantation of organs, | wuguat 2007 fsues and els rd ton, Coane ef Europe Publi! Dine 004/23/8¢ TNO7 of 8March2007 | ving tthe quliientons and heats | Dive 204/578 SGNo2,1eMach2007 | equtement ef pemons peerming vesing nerve proesing bling thu pean eee els W010 020 wach 2007 | ring tothe condos and ules fore | Dive 24723780 SGN038 20 Apea2007 | rotifeton rpasetion poring snd | forwarding rman iting serous | suerte raston and ceo adverse tens td lng to bhangra end desl | | tase ae ele Nowof4Apal 207 | reetingtotherulesforamening and | Guidetosatey and quay || assessing and SG No33,20 apil2007 | ceriyng the conditions when organs tissue =a certifying when gers, and cells can be harvested from a deceased | organs, tissues and cells tissue and cells can pee {Gre edition, Council oF be harvested from a Europe Publishing) decensed person. | Directive 2006/23/8C 7 'No 13 of & Apel 2007 relating tothe conditions and rules for Directive 2004/23/8C SG No34, 24 April 2007 | information to Bulgarian citizens relating to activities in harvesting and transplantation of organs, tissue and cells ‘No 16.0125 Apr 2007 | relating tothe conditions and les for | Direcve 204/287 SG No.8, 11 May 2007, | the granting of permission to healthcare amended No, july establishments for performing assisted } 2007 reproduction activites | No? of 3 May 2007 | relating tothe conditions and theta Dietve moa/2avEC SGNo39, 15 May 2007 | recorded inthe registers of IAT and the rales | on registration and usage of information | No 22 of 3 May 2007 relating to the conditions and rules for Directive 2008/25/8C | SG No39,15 May 207 | the registration and reporting of asivities on expertise, harvesting, transplantation, processing, preservation and labelling of organs, tissue and cells for the preparation ofthe annual report by healtheare establishments No28 of 20 June 2007 | relating to assisted reproduction activities | Directive 2004/23/6C | and the financing SGNo 55, 6 July 2007 ofthe national No 29 of 27 June 2007 relating tothe conditions rules and amount | Direcive 2001/23/EC | _splmtation system SGNos8, 10 augue 2007 | of inaringby te Minty alo one | nrc (© ira UK Ld 2008 ‘wwnueaipharma.com commen RAJ Pharma June 2008 369its eet coe Maer) References 1. Directive 2004/23/2C of the European Parliament and of the Council of 31 March 2004 on setting standards of quality and salely forthe donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells, Of, L102, 48,7 Apri 200, http: /eur-le. ‘europa.eu/smartap/cgi/2ga_doc?smartaplcelexapiiprod!CELEXnumdoctelg-endénumdoc= ‘20041 00234model-guichett 2. Directive 2008/17/EC implementing Directive 2004/23/EC ofthe European Parliament and ofthe Council a regards certain technical requirements for the donation, procurement and testing of human tissues and cells, Of, 138/40, 48, 9 February 2006, hitp://eur-lex europa.eu/LexUriSery /site/en/ 6)/2006 1038/1. 03820060208en00400052 pat 3. Directive 2006/86/EC implementing Directive 2004/23/EC of the European Parliament and of the Council as regards traceability requirement, notiieation of serious adverse reactions and events ‘ind certain technical requirements fr the coding, processing, preservation storage and distribution of human tissues and cells, Of, 1294/82, 25 October 2006, htp:/ /eur-ex europa.eu/LexUsiServ/ LexUriServdo?uri= O}:L:2006:294.0032.0050:EN:PDF 44. Health ée Consumer Protection Dinectorae-General, Directorate C-Public Health and Risk Assessment, (C6 Health measures, Brussels, 6 February 2007, htp:/ /ec.europa.eu/fealth/phthreats/human_ substance/ documents ev_20070208.si_en pdf 15. Bundesgesetblt (Federal Iw gazette) 1, p 1574, wwwbundesgesetzblat.de 6. Bundesgesetzblat 1, pp 1574-1585, 20 July 2007 7. Bundesgesetzblatt Past No 46, 12 September 2007 1. Bundesgsetzbltt Part I No 45, 5 September 2007 9. Law on transplantation of organs, tissues and cells, SG/88/2005, last amendment SG/71 /2006 Law on blood, blood donation and blood transfusion, SG/102/2003, last amendment SG/31/2007 11. Bulgarian Drug Agency (ww bda bg) Executive Agency for Traneplantation (owv-bgtransplantbs) Health Law, SG/70/2004, lst amendment SG/13/2008 14. Law on pharmaceutical products in human medicine, SG/31 /2007, last amendment SG/19/2008 Commission Directive 2003/94/8C, OJ, L262, 14 October 2003, hp: //ec.eurepa.cu/enterprise/ pharmaceuticals /eudalex/vol-1/dir 2008 94/dir 7003 94.en.pdf Law on heath facilites, SG /62/1998, last amendment SG/59/2007 European Union Standards and Training in the Inspection of Tissue Establishments, www.custteorg (treet i a Geneve-base cially active dig deslopment company dedated tthe development of therapeutic ge fr mmne- ‘ulated dares and ammo. The company has curently 7 monaco antibod deopment Reporting the CEO of he comport pston wl be response for eng and etn th oral ear oe fr he company Heil be Key ‘member ofthe maraamen connec and il ahem oie wero reap retin ofthe cova erro the Management Ten 0 ri hs po Ensure tine caipeton of rote regulatory sib misons ‘equ or maenonce oN rd NERS sy en a ecnig Sep pw so spon Sel ego Rng epee er sal mcs fore iterman Phase lane Postel Stes coms nen Ete eden wt commrcaton arc not Sia pn pratt 370 Teuton ing nme ‘sein mec © lnforma UK Lis 2008