Cell Tissue Bank (2012) 13:231–240 DOI 10.1007/s10561-011-9246-4
ORIGINAL PAPER
Temporal bone bank: complying with European union directives on human tissue and cells Vincent Van Rompaey • Wouter Vandamme Ludo Muylle • Paul H. Van de Heyning
•
Received: 6 September 2010 / Accepted: 18 February 2011 / Published online: 19 March 2011 Ó Springer Science+Business Media B.V. 2011
Abstract Background Availability of allograft tympanoossicular systems (ATOS) provides unique reconstructive capabilities, allowing more radical removal of middle ear pathology. To provide ATOS, the University of Antwerp Temporal Bone Bank (UATB) was established in 1988. ATOS use was stopped in many countries because of safety issues concerning human tissue transplantation. Our objective was to maintain an ATOS tissue bank complying with European Union (EU) directives on human tissues and cells. Methods The guidelines of the Belgian Superior Health Council, including EU directive requirements, were rigorously applied to UATB infrastructure, workflow protocols and activity. Workflow protocols were updated and an internal audit was performed to check and improve consistency with established V. Van Rompaey P. H. Van de Heyning (&) University Department of Otorhinolaryngology and Head and Neck Surgery, Antwerp University Hospital, University of Antwerp, Wilrijkstraat 10, 2650 Edegem-Antwerp, Belgium e-mail:
[email protected] W. Vandamme P. H. Van de Heyning University of Antwerp Temporal Bone Bank, Antwerp University Hospital, Edegem, Belgium L. Muylle Tissue and Cell Bank, Antwerp University Hospital, University of Antwerp, Edegem, Belgium
quality systems and changing legislations. The Belgian Federal Agency of Medicines and Health Products performed an inspection to examine compliance with national legislatives and EU directives on human tissues and cells. A sample of important procedures was meticulously examined in its workflow setting next to assessment of the infrastructure and personnel. Results Results are reported on infrastructure, personnel, administrative workflow, procurement, preparation, processing, distribution, internal audit and inspection by the competent authority. Donors procured: 2006, 93 (45.1%); 2007, 64 (20.6%); 2008, 56 (13.1%); 2009, 79 (6.9%). The UATB was approved by the Minister of Health without critical or important shortcomings. The Ministry accords registration each time for 2 years. Conclusions An ATOS tissue bank complying with EU regulations on human allografts is feasible and critical to assure that the patient receives tissue, which is safe, individually checked and prepared in a suitable environment. Keywords Tympanic membrane Ear ossicles Ossicular replacement implant Tissue banks Abbreviations ATOS Allograft tympano-ossicular system BSE Bovine spongiform encephalopathy CE Conformite´ Europe´enne CJD Creutzfeldt-Jakob disease EAC External auditory canal
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ENT EU GMP HBV HCV HIV SHC SMF SOP TM TPF UATB UZA
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Ear nose and throat European union Good manufacturing practice Hepatitis B virus Hepatitis C virus Human immunodeficiency virus Superior health council Site master file Standard operating procedure Tympanic membrane Tissue processing facility University of Antwerp temporal bone bank Antwerp University Hospital
Introduction The first clinical application of allogeneic ossicles for middle ear reconstruction purposes in chronic otitis media was established by Jean Marquet in 1963 (Marquet 1966, 1968, 1970, 1971). Allograft tympano-ossicular systems (ATOS) aimed at restoring the middle ear in its original anatomical and physiological situation, without jeopardizing full resection of afflicted tissues. Moreover, ATOS demonstrated excellent biocompatibility, even in chronically infected environment. Its value was universally recognised and ATOS were widely used in the nineties (Coulie and Ars 1990). However concerns on safety, especially regarding transmissible diseases, e.g. human immunodeficiency virus infection (HIV), limited its use. When the relationship between variant Creutzfeldt-Jakob disease (CJD) and bovine spongiform encephalopathy (BSE) became obvious, measures taken during the BSE endemy lead to the discontinuation of ATOS in many countries (Janssens de Varebeke et al. 1998). Meanwhile, new European Union (EU) regulations on tissues and cells endeavour quality assurance, traceability and safety procedures maximally to reduce the risk of transmissible diseases. Nowadays, ATOS are still preferred by many otolaryngologists to reconstruct the tympanic membrane (TM) and ossicles because of its specific structure and material (Claes et al. 1990; Van de Heyning et al. 1991; Ars and Piret-Ars 1993; Somers et al. 2004). To sustain human ATOS availability, an organised framework had to be created (Lacher 1970;
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Chiossone 1977; Savary 1980; Tempelman-Kluit 1996). Therefore in 1988, the Antwerp University Hospital (UZA) established the University of Antwerp Temporal Bone bank (UATB), complying with national legislation on donation and transplantation of organs, tissue and cells, specific legislation on human tissue and tissue banks and with the series of recommendations, published by the Belgian Superior Health Council (SHC) since 1993 (Belgisch Staatsblad/Moniteur Belge February 14th 1987 and April 29th 1988). Every Ear, Nose and Throat (ENT) surgeon with a specific training in ATOS use can participate and is entitled to use ATOS as a reconstructive material in middle ear surgery. In Belgium, the 2003 EU directives on human tissues and cells were transposed into a legislation, which was brought into force on December 1st 2009 (Belgisch Staatsblad/Moniteur Belge December 30th 2008; Directive 2004/23/EC of the European Parliament and of the Council of March 31st 2004; Commission Directive 2006/17/EC of February 8th 2006 and Commission Directive 2006/86/EC of October 24th 2006). In 2007, the SHC published a new version of the general quality criteria for tissues and cells of human origin (SHC guideline Nr. 7691-1). In this version almost all of the quality and safety requirements for tissues and cells of EU directives were included. This report describes the main issues in applying these requirements on the organization and activities of ATOS banks.
Materials and methods The SHC requirements, including the quality and safety requirements of EU directives on tissues and cells, were rigorously applied to the UATB activity, infrastructure, personnel, documentation and workflow protocols. Standard operating procedure’s were reviewed and modified to define and predetermine every step in the process mentioned in this section, as well as infrastructure, personnel and administrative requirements. An internal audit was performed to check compliance with the requirements. The FAMHP performed an inspection examining compliance with national legislation and the requirements of the SHC, including the safety and quality requirements of the EU directives on human tissues
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cumulative stay in the United Kingdom longer than 6 months between 1980 and 1996), progressive dementia or neurodegenerative diseases; hormonal treatment subtracted from human hypophyses; craniotomy; xenograft transplantation; transplantation of cornea, sclera, dura mater or ATOS; chronic otitis media; history of travelling abroad (e.g. malaria risk); vaccination with a weakened living virus; chronic systemic autoimmune diseases affecting tympanoossicular tissue; toxic exposure to cyanide, lead, gold, mercury; blood transfusion shortly before death. Further tissue-specific selection criteria include age over 16 years, sufficient hair to cover the cranial skin incision, absence of otoscopic disease, absence of oncologic temporal bone pathology, or radiotherapy of the temporal bone. Another criterium was procurement within 48 h after death if the body was cooled within 6 h postmortem, or within 24 h in all other situations. Without a premortem blood sample, the sample is taken up to 24 h postmortem. The mean number of donors per week dropped significantly to approximately 1 each week in the second half of 2007 and the first half of 2008, down from 1.8 each week in 2006. The turning point can be situated halfway 2007 and correlates with the publication of new general SHC guidelines (SHC guideline Nr. 7691-1). These guidelines omit the earlier exception to include ATOS donors with malignancies and are based on EU directives. Postmortem blood samples also had to be collected within 24 h after death (instead of 48 h). New specific SHC guidelines on ATOS were issued in August 2008, removing the upper age boundary, previously set at 75 year (SHC guideline Nr. 8298). This resulted in less exclusions, while significantly increasing the median donor age: 63.4 before and 81.4 years after August 2008. The effect of both guidelines’ changes on the mean number of ATOS donors per week is displayed in Fig. 1.
and cells. A sample of important procedures was meticulously examined in its workflow setting next to assessment of the infrastructure and personnel.
Results The UATB has agreements with 28 ENT physicians in 10 hospitals, where temporal bones can be procured and UATB ATOS are used in the middle ear. Donor screening Summarized data concerning donor screening are displayed in Table 1, including potential donors reported, potential donors opting out, donors rejected for biological or medical reasons and number of donors procured. In Belgium, the opting-out system provides the opportunity to register an explicit refusal to donate one’s organs or tissues. The first step involves consulting the national donor register. Some potential donors were excluded, because they had the explicit wish not to be a donor. In some hospitals an initial screening was already performed based on obvious contraindications (e.g. lack of hair or oncological patients), thus not reporting them as potential donors. The summarized data are therefore probably underestimating the number of potential donors. Taking into account the exact cause of death, all contraindications are checked with the treating physician, or general practitioner if necessary, using a checklist: diseases with unknown etiology; malignancies (contraindicated since June 2007); sepsis and systemic diseases including collagen disorders; risk factors for HIV, hepatitis B (HBV), hepatitis C (HCV) virus contamination; CJD, family history of CJD, Gerstmann-Strau¨ssler-Scheinker disease, fatal familial insomnia, risk factors for vCJD (i.e. a
Table 1 Donor screening summary data in the period 2006–2009 2006
2007
2008
2009
Total
Potential donors reported
206
309
429
1,222
2,166
Opting-out
10
9
19
9
47
Rejected for biological or medical reasons
103
236
354
1,134
1,827
Donors procured
93 (45.1%)
64 (20.7%)
56 (13.1%)
79 (6.5%)
292 (13.5%)
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Fig. 1 Effect of the SHC guidelines on the mean number of ATOS donors per week
The distribution of contraindications in the last 12 months (August 2008–September 2009, n = 1,042) was: logistical reasons (28.5%), malignancies (25%), risk of imperfect reconstruction after the transcranial Schuknecht approach (14.4%), uncontrolled systemic infection (7.8%), degenerative neurological disorder (7.1%), opting-out (2.9%) and 2.6% where patient history was unavailable or insufficient. Infrastructure Before entering the tissue processing facility (TPF), visitors (e.g. maintenance personnel) have to sign the attendance list and wear coats, gloves, mouth masks, hairnets and protective shoe covers. A clean room was installed and separated from the other facilities by a lock. An adhesive carpet decreases contamination of shoe covers when entering the TPF lock. Formaldehyde fumes are evacuated using a laminar airflow containment hood, following the recent upgrading of formaldehyde to a category 1 human carcinogen by the World Health Organisation’s
Table 2 Particle measurements of the clean room TPF are performed once each month and recorded in a dedicated logbook Particles/m3
2008
2009
0.5 micron
5 micron
0.5 micron
5 micron
182.318
999
160.922
4.246
Maximum
184.149
1.221
1.250.082
7.992
Minimum
180.486
777
48.618
333
Median
Data of 2008 (when measurements were started) and 2009 are displayed
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International Agency for Research on Cancer. TPF background air complies with class D air quality standards (in rest): \3.500.000 0.5-micron particles per cubic meter and \20.000 5-micron particles per cubic meter. Particle measurements of the clean room TPF are performed monthly and recorded in a logbook (Table 2). ATOS are not required to comply with class A air quality standards (Belgisch Staatsblad/Moniteur Belge October 23rd 2009) because a validated microbial inactivation process is applied after ATOS preparation, the application mode of the tissue or cell to the recipient implies a significantly lower risk of bacterial or fungal infection, and because a class A environment is technically impossible due to the use of a microscope for preparing the ATOS. Microbial testing (aerobic and anaerobic bacteria, fungi and yeast) of the TPF is performed monthly using 90-mm blood agar plates opened for 4 h (no activity) on two laboratory benches in the TPF. Until now, no colony forming units have been observed. The working surface is cleaned with 2% sodium hypochlorite 20.000 parts per million before and after preparation. Contaminated waste is disposed of in designated containers and destroyed by a company using a validated destruction process. Where tissues or cells are exposed to the environment during processing, without a subsequent microbial inactivation process, an air quality with particle counts and microbial colony counts equivalent to class A as defined in the current European Guide to Good Manufacturing Practice (GMP), Annex 1 of Directive 2003/94/EC, is required with a background environment appropriate for tissue processing but at least equivalent to GMP Grade D in terms of particles and microbial counts. Therefore ATOS banks do not
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have to check air quality and microbial colony counts as frequently as GMP guidelines specify for the production of medical drugs (Commission Directive 2003/94/EC of October 8th 2003). Personnel Job descriptions on every function are available and include professional profile, responsibilities and tasks within the UATB setting. Functions include: director (responsible person), quality manager, unit manager, tissue technologist, administrative collaborator and person performing procurement. Replacements are explicitly mentioned in case of absence. Each function has its own educational trajectory required to qualify for this function. Personnel, including collaborating medical doctors, are trained to independently perform all designated tasks and continue permanent education on the subject. Training sessions are organised and recorded. Documentation Documents concerning screening, procurement, processing, testing, storage, liberation, distribution and transportation of ATOS are archived in the administrative section. All data on potential donors excluded on screening are bundled. A new file is created for each donor screened for qualification. Access is restricted to UATB personnel. The minimal archiving period is 30 years. Traceability is essential: each tissue manipulation is dated in order to trace the corresponding protocol in the past. The lot number and expiry date of every product and device making contact with the tissue are registered. Standard operating protocols are periodically updated. Procurement and preservation If donor screening is safe and otoscopic examination reveals a normal tympanic membrane, the 1-h procurement can start (Ars and Piret-Ars 1993). At the moment, the transcranial technique is being used as described by Schuknecht (1974). This technique provides a bone plug, which is easy to handle when dissecting the allograft. The specimen is placed immediately in a buffered 2.7–4% formaldehyde solution (pH 5–6 at 4°C or room temperature),
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hereafter called formaldehyde. The effect of formaldehyde on viruses, bacteria, fungi and yeast has already been established (Spicher and Peters 1976; Tadeusiak 1998; Mazzola et al. 2003; Aarestrup and Hasman 2004; Sauerbrei et al. 2006). The outer packing of the container is dated and labeled with contact and transportation details mentioning the presence of human tissue. At that time a donation number is issued. The tissue is kept in quarantine at 4°C until serologic marker results are available. The samples are tested for the presence of markers for HBV, HCV, HIV-1, HIV-2 and syphilis in the clinical laboratory of the hospital using CE marked assays. The clinical laboratory is authorized by the competent authority. When sample analysis does not indicate presence of serologic markers for HIV, HBV, HCV or syphilis, dissection of the allograft can begin. Table 3 illustrates the age distribution of the donors. Processing and graft quality scoring Processing is performed with the same meticulous care and microsurgical instruments as during a live surgical procedure (Ars and Piret-Ars 1993). It consists of dissecting the external auditory canal periosteum (EAC), removing the bony surroundings with a rongeur and sectioning all suspensory ligaments, the chorda tympani, the stapedius muscle tendon and the annular ligament of the stapedial footplate. This process takes approximately 30 min and typically leads to a tympanic membrane (TM) with malleus and incus attached (Fig. 2). The presence of an EAC cuff is essential for reconstruction of the TM, i.e. allograft tympanoplasty type I. The preparation protocol can be found in ‘‘Appendix 1’’. Each donor can provide up to 6 allografts, i.e. 2 TM allografts, 2 malleus allografts and 2 incus Table 3 Age distribution of qualified tissue donors 2006
2007
2008
2009
[16–25 years
0
2
2
0
[25–35 years
0
4
0
2
[35–45 years
5
1
4
3
[45–55 years
16
9
3
3
[55–65 years
29
20
16
9
[65 years
43
28
31
62
Total
93
64
56
79
123
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Before sealing the graft in its container, a sample is taken from the suspension to check for microbial contamination. Liberation and distribution
Fig. 2 Allograft tympano-ossicular chain (ATOS) as seen from the middle ear. The tympanic membrane (TM) with malleus (M), incus (I) and stapes (S) chain. The periosteum of the external auditory canal (EAC) is in continuity with the fibrous annulus
allografts. After preparation, the allograft is fixed in formaldehyde. The container is labelled with graft information: i.e. graft type, donation number, tissue code, expiry date, UATB contact details and graft quality score. Acronyms are used to distinguish graft type, i.e. homo-tympanum (HT), TM and EAC cuff are included; homo-tympanum ? malleus (HTM); homotympanum ? malleus ? incus (HTMI); homotympanum ? malleus ? incus ? stapes (HTMIS); homo-tympanum ? malleus ? incus ? 1 stapes crus without footplate (HTMISp); homo-tympanum ? malleus ? incus ? 2 stapes crura without footplate (HTMISpp). The use of homo is historical because the grafts were of human origin, and should nowadays be replaced by allo to clarify that these are allografts and not homografts. Tissue quality of EAC cuff, fibrous annulus and tympanic membrane are scored by the tissue technologist and a medical doctor. Perforations, tears, attenuations, retractions or other disconformities are actively checked. Three grades can be entitled: grade 1, excellent quality, no comments; grade 2, good quality, some morphological comments without functional impairment (e.g. EAC cuff defects without compromising the annulus); grade 3, functional and morphological artefacts present (e.g. annulus defect present). The quality is matched for different purposes, e.g. canal wall down tympanoplasty, primary or second-stage cholesteatoma surgery, etc.
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The process from donor screening to graft liberation takes approximately 3–4 weeks, mainly provoked by the microbial contamination check. Meanwhile, the allograft is held in quarantine until its acceptance or rejection by a formal liberation process verifying donor and allograft compliance with all requirements. There is a patient queue for ATOS myringoplasty or ossiculoplasty due to the disequilibrium in supply and demand. Whenever an allograft is available, the treating physician is contacted to plan surgery. Internal audit, inspection and clinical evaluation After performing an internal audit, using the SHC aide-memoire for inspection of tissue banks (SHC guideline Nr. 8029), an extensive checklist concerning all essential administrative, infrastructural (including personnel) and clinical processes, several deviations from the SHC guidelines were found. The educational trajectory was present but had to be put in writing in a SOP. The same issues existed in other topics: explicit job descriptions and responsibilities, outline of persons responsible for external donor procedures and transportation. Although these tasks and responsibilities were present implicitly, they were never put in writing. SOPs were available for critical activities (i.e. donor selection, procurement, preparation, laboratory investigations, preservation, storage and distribution), but were not detailed enough for transportation and lacking on internal audit and SOP update frequency. All these issues were tackled appropriately. A manual numbering system was replaced by a barcode system, which is more reliable. An inspection was performed by a dedicated tissue bank inspector of the Belgian Federal Agency of Medicines and Health Products (FAMHP), which is the competent authority, to examine compliance with existing legislation and SHC recommendations concerning human tissue and cells. Important aspects include the presence of a regularly updated site master file (SMF) with change control. It summarizes all active SOPs and their updates during a production
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and auditing process. The documentation within the UATB, and from a randomly chosen peripheral hospital was checked for consistency with the SMF and compliance with dedicated legislations and SHC recommendations. A summary of shortcomings reported by the competent authority can be found in ‘‘Appendix 2’’. After this inspection, the UATB was approved by the Minister of Health without critical or important shortcomings. The Ministry accords registration each time for 2 years (Belgisch Staatsblad/Moniteur Belge January 14th 2009). Hearing and clinical outcome results on tympanoplasties using an UATB allograft are compared to similar techniques using autologous material in the Common Otology Database, an international prospective multicenter auditing collaboration on middle ear surgery, including tympanoplasty (Yung et al. 2005, 2008; Yung and Van de Heyning 2007).
Discussion Transplantation of tissue is a highly regulated procedure because of ethical implications and the possible risk of transferring infectious or malignant diseases. Extensive national and international regulations overlap on the subject of tissue transplantation. Standards of quality and safety concerning donation, procurement, testing, processing, preservation, storage and distribution of human allografts were laid down by the EU. These standards were transposed into national legislation and are legally binding. In Belgium, the SHC is the public health link between government and the scientific, providing independent advice and recommendations to the Minister of Health. On a regular basis, general and specific quality standards for tissues and cells of human origin intended for transplantation are published. The latest publication (Belgisch Staatsblad/Moniteur Belge October 23rd 2009) included the aforementioned EU directives (SHC guideline 7691-1). Changes in these recommendations have direct consequences on potential donor qualification rate. Omitting the exception to include ATOS donors with malignancies and the postmortem interval reduction for blood samples from 48 to 24 h resulted in a significant drop in donor qualification rate, while the upper age limit removal resulted in an increased donor reporting. On
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average, 7.4 potential donors have to be screened to result in one procurement. Currently, we have to screen 15.4 potential donors to achieve one procurement. By increasing the median age of potentially qualifying donors, the number of potential donors increased from 206 in 2006 to 1,222 in 2009. However, while the number of donors qualifying for procurement increased in 2009, the number of actual procurements decreased to 6.5%. This is due to the presence of more contraindications in the population over 75 years, including dementia, oncologic diseases and the lack of hair. It should be stressed that transmission of malignancy in ATOS, to our knowledge, has never been reported and omitting the former exception of malignancy for ATOS (while keeping it for cornea allografts) is highly controversial. The SHC published recommendations on the transcranial ATOS procurement procedure and how to check for (variant) CJD (SHC guideline 8298 and 8340). It should be stressed that there is no evidence that ATOS have been responsible for disease transmission (Hotz and Hausler 2003). The main obstacles encountered are of logistic nature. They are most frequently due to late reporting of the donor, absence of a premortem blood sample (reducing postmortem procurement interval to 24 h), early collection of the donor by the undertaker. They are rarely caused by the fact that no procurement person was available or procurement infrastructure being occupied at the time of reporting (because of the 48-h postmortem procurement interval). The challenge will be to maintain an optimal communication between the contact persons of the collaborating hospitals and the ATOS tissue bank to avoid the abovementioned problems. An inspection performed by the FAMHP examined compliance with existing legislation and SHC recommendations, and authorised the UATB for a period of 2 years, which is the maximum period. One of the shortcomings reported by the competent authority was the absence of validation of serological testing on postmortem blood samples by the laboratory. The most important problem in this matter is the high number of false positive reactions, which is caused by natural changes in blood and tissue after death. The number of unspecific reactions increases in direct proportion to the time between the death and the sample collection. (Pruss et al. 2010)
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Therefore the postmortem interval must be limited to 24 h in order to reduce the risk of a false positive reaction. Although the serologic assays used in the laboratory were unaffected by hemolysis to a high level (free hemoglobin \ 1.6 g/dl), the assays were not validated for cadaveric samples and therefore should be validated by the user (Pruss et al. 2010). In conclusion, we have demonstrated that running an ATOS tissue bank, complying with national and international regulations, is possible and critical to assure that the patient will receive tissue which is safe, individually checked and prepared in a suitable environment. Our example can support other ATOS tissue banks to comply with these dedicated legislations.
Appendix 1 Allograft preparation 1.
2.
3.
4.
5.
Inspect the temporal bone plug for defects created during procurement. If the tegmen is defect, check the patency of the ossicular chain and tympanic membrane. Incise the external auditory canal (EAC) skin to the bone with a scalpel or Berckmans decollator creating a distal approach to produce the EAC cuff. Avoid cartilage and hair follicles. Remove the defunct distal EAC periosteum with the flat part of the Marquet decollator. The EAC cuff is released circumferentially from the bony canal approaching the bony annulus by using a Marquet decollator or a small Rosen knife. Possibility to skip to step number 7. Cut the anterior bony wall perpendicularly (using a cutting forceps and a rongeur) to avoid fracturing the bony EAC and allow further release of the EAC cuff. Release the fibrous annulus carefully from the bony annulus with a microchisel. The mucosa can be incised using a scalpel to reach the middle ear cavity. Avoid manipulating the tympanic membrane near the head of the malleus. Mobilising the malleus puts too much strain on the ossicular chain, which is still attached to all ligaments and muscles, and can lead to luxation of the ossicles.
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6.
The chorda tympani and the stapedial muscle tendon are cut. Put the annulus tympanic membrane and EAC cuff back in its original position. 7. Remove the dura mater on the roof of the temporal bone. Find a weak spot to enter the antrum. with a Bo¨hler bone forceps. Possibility to skip to step number 9. 8. Removal of the cochlea and its surrounding bony structures by cutting between the internal carotid artery and the internal auditory meatus using a Bo¨hler forceps. The circular ligament of the stapes footplate is cut with a scalpel. 9. Cut the tensor tympani muscle tendon, and the incudal and malleal ligaments with a scalpel. 10. Place the slightly curved point of the microchisel or a microhook on the annular ligament and carefully luxate the stapes out of the oval window. 11. The ossicular chain now has a reasonable freedom of motion, so the remaining ligaments around the malleal head can be cut through the EAC. 12. Cut the bone between the EAC and the antrum longitudinally to the EAC using a cutting forceps. Bend this bony part to allow sufficient space to remove the tympanic membrane and ossicular chain in toto. 13. Check the allograft using the microscope – – – –
length of the ossicular chain state of the tympanic membrane EAC cuff characteristics annulus integrity
Appendix 2 List of shortcomings Critical shortcomings: none. Important shortcomings: none. Other shortcomings: 1.
The lab result of the serological determinations did not mention the type of blood (premortem or postmortem); the date of blood collection was not mentioned in the lab report; the serological testing on postmortem blood samples was not validated.
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2. 3.
4. 5. 6. 7.
8. 9.
10. 11.
12.
The follow-up of the corrective actions of the internal audit was not documented sufficiently. The lot number and peremption date of the physiologic water used for washing of the bones prior to the preparation were not recorded. The new clean room for the preparation of the allografts was not validated sufficiently. The medical history form was not always signed by a physician. Lab test requests mentioned the name of the donor, instead of donor codification numbers. The time of tissue receipt at the tissue bank and the name of the person responsible for the reception must be documented. A procedure must be made to determine clearly the peremption date of the allografts. The insert accompanying the distributed allograft must be completed (information on a quality parameter, on the microbiologic safety, the conditions for storage and the maximum storage time after opening the container). The time of the start of body cooling is not registered in the donor file. Solutions for cleaning of surfaces must be stored separated from solutions coming into contact with allografts. The agreements with cooperating hospitals must be reviewed.
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