Each MPHO intended for transfusion, transplantation, implantation or transfer has specific quality attributes and characteristics determined by anatomy and usual function. Handling activities that support the maintenance of desired efficacy or utility of the organ, tissue or cells can affect clinical outcome. When a gap exists or a step or process fails, a serious risk of harm or actual harm can occur.
18.1 ORGANS, TISSUES AND CELLS
The overall activity or process from donation to clinical use involves multiple steps in handling and is carefully developed to maintain certain characteristics of the allograft so it serves a specific clinical need. Handling varies among many different subtypes within general types of MPHO, but there are also general processes to which each MPHO is exposed that can affect outcome. This section addresses those adverse occurrences relating to the physical properties (characteristics) of organs, tissues and cells and to changes in the properties due to events surrounding procurement, storage and processing or other aspects that may alter viability or other physical or chemical properties desired. To maintain desired allograft characteristics, clinical utility, and availability for use, controls should be in place for steps involving:
- Donor screening, testing (including controls regarding the blood sample) and test kits;
- Recovery, procurement or collection;
- Preservation/processing (this can include qualification of materials, reagents, equipment and facilities as well as maintenance, where applicable, and validation of processes that incorporate process controls and/or verification of steps);
- Storage, transport and distribution;
- Selection for use and allocation (where applicable);
- Preparation for use (or other final disposition);
- Qualified personnel with sufficient training who are deemed competent;
- Documentation and maintenance of records for all the above.
Some clinical outcomes and risks are anticipated (expected) while some may be unanticipated (unexpected). Additionally, steps taken to report or notify are critical when an unexpected outcome occurs. There is value in collection, analysis, and sharing this type of information because there may not only be national or regional implications, but also concerns on an international scale.
The process surrounding the handling of an allograft so it performs as expected involves careful development and execution of protocols. The well-being of living donors is also included in protocol development and evaluation.
The concept of ‘properties’ is described as it can be applied to blood components, organs, tissues, hematopoietic progenitor/stem cells, corneas, human breast milk and gametes and embryos used for transplantation or application, and how those properties can affect the outcome. There are examples when failures occurred and the allograft could not be used; the potential affect this has on the intended patient must be assessed. Adverse occurrences where patients were exposed to a risk, or harmed, by some intrinsic property of the product related to its recovery, processing, evaluation, storage, transport, and distribution are addressed according to the “Vigilance and Surveillance of Tissues and Cells in the European Union -Final Recommendations of the European Union Standards and Training for the Inspection of Tissue Establishments (EUSTITE) project”, June 7, 2010. As an example, ocular tissues are examined in some detail and the same principles of how product properties can influence outcomes extend to other types of traditional non-ocular tissues. Another example is the purchase of human breast milk on the internet where collection and distribution are not controlled and unacceptable microbial contamination and dilution with cow’s milk have been reported (83;84).
Traditional (conventional) tissues transplanted include skin, bone with or without cartilage, musculoskeletal soft tissues, and cardiac and vascular tissue types. While these tissues can be gifts provided by deceased donors, living donors also provide them. Steps in allograft donor screening or donor testing, tissue recovery and handling throughout production can be discovered to be the root cause of an adverse occurrence. Tissue allografts made available for transplantation that come from one donor can number a few to over 100, and these can be used to alleviate pain and/or restore function in as many recipients. Tissue risk reduction measures include: obtaining valid consent/authorization for donation; qualification of donors through standardized donor screening and testing; applying controls to recovery/procurement procedures; use of tissue treatment (processing) steps that reduce, eliminate, or inactivate contaminants; selecting equipment and materials that are qualified for their intended use; properly validating tissue culture methods and other procedural steps; establishing controls for tissue storage environments that are conducive to the tissue preservation method selected; establishing tissue tracking measures to be able to (quickly) trace each tissue allograft from the donation event through final use or other disposition; and, evidence of all steps taken are maintained via detailed recordkeeping. In the event that, after a thorough investigation, a tissue allograft is implicated as the cause of an adverse occurrence involving harm to a recipient, all of these risk mitigation measures may need to be reviewed.
Adverse occurrences can be linked to dysfunctions identified in tissue establishment operations that resulted in a significant loss of product, reducing availability for use. In the case of reactions in recipients of ocular tissue most cases are limited to graft failure, which can be influenced by the tissue itself, its handling, surgical technique or the recipient. The recent evolution of corneal transplantation has increased the involvement and responsibility of eye banks in the preparation of suitable tissues for keratoplasty, but this also means an increase in handling. Sound validation of methods and procedures, good communication between tissue and cell establishments and clinical users of their allografts, and a reliable reporting system are essential in order to identify trends and opportunities for process improvement.
In the case of haemapoietic progenitor/stem cells (HPCs), donations may be from the patient or family members, or from unrelated donors (e.g., bone marrow registry donors, cord blood bank). Autologous cells, usually peripheral blood stem cells (PBSC), are collected, cryopreserved, and stored for subsequent use, whereas related or unrelated donations are collected and transplanted quickly. The same applies for all three types of HPC donation if in the form of bone marrow. Cord blood donation can be from unrelated or family HSC donations and banked for an extended period of time prior to use. Autologous cord blood banking can be a commercial activity but autologous units from low risk families are rarely used. Any HSC donation requires an expectation of a high level of cell viability. There are specific critical aspects relating to the quality of banked HSCs including initial cell dose (potency), cryopreservation methodology and preservation agents, potential for contamination, rate and mode of freezing and thawing as well as maintaining a controlled, deep frozen state throughout storage and during transportation that ends at time of use. The recipient must receive conditioning therapy prior to transplant, and immunosuppression afterwards in the case of an allograft.
Adverse occurrences where no patient has been harmed but where a risk of harm was identified, should be reported in certain circumstances. For tissues and cells, it was recommended by the EUSTITE project that deviations from Standard Operating Procedures in tissue or cell processing facilities, or other adverse incidents, which have implications for the quality and safety of tissues and cells should result in reporting to the regulator when one or more of the following criteria apply:
- Inappropriate tissues/cells have been distributed for clinical use, even if not used
- The event could have implications for other patients or donors because of shared practices, services, supplies or donors
- The event resulted in loss of any irreplaceable autologous tissues or cells or any highly matched (i.e. recipient specific) allogeneic tissues or cells;
- The event resulted in the loss of a significant quantity of unmatched allogeneic tissues or cells.
Reporting of such occurrences allows the identification of corrective actions that can be shared widely to prevent recurrence in other facilities.
Organ transplantation differs in some regards from tissue and cell transplantation, with two major aspects being: 1) the time constraints in procurement and transplantation including the lack of processing and banking, and 2) the typically life-saving nature of organ transplantation. These two aspects have an influence on the strategy taken in organ transplantation by involved stakeholders; some risks that can be excluded in tissue and cell transplantation through extensive testing have to be accepted as "calculated risks" in organ transplantation. This idea is reflected in the EU directive 2010/53/EU of the European Parliament on standards of quality and safety of human organs intended for transplantation: “The risk-benefit ratio is a fundamental aspect of organ transplantation. Owing to the shortage of organs and the inherent life-threatening nature of diseases leading to the need for organs for transplantation the overall benefits of organ transplantation are high and more risks are accepted than with blood or most tissues and cell-based treatments. The clinician plays an important role in this context by deciding whether or not organs are suitable for transplantation.”
Nevertheless, the EU considers that there is “a need for common quality and safety standards for the procurement, transport and use of organs at Union level.” This is of special importance in the light of the fact that organs are exchanged daily between Member States. According to Article 11 of the Directive a reporting system shall be in place for “serious adverse events that may influence the quality and safety of organs and that may be attributed to the testing, characterization, procurement, preservation and transport of organs as well as any serious adverse reactions observed during or after transplantation which may be connected to those activities.” Similar events and concerns apply to other regions (e.g., Canada, the United States, Australia) where allocation of organs can occur across provincial, state or territorial borders.
There are quite a number of incidents that might fulfil the criteria above and it is of central importance that selection of incidents expected to be reported is organized in such a way that it can be readily managed by stakeholders (organ procurement organizations, organ exchange organizations, transplant centers). In the context of organ shortage, events that result in loss of organs have a direct impact on patients waiting for an organ transplant; such events should be centrally collated to maximize the opportunities for process improvement.
Serious reactions can also occur that result from errors/inadequate procedures at the level of the clinical user as opposed to reactions due to product-related causes. Three types of serious reactions include: acute haemolytic reaction, Graft versus Host Disease (GvHD), and circulatory overload associated with the transfusion of haematopoietic progenitor/stem cells (HPCs). All three are known from haemovigilance, as acute haemolytic reaction, transfusion associated GvHD (TAGvHD) and transfusion associated circulatory overload (TACO) respectively.