Language selection

Government of Canada / Gouvernement du Canada

Search

Guidance on the Safety of Human Cells, Tissues and Organs for Transplantation Regulations: Implementation

"Should" indicates a recommendation made by Health Canada. Where standards are recommended, an establishment should use a risk-benefit analysis on which to base decisions on their implementation.

Note: The Safety of Human Cells, Tissues and Organs for Transplantation Regulations (CTO regulations) specify minimum safety standards, which CTO establishments may exceed. The statements, definitions and tables on labelling requirements under sections 30 to 32 are taken directly from the CTO regulations.

On this page

Interpretation

Section 1

This section lists the terms used in the CTO regulations.

Accident:

An unexpected event that:

  • is not attributable to a deviation from the standard operating procedures or applicable laws and
  • could adversely affect the safety of a transplant recipient or the safety, efficacy or quality of cells, tissues or organs
Act:

Refers to the Food and Drugs Act.

Adverse reaction:

An undesirable response in the recipient to transplanted cells, tissues or organs, including the transmission of a disease or disease agent.

Banked:

For cells and tissues, means processed cells and tissues that:

  • have been determined safe for transplantation and
  • are stored by the source establishment in its inventory and available for distribution or transplantation
Cell:

The fundamental biological unit of a human organism that's for use in transplantation.

Distribute:

Does not include to transplant.

Donor:

A living or deceased person from whom cells, tissues or organs are retrieved.

Donor assessment record:

Includes the donor screening, any available donor testing results, information obtained from the donor's medical records and a copy of the donor consent.

Donor identification code:

The unique numeric or alphanumeric designation that:

  • is assigned by the source establishment to a donor under section 56 and
  • associates each cell, tissue and organ, or part of one, to that donor
Donor screening:

An evaluation based on the donor's medical and social history and physical examination, the results of any diagnostic procedures performed and, if applicable, the autopsy.

Donor suitability assessment:

An evaluation based on the donor screening and

  1. for lymphohematopoietic cells, tissues and organs retrieved from live donors and of tissues retrieved from deceased donors, all donor testing results and
  2. for fresh skin, islet cells and organs retrieved from deceased donors, the donor testing results that are necessary at the time of transplantation
Donor testing:

The laboratory tests and measurements done on a donor or donor specimen to determine all of the following:

  • if the donor has or ever had a transmissible disease or is or ever was infected with a transmissible disease agent
  • donor compatibility and
  • the degree of functionality of the cell, tissue or organ that is to be retrieved
Error:

A deviation from the standard operating procedures or applicable laws that could adversely affect the safety of a transplant recipient or the safety, efficacy or quality of cells, tissues or organs.

Establishment:

A person, a partnership or an unincorporated entity, or a part of any of them, that carries out any of the following activities in respect of cells, tissues or organs:

  • importation
  • processing
  • distribution and
  • transplantation
Exceptional distribution:

The distribution under sections 40 to 42 of cells, tissues or organs that have not been processed under these regulations.

Exterior label:

The label that is affixed to the exterior package.

Exterior package:

The outermost package in which a cell, tissue or organ is delivered, transported or shipped.

General standard:

Canada's national standard CAN/CSA-Z900.1, "Cells, Tissues, and Organs for Transplantation: General Requirements", as amended from time to time.

Homologous:

in respect of a cell, tissue or organ, means that the cell, tissue or organ performs the same basic function after transplantation.

Interior label:

The label that is affixed to the interior package.

Interior package:

The innermost package of a cell, tissue or organ that has a non-sterile exterior.

Lymphohematopoietic standard:

Canada's national standard CAN/CSA-Z900.2.5, "Lymphohematopoietic Cells for Transplantation", as amended from time to time.

Medical director:

With respect to an establishment, means a physician or dentist who is:

  • licensed under the laws of the jurisdiction in which the establishment is situated to provide health care or dental care and
  • responsible for the application of the standard operating procedures and for all medical or dental procedures carried out there, as the case may be
Minimally manipulated:
  • in respect of a structural tissue, that the processing does not alter the original characteristics that are relevant to its claimed utility for reconstruction, repair or replacement and
  • in respect of cells and nonstructural tissue, that the processing does not alter the biological characteristics that are relevant to their claimed utility
Ocular standard:

Canada's national standard CAN/CSA-Z900.2.4, "Ocular Tissues for Transplantation", as amended from time to time.

Organ:

A perfusable human organ for use in transplantation, whole or in parts, and whose specific function is intended to return after revascularization and reperfusion. Includes adjunct vessels that are retrieved with the organ for use in organ transplantation.

Organ standard:

Canada's national standard CAN/CSAZ900-Z900.2.3, "Perfusable Organs for Transplantation", as amended from time to time.

Package insert:

The document that the source establishment prepares to accompany a cell, tissue or organ.

Note: This may also refer to the package insert the establishment prepares in accordance with the standard operating procedures.

Processing:

For cells, tissues and organs, means any of the following activities:

  • donor screening
  • donor testing
  • donor suitability assessment
  • retrieval, except for organs and islet cells
  • testing and measurements performed on the cells, tissues or organs after they are retrieved
  • preparing for use in transplantation, except for organs
  • preservation
  • quarantine
  • banking
  • packaging and labelling

Retrieval

Under the CTO regulations, a source establishment is responsible for retrieving cells and tissues. For organs, retrieval is not considered processing, and thus is not the responsibility of the source establishment.

Organ retrieval is a surgical procedure that's adapted to the donor organ and the needs of the recipient. It is considered to be within the domain of medical practice.

Health Canada does not regulate medical practice. Thus, the retrieval of organs and islet cells is exempt from the definition of processing. While the retrieval of a pancreas for further processing is exempt from the definition of processing, activities associated with isolating islet cells are captured under the definition of processing since it is considered preparation for use in transplantation.

Post-retrieval testing and measurements performed on the cell, tissue or organ includes, for example, bacteriological testing and biopsy results of the cells, tissues and organs, if performed.

Preparing for use in transplantation

Source establishments are responsible for preparing cells and tissues for use in transplantation, except final preparation. This is done by the transplant program at the time of transplantation.

Preparing cells and tissues may include:

Also included are:

Preparing organs for use in transplantation is not considered processing, and is not the responsibility of the source establishment.

As stated in the retrieval section, the preparation that an organ undergoes for use in transplantation is adapted to the donor organ and the needs of the recipient. This is within the domain of medical practice, which Health Canada does not regulate.

Also stated, retrieving a pancreas for further processing is exempt from the definition of processing. However, the activities associated with isolating islet cells are not exempt, as they are considered preparation for use in transplantation. Apart from this distinction, islet cells are regulated according to the same criteria as organs. This means the same donor screening and testing requirements apply to organs and islet cells.

Preservation

Preservation (for example, cryopreservation, lyophilization) is the act or process of preserving cells and tissues or keeping them from deteriorating or decaying before they're used in transplantation.

Banking

Banking is storing processed cells and tissues (including adjunct vessels that are not used immediately for transplantation with the organ with which they were distributed). This is done by the source establishment after all other processing activities have been completed in accordance with the regulations.

Cells and tissues that are stored by an importer for further distribution or by an end user establishment for transplantation after the source establishment has released them from their inventory are not considered banked.

Storing lymphohematopoietic cells collected from bone marrow or peripheral blood is not considered banking if the donation is intended to be used to treat a designated recipient.

Note the following definitions that apply to this section.

Quality assurance system:

The coordinated activities of an establishment that relate to the safety of cells, tissues and organs. It includes:

  • the standard operating procedures
  • records to demonstrate that the standard operating procedures have been implemented and
  • audit processes to verify that the standard operating procedures are being implemented
Scientific director:

For an establishment, means an individual who is responsible for the application of the standard operating procedures and for all technical procedures carried out there.

Serious adverse reaction:

An adverse reaction that results in any of the following consequences for the recipient:

  • in-patient hospitalization or its prolongation
  • persistent or significant disability or incapacity
  • medical, dental or surgical intervention to preclude a persistent or significant disability or incapacity
  • a life-threatening condition and
  • death
Source establishment:
  1. subject to paragraph b), for an organ from a deceased donor, the relevant organ donation organization
  2. for adjunct vessels that are retrieved with an organ and not used immediately in the organ transplantation, the relevant tissue bank
  3. for an organ from a living donor or lymphohematopoietic cells that are not banked, the relevant transplant establishment
  4. for tissues or banked lymphohematopoietic cells, the relevant cell or tissue bank and
  5. for islet cells, the establishment that prepares the cells for transplantation
Standard operating procedures:

The component of the quality assurance system that comprises instructions that set out the processes and procedures to follow in carrying out the activities of an establishment.

Tissue:

A functional group of human cells for use in transplantation. Includes the cells and tissues listed in the definition "tissue" in section 3.1 of the general standard, except for paragraphs (g) and (l).

Tissue standard:

Canada's national standard CAN/CSA-Z900.2.2, "Tissues for Transplantation", as amended from time to time.

Transplant:

To implant cells, tissues or organs into a recipient.

Additional definitions

Importer:

An establishment that brings in or facilitates the transfer of cells, tissues and organs from a foreign source located outside Canada and then distributes to CTO establishments in Canada. An establishment that imports cells, tissues and organs from inside Canada (from a different province or territory) is not an importer. If an establishment only ships cells, tissues and organs for an importer, the shipping company (for example, FedEx) does not have to register as an importer.

Establishment that distributes as an intermediary:

An establishment that further distributes cells, tissues and organs determined safe for transplantation by a source establishment from an establishment to another.

Retrieval establishment:

The organization affiliated with the physical building in which the retrieval takes place. The retrieval team is not necessarily affiliated with the retrieval establishment.

Application

Sections 2 and 3 of the CTO regulations

Scope of regulations

2. These regulations apply only to organs and minimally manipulated cells and tissues.

Cells and tissues can be manipulated by varying degrees:

Cells, tissues and organs for transplantation are generally retrieved from a donor in a functional state. It's expected they will maintain the same function in the recipient, as long as their integrity and function are preserved during processing.

The CTO regulations are based mainly on safety. They do not contain requirements for evaluating clinical effectiveness. For this reason, they only apply to tissues that are minimally manipulated, because such tissues are more likely to maintain their integrity and function during processing.

A minimally manipulated structural tissue (defined in section 1 of the CTO regulations) must still have the characteristics that enable it to carry out reconstruction, repair or replacement. Examples:

Other examples:

To be considered minimally manipulated, and therefore included in the scope of the CTO regulations, the structural tissue:

A tissue characteristic is:

A minimally manipulated cell or non-structural tissue must still have the biological characteristics (and thus potentially the function or integrity) that are relevant to their claimed utility. Examples of minimal manipulation:

Other examples:

Note: Enzymatic digestion of a pancreas to dissociate islet cells before isolation is minimal manipulation because clinical trials have demonstrated that these cells maintain their biological function. You must notify Health Canada before:

Our decision tree will help you determine if a cell or tissue falls under the scope of the CTO regulations.

In some cases, it may be difficult to classify cells and tissues as minimally manipulated or more than minimally manipulated. The decision will have to be made case by case, based on a review of the manufacturing process and/or the availability of clinical data to support their intended use.

For questions on the classification of cells, tissues and organs, please email us: brdd-cppic_brdd-cppci@hc-sc.gc.ca.

To determine which cells, tissues and organs are subject to the regulations, minimally manipulated cells and tissues could be classified further based on other criteria. For example, to be included in the scope of these regulations, minimally manipulated tissues must not meet any of the criteria specified in section 3 of the CTO regulations.

The regulations only apply to minimally manipulated cells and tissues that meet all of the following criteria:

Note: Autologous cells, tissues and organs are not within the scope of the CTO regulations.

Non-application of various therapeutic products:

3. (1) The regulations do not apply to any of the following therapeutic products:

  1. cells, tissues and organs that are for non-homologous use
  2. cells, tissues and organs that are for autologous use
  3. heart valves and dura mater
  4. tissues and cells - except for islet cells and lymphohematopoietic cells that are derived from bone marrow, peripheral blood or cord blood - that have a systemic effect and depend on their metabolic activity for their main function
  5. medical devices containing cells or tissues and are the subject of investigational testing involving human subjects under Part 3 of the Medical Devices Regulations
  6. cells, tissues and organs that are the subject of clinical trials under Division 5 of Part C of the Food and Drug Regulations
  7. Class IV medical devices that are regulated under the Medical Devices Regulations
  8. blood components, blood products and whole blood, except for:
    • cord blood and peripheral blood for use in lymphohematopoietic cell transplantation
  9. cells and tissues that are regulated under the Assisted Human Reproduction Act or any of its Regulations
  10. semen that is regulated under the Processing and Distribution of Semen for Assisted Conception Regulations

Non-application of regulations:

2) No other regulation made under the Food and Drugs Act (act) applies to cells, tissues or organs that are the subject of these regulations.

All cells, tissues and organs intended for transplantation are regulated under the act, which provides the authority for developing regulations that are specific for different types of products.

Cells, tissues and organs used for transplantation all share an inherent risk of infectious disease transmission. However, because they vary significantly when it comes to other criteria, they are subject to different regulations developed under the act.

In general, cells and tissues are excluded from the CTO regulations if they meet any of the following criteria:

Note: Autologous cells and tissues are excluded from the scope of the regulations. However, autologous and allogeneic cells and tissues that meet any of the criteria listed that are for transplantation or assisted reproduction may be subject to federal acts, such as the Food and Drugs Act and the Assisted Human Reproduction Act and their regulations.

More than minimal manipulation of cells and tissues may involve adding a wide variety of substances or removing biological components during processing. This could alter their safety as well as the original or biological characteristics that are relevant for their claimed utility. Thus, clinical trials or investigational testing involving humans may be required to assess their safety and effectiveness.

For cells and tissues that are intended to be used in a manner that is not generally accepted to be a homologous use, sponsors must provide evidence to support a claim of homologous use. Health Canada has the authority to require information on relevant characteristics that must be maintained in order for a product to be considered homologous when distributed for a particular indication. Such information may include evidence that shows:

As noted, cells and tissues are not in the scope of the regulations if they have a systemic effect and depend on their metabolic activity for their main function.

When applied to cells and tissues, a systemic function can be interpreted as "a consequence or effect that is either of a generalized nature or that occurs at a site distant or not related to the location of the cell or tissue". Example: the transplantation of cells that can produce and secrete hormones that act on diverse cells throughout the body. In general, these cells depend on their metabolic activity (for example, the production of hormones and other substances) for their primary function.

In general, cells and tissues that have a systemic effect are excluded from the CTO regulations.

However, islet cells as well as lymphohematopoietic cells that are from bone marrow, peripheral blood and cord blood that have this effect are included in the CTO regulations. These particular cells are included because their safety and effectiveness have been demonstrated through clinical trials and/or established practice. These cells will only be subject to the regulations if they are minimally manipulated. That is, their processing only involves procedures used for pancreas digestion and for purifying specific cell populations from a mixture of cells.

Establishments must fully characterize these products and evaluate their cell preparations to ensure they meet the specifications set for cell number, identity, purity, viability and potency, for example. Note: If these cells are subject to procedures that are considered more than minimal manipulation (for example, ex-vivo expansion, cell differentiation or genetic manipulation), they will be subject to other regulations, including the Food and Drug Regulations and Medical Devices Regulations.

Demineralized bone that's combined with a:

Adding a handling component such as calcium carbonate or gelatin, used to modify the structure of the body, results in the product being regulated as a medical device under the Medical Devices Regulations.

For questions on the classification of a cell, tissue and organ, please email the Biologic and Radiopharmaceutical Drugs Directorate of Health Canada at brdd-cppic_brdd-cppci@hc-sc.gc.ca.

Prohibition

Section 4 of the CTO regulations

Transplantation:

4. (1) Subject to sections 40 to 42, no establishment shall transplant a cell, tissue or organ unless it is processed by a registered establishment under these Regulations and determined safe for transplantation.

Importation of cells and tissue:

(2) Subject to sections 40 to 42, no establishment shall import tissue or a cell, other than a lymphohematopoietic cell, unless it is processed by a registered establishment under these regulations and determined safe for transplantation.

Importation of organs and lymphohematopoietic cells:

(3) An establishment may import an organ or lymphohematopoietic cells from an establishment that is not registered.

For imported tissue, evidence of the source establishment's Health Canada registration must be included on the exterior label. Refer to section 31 of the regulations for further guidance on labelling tissues.

The importer must have a system in place to verify that a registered source establishment has processed the products and they are declared safe for transplantation. This should be done before importing from a new source establishment. The products should be assessed periodically to ensure the source establishment continues to meet these requirements.

The term "importation" refers to the importation of cells, tissues and organs from outside Canada. Health Canada does not consider the shipment of these products between different provinces or territories as importation.

Registration

Sections 5 to 14 of the CTO regulations

Requirement to register:

5. (1) Every establishment must be registered under these regulations, except a retrieval establishment and, subject to subsection (2), a transplant establishment.

Exception:

(2) A transplant establishment that distributes cells, tissues or organs must be registered under these regulations.

Establishments that must register with Health Canada include:

Establishments that do not have to register with Health Canada include:

Application:

6. (1) An application for registration of an establishment must be made in the form established by the Minister, be dated and signed by the medical director or scientific director, and contain all of the following information:

  1. the establishment's name and civic address, and its postal address if different, and the name and telephone number of a person to contact for further information with respect to the application
  2. in the case of an establishment that previously carried out its activities under another name, that other name
  3. a description of the types of cells, tissues and organs that the establishment processes, distributes or imports
  4. a description of the types of processing, distribution or transplantation activities that the establishment carries out or for which it is responsible
  5. the period during which the establishment has been in operation and
  6. a statement dated and signed by the medical director or scientific director that certifies that the establishment is in compliance with these regulations
Information on request:

(2) An establishment must provide the Minister, on written request, with any relevant information necessary to complete the application, by the date specified in the Minister's request.

The registration requirements for cells, tissues and organs:

Section 6 of the CTO regulations outlines the information that an establishment must provide in its registration application form. This information is mandatory and so must be included in the application form.

Establishments dealing with distinct programs may benefit by submitting a different application form for each program. This would ensure the continuity of other services in the event that 1 program experiences complications. However, separate applications are not required.

Distinct programs include, for example:

Part 1: Type of application

Part 1 of the application form must include the type of registration. If this is the first time an establishment is applying for a registration number, then the establishment must indicate: "Initial application". For change of information applications, make sure to select the correct box and identify the changes clearly.

Part 2: Establishment information

Establishment must indicate:

Enter the full civic address of the establishment, including the postal or zip code and the mailing address if it is different from the civic address.

Put down contact information for 2 persons who are directly involved in their program. Make sure the establishment and contact information are accurate and complete, as Health Canada will use this to communicate with your establishment. Keep this information up to date and submit any changes within 30 days of making the change.

Complete the additional address section if your establishment has multiple addresses that do not function independently and are part of the same quality management system. Enter the full civic address for these additional addresses. You may add the first 4 additional addresses to the form. Complete a separate annex 1 for each additional address.

Part 3: Source establishment

In part 3 of the registration application form, you must identify whether the establishment is a source establishment. List the cells, tissues and organs they are responsible for as a source establishment, based on the definition of a source establishment:

Indicate for each of the cells, tissues and organs if the program is for deceased or living donors.

Part 4: Importation and distribution of CTO

Canadian establishments that import or distribute cells, tissues and organs must register with Health Canada. You do not have to register if you only transplant or retrieve these products.

Refer to part 4 of the application form for further instructions if you're a:

Part 4 of the registration application form requires you to provide details on the types of CTO your establishment is importing and/or distributing. You also must indicate if you will be storing the cells, tissues and organs and the type of donation (deceased or living donation) for each type of CTO.

You should list the products distributed to Canadian establishments as well as the name and the CTO registration number of the source establishment.

If you're not sure how to classify a product, please contact us by email: brdd-cppic_brdd-cppci@hc-sc.gc.ca.

Limit the information in part 4D to a description of the types of processing, distribution or transplantation activities that your establishment carries out and that you did not already provide this information in part 4. We do not require you to provide details of the safety and efficacy of the products for registration. Please do not submit. We ask that you hold onto this information until we request it. Please provide only a note in part 4D that it's available if needed.

Canadian importers and Canadian distributors should identify the:

Part 5: Other entity information

"Other entity" refers to an establishment that performs regulated activities such as transmissible disease testing or donor screening. For example, a lab performs infectious disease testing.

Part 6: Statement of compliance

The declaration section of the application contains the following statement:

"I hereby certify that the establishment named in this application is in compliance with the Safety of Human Cells, Tissues and Organs for Transplantation Regulations."

The medical director or scientific director must sign and date the declaration in order for the application to be processed. It should not be signed by the CEO, unless the CEO is also the scientific or the medical director. Your establishment can delegate this authority to another individual if this delegation of authority is clearly expressed in your establishment's standard operating procedures (SOP). By signing the declaration, the signatory is attesting that the establishment is in compliance with the CTO regulations. Making false, misleading, inaccurate or incomplete statements is grounds for refusal to issue a registration number, as per section 8 of the regulations.

The declaration of compliance signed by a medical or scientific director assures Health Canada that the establishment acknowledges its responsibilities under the CTO regulations. This provides a level of assurance that:

The declaration does not preclude us from conducting inspections to verify compliance with the CTO regulations.

The medical director or scientific director is also attesting that the information in the application, including any identified changes, is accurate and complete as required under section 6(1), Application of the Safety of Human Cells, Tissues and Organs for Transplantation Regulations.

Send completed applications by email to roeb.cto-dgoral@hc-sc.gc.ca.

To inquire on the status of your establishment's registration, please email us: roeb.cto-dgoral@hc-sc.gc.ca.

Direct all other inquiries to brdd-cppic_brdd-cppci@hc-sc.gc.ca.

Registration number:

7. (1) On review of an application for registration, if the Minister determines that the information provided in the application is complete, the Minister must register the establishment and issue a registration number.

Validity:

(2) Subject to section 9, a registration is valid until December 31 in the year after the year in which the registration number is issued.

All CTO registration numbers expire on December 31 of the year following the year in which it was issued. For instance, certificates of registration issued in January 2022 expire on December 31, 2023, as do certificates of registration issued in December 2022.

The establishment must provide the application for renewal to Health Canada's Biological Product Compliance Program before the issued certificate of registration expires. When submitting an application, you must ensure that you have appropriately referenced all relevant changes.

Registration certificates are issued electronically. We will not mail physical copies of the registration certificates to your establishment.

Refusal:

8. The Minister may refuse to register an establishment if he or she has reason to believe that any of the information provided by the establishment in its application is false, misleading, inaccurate or incomplete.

When registration may be cancelled:

9. The Minister may cancel a registration in the following circumstances:

  1. the application for registration contains false or misleading information
  2. the Minister receives a notice under section 13 that states that the establishment has ceased an activity
  3. the establishment has not complied with a request for additional information made under section 14 or
  4. the Minister has reason to believe that the establishment is not in compliance with these Regulations or that the safety of cells, tissues or organs has been or could be compromised
Actions before cancellation:

10. (1) The Minister must take all of the following actions before cancelling a registration:

  1. send a written notice to the establishment that sets out the reasons for the proposed cancellation and specifies the corrective action, if any, that the establishment must take and the time within which it must be taken and
  2. give the establishment an opportunity to be heard in writing with respect to the cancellation

Notice of cancellation:

(2) If the establishment does not carry out the corrective action to the Minister's satisfaction, or does not carry it out within the required time, the Minister must send a notice of cancellation of the registration that includes the reasons for the cancellation and the effective date.

Action by establishment when registration cancelled:

11. On the cancellation of its registration, the establishment must immediately take both of the following steps:

  1. cease carrying out the activities that were authorized by the registration and
  2. notify the establishments to whom it has distributed a cell, tissue or organ or made a donor referral, during the period specified in the notice, of the cancellation, the reasons for the cancellation and the effective date
Cancellation in urgent circumstances:

12. (1) Despite section 10, the Minister may cancel a registration immediately if he or she considers it necessary to do so in order to prevent injury to the health or safety of the public, by giving the establishment a notice of the cancellation in writing that states the reasons for the cancellation.

Request to reconsider:

(2) An establishment may, in writing, request the Minister to reconsider the cancellation.

Opportunity to be heard:

(3) The Minister must, within 45 days after receiving a request for reconsideration, provide the establishment with an opportunity to be heard in writing with respect to the cancellation.

Ongoing requirement to notify Minister:

13. (1) Subject to subsection (2), an establishment must notify the Minister in writing of any change in the information provided in its application for registration, within 30 days after the change is made.

Cessation of activity:

(2) If an establishment ceases to process, distribute or import cells, tissues or organs, it must notify the Minister in writing of that fact, within 90 days after it ceases that activity.

Contents of notice:

(3) The notice must be dated and signed by the medical director or scientific director and include all of the following information:

  1. the establishment's name and civic address, and its postal address if different
  2. the establishment's registration number
  3. the date on which the change or cessation became effective and
  4. in the case of the cessation of an activity, the disposition of the cells, tissues and organs in the establishment's possession

You must inform us in writing of any changes to the information that you provided in your most recent application within 30 calendar days after the change is made.

Complete and submit the Human Cells, Tissues and Organs (CTO) for Transplantation Registration Application Form (FRM-0171) along with an accompanying cover letter.

Examples of amendments include:

The notice must be signed and dated by the medical or scientific director (or their designate) and include all of the information stated under subsection 13(3). The information that we require in the notice can be found in the application form. The medical or scientific director must sign and date part 6 of the application form attesting that the establishment is in compliance with the CTO regulations.

Part 7 of the application form contains the information we require to cancel the registration.

Submit changes electronically by emailing us at roeb.cto-dgoral@hc-sc.gc.ca.

For any questions or clarifications, email the Biological Product Compliance Program at bpcp-pcpb@hc-sc.gc.ca.

Additional information:

14. An establishment must provide the Minister, on written request, with any additional relevant information to demonstrate that the activities it carries out are in compliance with these regulations, by the date specified in the Minister's request.

Under section 14 of the CTO regulations, an establishment must provide us any relevant information that we require to determine if your establishment is in compliance with the CTO regulations.

Source establishment

Section 15 of the CTO regulations

Responsibility:

15. A source establishment is responsible for the processing of cells, tissues and organs, whether the processing is carried out by the source establishment itself or by another establishment, and for determining whether the cells, tissues and organs are safe for transplantation.

The source establishment is responsible for:

The determination of the source establishment depends on the CTO in question. Source establishment refers to the source of the CTO that has been processed and deemed safe for transplantation.

For organs from a deceased donor, the organ donation organization (ODO) is the source establishment responsible for processing the organs. This reflects current practice as the ODO will typically conduct donor screening and testing or donor suitability assessment. This is a key component in determining if an organ is safe for transplantation.

When an organ is retrieved from a deceased donor, it is common practice to simultaneously retrieve blood vessels from that donor. This aids organ transplantation. Under the CTO regulations, these vessels are referred to as adjunct vessels. They are subject to the same regulatory requirements as organs.

If the adjunct vessels are not used immediately in the transplantation of the organ with which they were retrieved, the establishment that is responsible for storing and then distributing the adjunct vessels must register as a source establishment. The source establishment must ensure that adjunct vessels intended for transplantation are stored and documented appropriately.

The source establishment must follow the requirements for organs in the CTO regulations since the adjunct vessels continue to be regulated as organs under the regulations and are not regulated as tissues. The source establishment is responsible for receiving and reviewing the relevant organ donor suitability assessment information, including the questionnaire, test results and physical exam results, before transplantation. This is very important in cases where the vessels are transplanted in an individual other than the original organ recipient.

Health Canada recommends that organ transplant establishments keep records of any adjunct vessels that are stored for future use, regardless of whether the transplant establishment:

We also recommend that organ transplant establishments let source establishments know if and where they store adjunct vessels that are not used during the surgical procedure of the organ recipient. Doing so ensures that adjunct vessels can be appropriately identified and either quarantined or traced to a recipient in the event that any adverse reactions are reported in organ recipients who received an organ from the donor of the adjunct vessels.

The source establishment must also:

In some cases, adjunct vessels will need to be released before the source establishment has reviewed the documentation. Under these conditions and if appropriate, the transplanting physician may authorize the exceptional distribution of these vessels (sections 40 to 42 of the CTO regulations).

Where exceptional distribution is applied to an organ of a donor, the exceptional distribution process does not have to be repeated for using the adjunct vessels retrieved from that same donor if the person receiving the organ and the vessels and if the reason for the exceptional distribution are the same. However, the documentation requirements of sections 40 to 42 of the regulations must still be met.

For organ donation from a living donor, the source establishment responsible for processing the organ is the relevant transplant establishment, which will need to register. The same is true for allogeneic (for use in another individual) lymphohematopoietic cell donations that are not banked.

The transplant establishment is still the responsible source establishment regardless of which establishment assesses the donor or which organization looks after matching the donor and the recipient. For example, the transplant establishment is still considered the source establishment for living donor kidney transplants that involve a donor who travels from the program where the donor workup and testing took place or that involve an organ that is shipped for transplantation.

The transplant establishment is responsible for obtaining and reviewing the appropriate documentation and determining the safety of the organ. The transplant establishment does not, however, need to repeat the donor screening and testing if it deems the existing results acceptable.

Health Canada recommends that the living donor organ donation and transplantation community work together to develop standardized SOPs and questionnaires. This help to ensure consistency of donor screening and testing practices among the different organizations involved.

We recognize that for unrelated lymphohematopoietic cell donations, the different activities carried out by establishments may be on a continuum. In this case the source establishment is the transplant establishment, and will need to register. For example, even if a stem cell registry or a retrieval establishment initiates donor testing, the transplant establishment is responsible for reviewing these results and determining the safety of the donation.

For all tissues and lymphohematopoietic cells that are banked, the tissue or cell bank is the source establishment responsible for processing and the safety of the cells and tissues. This bank may be either a specific or a comprehensive tissue or cell bank.

Note: The term "banked" in this context does not refer to cells and tissues that are obtained from a source establishment and stored by the end user for a period of time before use in transplantation. Under the CTO regulations, "banked" cells and tissues are those for which all other processing activities (with the exception of final labelling) have been completed, are stored by the source establishment in their inventory and are available for distribution and transplantation.

For lymphohematopoietic cells collected from bone marrow or peripheral blood, any storage of the cells is not considered banking if the donation is reserved for treating a designated recipient.

Example illustrating the definition of source establishment in the case of a multiple tissue/organ donor, where there may be more than 1 source establishment for a given donor (where bone, ocular tissue, kidney and liver were to be retrieved from a donor):

As per the definition in the CTO regulations, the organ donation organization (ODO) would be the source establishment responsible for processing and the safety of the organs. The bone and eye bank would be responsible, respectively, for processing and the safety of the bone and ocular tissue. Similarly, if the bone and ocular tissue were retrieved for a comprehensive tissue bank, the tissue bank would be responsible for processing and the safety of the tissues.

Note: Being the source establishment in 1 circumstance for a particular CTO does not mean the establishment is the source establishment for all CTOs that it handles or processes.

A good example of this is an ODO. An ODO is the source establishment for organs from deceased donors. While it may be involved in tissue donation, it is not the source establishment for tissues.

Each establishment must rely on the CTO regulations and their definitions, along with this guidance document, to determine its responsibilities for the safety and processing of CTOs under these regulations. All establishments involved in processing the CTO should agree on which establishment will function as the source establishment.

Note that composite tissues, which are vascularized composite allografts consisting of multiple tissue types (for example, a full face or hand transplant), can meet the definition of a tissue or an organ under the CTO regulations. It is up to the source establishment to determine which set of regulatory provisions is most appropriate for their circumstances. Provided the relevant regulatory provisions relating to either tissues or organs are met, the organ or tissue source establishment that's registered as per Section 5 of the regulations may distribute composite tissue (without using exceptional distribution).

Processing

Sections 16 to 27 of the CTO regulations

The extent of the responsibility of source establishments for the processing and safety of CTOs under section 15 of the regulations is determined by the meaning of the term "processing". Processing (defined in section 1 of the regulations) includes:

Each of these activities is described in more detail under the following applicable regulatory requirements. Information about donor suitability assessment, including donor screening and testing, is organized as follows:

The responsibility of source establishments for the activities described applies whether or not the source establishment carries out the activities itself, or if they are performed by another establishment on behalf of the source establishment.

Documented evidence:

16. An establishment must have documented evidence that demonstrates that the activities, processes and technical procedures that it uses in processing cells, tissues and organs will consistently lead to the expected results.

For these regulations, documented evidence refers to activities, processes and technical procedures that:

When pooling permitted:

17. An establishment may only pool cells, tissues or organs from different donors during processing to create a therapeutic dose for a single recipient.

Requirements for cell, tissue and organ donors:

18. In assessing the suitability of a donor of cells, tissues or organs, except a donor of lymphohematopoietic cells, an establishment must perform all of the following steps:

  1. obtain the donor information and history in accordance with sections 12.2 and 12.3 of the general standard
  2. determine that the donor is not unsuitable to donate on the basis of the contraindications or exclusion criteria set out in section 13.1.3 of the general standard and in Annex E to that standard
  3. perform a physical examination of the donor in accordance with section 13.2 of the general standard
  4. perform appropriate and effective tests for the diseases or disease agents specified in section 14.2.6 of the general standard

Section 18 applies to all cells, tissues and organs with the exception of lymphohematopoietic cells. Refer to section 23 for donor suitability requirements for lymphohematopoietic cells.

Donor suitability assessment

Donor suitability assessment (section 12.2 of the general standard), which is intended to elicit risk factors, is based on the donor's medical and social history, clinical status, physical examination, tests and, if performed, an autopsy. Documentation of this assessment must include all the elements specified in section 12.3 of the general standard.

Where an autopsy is to be performed and it's determined the integrity of the CTO will be compromised before the report is completed, you do not need to wait for the final report of the autopsy results. Rather, the presumed cause of death and other pertinent preliminary autopsy findings should be taken into consideration and documented.

Donor screening

Donor screening is 1 component of donor suitability assessment. It's done to elicit general health information and identify risk factors (such as infectious disease risks) that could impact the safety of the CTO.

This risk assessment is based on the donor's medical and social history, clinical status, physical examination, tests and, if performed, an autopsy. The donor's medical and social history and clinical status can be obtained through a donor interview and a review of the donor's medical records or charts. The interview must be conducted using a medical/sexual/social history questionnaire that includes the applicable contraindications/exclusion criteria and other relevant questions required under the CTO regulations. The interview should be documented in the form of a checklist where the response/outcome for each criterion is recorded.

If the donor is deceased or cannot participate in the interview, at least 1 person who can provide the necessary information may be interviewed. This person could be:

The interview should take place in person or by telephone.

An establishment must develop and maintain SOPs for all steps performed during donor screening. This includes the steps involved in conducting the donor medical/sexual/social history interview and administering the donor screening questionnaire(s). If a questionnaire developed by a professional organization is to be used, an establishment must review the questionnaire to determine if it meets all the requirements of the CTO regulations for donor screening.

Screening of living donors should be done as close to the time of retrieval as feasible. If more than 1 month has elapsed since the donor screening questionnaire was completed and the retrieval has not yet occurred, we recommend that you review the living donor screening results with the donor as close to the time of retrieval as feasible to see if any information has changed. An abbreviated donor screening questionnaire is acceptable provided it addresses all the necessary exclusion criteria.

When a potential donor is part of the medical assistance in dying (MAID) program, the information communicated by the living potential donor may be considered part of the donor screening assessment. However, you must verify that the information is still true within the necessary timeframes for donation and that the assessment is completed in accordance with the establishment's SOP.

The donor suitability requirements that apply to living donors apply for conscious and competent donors. Once organ retrieval begins, the requirements for deceased donors apply.

When screening donors under 11 years of age, you should collect answers to screening questions used to determine high risk for HIV, HBV or HCV in a manner that is appropriate to the donor's age. This should be described in the establishment's SOP.

Contraindications or exclusion criteria

The conditions and behaviours set out in section 13.1.3 and Annex E of the general standard may increase the risk that a donor may have and/or could potentially transmit an infectious disease to the recipient. Donors are to be excluded from donating a CTO on the basis of these contraindications/exclusion criteria. The exception is when exceptional distribution is used (for more information, consult sections 40 to 42 of the CTO regulations).

Note that recent changes to Annex E in the 2022 edition of the CSA Z900.1 standard include the following:

Examples of prion-related disease that are described as exclusion criteria in section 13.1.3 of the general standard include, among others:

Examples of degenerative neurologic disorders of viral or unknown etiology that are described in section 13.1.3 of the general standard include, among others:

Section 13.1.3 of the general standard states:

"A donor shall be excluded if any of the following contraindications apply:
persons with a history of infection with HIV, clinically active HCV or clinically active HBV."

This clause has been amended to refer to persons with a history of clinically active HBV or HCV. The amendment clarifies that where there was a suspicion of hepatitis in the donor's medical history (outside of the current donor suitability assessment) it may be possible to requalify the donor if the validity of this information is in question. Requalification can be done by performing the necessary donor screening and testing required under the CTO regulations. We also recommend that you perform nucleic acid testing (NAT) under these circumstances as a precaution.

Section 13.1.3 (f) of the general standard excludes donors "with active encephalitis or meningitis of infectious or unknown etiology". Undiagnosed meningitis or encephalitis has been linked to high rates of transmission of infection to organ recipients, which can lead to significant morbidity and mortality.

The Organ Procurement and Transplantation Network, together with the United Network for Organ Sharing, has developed a guidance document for evaluating potential organ donors for meningoencephalitis during the donor screening process.

Learn more:

Other infections may also exclude the donation of a CTO, if the infection would pose a significant risk to the recipient if transmitted.

Physical examination

Before a CTO is donated (with the exception of lymphohematopoietic cells, which are dealt with under section 23) from a potential donor, a qualified person must perform the physical examination. This must be done in accordance with the establishment's SOP, which must comply with section 13.2 of the general standard.

When a potential donor is part of the medical assistance in dying (MAID) program, a physical exam of the conscious and competent potential donor may be considered part of the donor screening assessment. However, the information must be verified as true within the necessary timeframes for donation and the assessment must be completed in accordance with the establishment's SOP. Any mandatory living donor tests for which results are not obtained must result in the organs being distributed under exceptional distribution only.

For conscious and competent patients, the physical examination must be performed within 30 days of the scheduled date of the medical assistance in dying procedure or when life-sustaining measures are withdrawn.

Deceased donors

In the case of a deceased donor, the mandatory physical examination includes a recent antemortem or postmortem physical examination and a directed physical examination. It may include a limited autopsy, if performed. The directed examination should include any of the following applicable items that would help determine evidence of high-risk behaviour.

Along with information gathered as part of the donor medical/social history, the following physical evidence is used to evaluate the donor's risk of having a transmissible disease. While not all of the identified risk factors will necessarily lead to the donor being excluded, the information could help in clinical decision-making.

The following physical evidence are examples that may be associated with the presence of a transmissible disease and should be assessed in a directed physical examination performed on all potential deceased CTO donors:

It's very rare that you will encounter signs of physical evidence associated with a recent smallpox (vaccinia) immunization. However, you could encounter these signs in:

A physical examination of skin donors must include documentation of findings and conditions that may affect the quality or quantity of skin retrieved.

For deceased donors, a full visualization of the external body shall be performed. If full visualization is not feasible, the assessment shall be deemed incomplete.

Living donors

In the case of a potential living donor, all donors must be given a physical exam. The exam must look for evidence of:

Physical exams should be done as close to the time of retrieval as is reasonable and practical. We recommend within 30 days of the anticipated date of retrieval.

If the retrieval of the organ or tissue is postponed, the source establishment will need to determine if a repeat physical exam or a limited repeat physical exam is warranted.

If an examination of the donor was already done for other reasons (for example, to determine if donation is safe for the donor), the findings from this previous examination can be reviewed and documented in the donor's records. However, the exam must have been performed within the recommended timeline.

In general, the findings of a physical exam performed for other reasons may not be reported in a manner that specifically addresses the risk factors of interest. In this case, a new physical exam must be performed to confirm or rule out potential risk factors that are identified during the medical/social history review. The new physical exam must assess any physical evidence that could indicate high-risk behaviour associated with the presence of a transmissible disease.

For donations of amniotic membrane tissue, a surrogate physical examination of the mother must be performed and the results must be documented.

Standard operating procedures (SOPs)

An establishment must have SOPs describing how to conduct physical examinations of donors.

Donor testing

General requirements

Donor testing may include:

The following guidance for donor testing focuses on laboratory tests for the various transmissible disease agents that apply to CTO donors.

For information on donors of lymphohematopoietic cells, refer to section 23 of the CTO regulations.

Timeframe for collecting specimens

Health Canada considers the timeframes in Table 1 to be appropriate and effective.

Ideally, specimens for infectious disease testing for all CTO donors should be collected as close to the donation as possible.

Table 1: Timeframe for collecting specimens for testing HIV-1, HIV-2, HCV and HBV and diseases or disease agents specified in the infectious disease testing requirements of the applicable subset standards
Type of CTO Type of testing required Timeframe
Tissue from deceased infant donor ≤ 28 days old and who had no obvious potential exposure to a blood born pathogen after birth serological screening tests plus NAT for HIV-1 and HCV performed on the person who carries the infant donor to delivery Refer to the sub-section on deceased tissue donor test specimen collection timeframes
Tissue from deceased infant donor > 28 days old* serological screening tests plus NAT for HIV-1 and HCV performed on infant donor Refer to the sub-section on deceased tissue donor test specimen collection timeframes
Tissue from deceased donor* serological screening tests performed on donor plus NAT for HIV-1 and HCV Refer to the sub-section on deceased tissue donor test specimen collection timeframes
Tissue from live donor serological screening tests performed on donor within 7 days before retrieval or 7 days after retrieval
deceased organ donor serological diagnostic or screening tests performed on donor as close to the time of donation as possible, with tests performed on the most recent sample for which donor identity and sample quality can be ensured
live organ donor (including conscious and competent donors) serological diagnostic or screening tests performed on donor within 30 days before donation and it is recommended to retest at the time of donation
organ from infant donor ≤ 28 days old serological diagnostic or screening tests performed on the person who carries the infant donor to delivery within 7 days before or at the time of donation
organ from infant donor > 28 days old but < 18 months or who was breastfed in the last 12 months serological diagnostic or screening tests performed on the infant donor as well as the person who carries the infant donor to delivery, unless HIV-1 and HCV NAT is performed on the infant, in which case all tests should only be performed on the infant within 7 days before or at the time of donation

*While antemortem or postmortem specimens are acceptable, we recommend that a pre-mortem specimen be used, if available. This specimen is likely to be less hemolyzed, and excessive hemolysis can interfere with the test results. The donor may have received fluid infusions shortly before dying as well, which would dilute the plasma enough to affect test results.

Note: NAT for HIV-1 and HCV is mandatory for tissue (including ocular tissue) from deceased donors. It is not necessary for tissue from living donors if the 180 quarantine and donor retesting protocol is followed (outlined in section 17.2 of the tissue standard).

Establishments must have SOPs that specify the timeframes for collecting blood specimens from donors of each type of CTO.

For deceased donors, blood testing results are acceptable if sample collection takes place within 7 days before the time of cardiac death or cross clamping of the aorta.

For cadaveric donors (non-heart beating donors), blood testing results are acceptable if sample collection takes place:

  1. as specified in the relevant sections of the package inserts of test kits approved for cadaveric specimens
  2. within 24 hours after the time of death in cases where the test kit package insert does not specify a timeframe and the validation section of the package insert does not specify the hours after death within which the specimens were collected or
  3. up to 24 hours after the time of death in situations where the package insert specifies a collection timeframe of less than 24 hours, if in this instance, the establishment that made the decision to extend the collection time up to 24 hours has a documented risk-based rationale approved by the medical director available to support the decision

Note: The documentation under item c) is to support the approval of the overall procedure relevant to the collection timeframes for deceased donor samples at the establishment. The supporting information used in the document may include, among other things:

Infectious disease testing

All source establishments are responsible for infectious disease testing, including testing that another establishment carries out on its behalf. They must have appropriate documentation (such as SOPs, agreements, contracts or audit reports) to support that infectious disease testing is performed in accordance with the following:

Interpreting infectious disease test results

The terms used by test kit manufacturers for interpreting serological test results are determined, in part, by the testing algorithms used.

In general, the initial serological screening test is performed using a single blood sample. A nonreactive sample is considered a negative test result and further testing is not required.

In contrast, a reactive sample is considered initially reactive instead of positive because the:

These 2 additional steps are necessary to achieve the final outcome ("positive" or "negative") of the test kit in the event that a sample is initially reactive.

Note: This testing algorithm is an example only. Establishments must always apply the specific testing algorithm indicated in the test kit's instructions for use.

Also, some test kit manufacturers may recommend confirmatory or supplemental testing with a different test kit to confirm the results of the first test kit. While confirmatory testing is necessary for patient diagnosis, it should not be considered for screening donors because false negative confirmatory test results cannot be ruled out. Thus, in these circumstances, donors must still be excluded regardless of the confirmatory test results.

In cases where confirmatory testing is performed for patient diagnosis, establishments that use third-party testing labs must ensure that they are given the results of the initial test kit so they may determine donor eligibility.

In addition, instead of using the term "repeatedly reactive" for the final outcome of a particular screening or diagnostic test, some test kit manufacturers use the terms "reactive" or "positive".

In this guidance document:

A determination of donor eligibility includes the interpretation of the following infectious disease test results:

If a donor's specimen tests positive for HIV, HBV or HCV using a required serological test but is negative using NAT, the CTO cannot be distributed, unless done under exceptional distribution.

Note: Exceptional distribution may be used if the donor specimen is repeatedly reactive or positive for markers of infectious disease agents. More information on exceptional distribution can be found in sections 40 to 42 of the CTO regulations.

Results of all tests, including optional tests, must be included in the donor records. Establishments must have SOPs for interpreting and handling test results, including communicating results to transplant physicians or to establishments to which the CTO are distributed. Procedures must also be established for handling the results of tests that become available after the CTO has been released for distribution. Such procedures must include notification of transplant physicians or establishments to which the CTO is distributed.

Archived samples

The CTO regulations do not require that samples be collected for archiving as this has no impact on the safety of CTOs that meet current regulatory requirements. However, cell, tissue, plasma or serum samples from each donor should be archived for retrospective testing of donors of cells and tissues that are still in inventory when new tests are adopted to screen donors for existing or emerging pathogens.

Retrospective testing is based on the degree of safety enhancement afforded by the new tests, as well as the availability of tests that are appropriately validated or approved under the Medical Devices Regulations for testing frozen specimens. Health Canada will inform CTO establishments if retrospective testing is required.

If establishments choose to archive samples, they must have SOPs for collecting and storing samples being archived. Samples must be stored frozen and should be kept for at least 5 years. Establishments must have documentation to show that the archived samples are stored at the appropriate temperature.

Tests that are considered appropriate and effective

Mandatory testing

All CTO donors must be tested for the infectious disease agents listed in the sections of the general standard referenced in the CTO regulations, using appropriate and effective tests. We consider a test to be appropriate and effective if it is:

Section 14.2.6.1 of the general standard:

The following sections list infectious disease markers that are considered appropriate and effective for detecting donors infected with the disease agents listed in the general and subset standards. This list may be revised when new infectious disease tests become licensed or when new information necessitates an amendment.

Health Canada considers tests for the following infectious diseases markers to be appropriate and effective in order to comply with section 14.2.6.1 of the general standard:

The person who carries the infant donor to delivery and donor must be tested for infectious disease agents for infant donors under the age of 18 months or who were breastfed at any time during the 12 months before donation. This is to address vertical transmission of infectious agents to the donor (section 14.2.6.2 of the general standard).

The following exceptions apply:

Establishments must have SOPs that describe which infectious disease tests must be performed and when surrogate testing is required for infant donors.

Recommended testing

Living organ donors should also be tested for HIV-1 and HCV using NAT.

NAT should be performed on organ donors (living and deceased) where it is clinically indicated. An example is if a decision is made to use exceptional distribution for a CTO from a donor with a history of high-risk behaviour and a negative serological test for HIV and HCV.

Organ, islet cell and tissue donors (including ocular tissue donors) should be tested for WNV using a test kit that is licensed to detect viral nucleic acid. Testing could be done seasonally if specific procedures are in place to determine:

Given the transient nature of WNV viremia, Health Canada recommends that blood samples be tested on the day of donation or as close to the time of donation as is feasible. WNV testing turnaround times should be considered. As with other infectious diseases, donors could become infected with WNV after sample collection but before donation if the samples are collected before donation. Additional screening and/or testing samples collected on the day of donation could address this risk.

Health Canada has licensed a test kit to detect WNV ribonucleic acid in plasma specimens from both living and deceased donors. (Our Medical Devices Directorate is the Canadian federal regulator responsible for licensing in accordance with the Medical Devices Regulations.)

Medical devices active licence listing (MDALL)

Health Canada has a database of licensed Class II, Class III and Class IV medical devices for sale in Canada. You can verify the licensing information of test kits approved for donor screening by visiting the medical devices active licence listing (MDALL) web page and then using the "active licence search" function.

Note that test kits approved for donor screening are licensed as class 4 devices, but not all class 4 test kits are necessarily approved for donor screening.

As of 2024, the names of all newly authorized infectious disease tests kits approved for donor screening in MDALL will not indicate that they are approved for donor screening. However, all newly authorized infectious disease tests kits will have published regulatory decision summaries that can be used to verify whether new test kits are licensed for donor screening.

Plasma dilution algorithm:

19. In assessing the suitability of a donor, an establishment must apply a plasma dilution algorithm if a donor pre-transfusion or pre-infusion blood sample is unavailable.

Blood transfusion or infusion of intravenous fluid could dilute the donor's blood. This could lead to:

Testing must be performed on a suitable blood sample (as defined by the establishment's SOPs) that's collected as close to the time of retrieval as possible. Testing should be done on the most recent pre-transfusion/infusion blood sample for which identity and quality can be ensured. If no suitable pre-transfusion/infusion blood sample is available, benchmarks for plasma dilution shall be applied to determine whether the degree of plasma dilution is or is not sufficient to affect test results. If no suitable pre-transfusion/infusion blood sample and no other suitable specimen is available for testing based on the results of the plasma dilution algorithm, this constitutes a contraindication to donation.

Establishments must have SOPs that describe situations that could result in plasma dilution, as well as the collection of pre-transfusion/infusion samples.

Health Canada does not provide guidance on the types of infused fluids to consider when calculating plasma dilution. We also do not recommend or review plasma dilution algorithms. Establishments must develop their own SOPs that outline their plasma dilution algorithms. Algorithms must be validated, established in standards developed by recognized professional organizations or supported by information available in the scientific literature.

Additional exclusion criteria for tissue donors:

20. In assessing the suitability of a tissue donor, except an ocular tissue donor, an establishment must perform both of the following steps:

  1. determine that the donor is not unsuitable to donate on the basis of the contraindications or exclusion criteria set out in section 13.1.2 of the tissue standard
  2. perform appropriate and effective tests for the diseases or disease agents specified in section 14.2.6 of the tissue standard
Contraindications/exclusionary criteria

In addition to the exclusion criteria of section 13.1.3 of the general standard, donors are excluded from donating tissues on the basis of the exclusionary criteria in section 13.1.2 of the tissue standard.

Note: Two new exclusion criteria have been added to section 13.1.2 of the tissue standard in the 2022 edition:

Tests that are considered appropriate and effective

Mandatory testing

In addition to tests for the disease or disease agents specified in section 14.2.6 of the general standard, Health Canada considers the following tests are appropriate and effective for testing tissue donors in order to comply with section 14.2.6 of the tissue standard:

Please refer to Table 1 for timeframes for collecting specimens.

Note: Health Canada will permit exemptions from the requirement to perform NAT for fresh tissue grafts that cannot be stored for a sufficient period of time to allow for receiving nucleic acid test (NAT) results before transplantation. Establishments that wish to exempt fresh tissue grafts from NAT must make sure their SOPs:

In these cases, fresh tissue grafts can be distributed without having to use exceptional distribution when NAT is not performed.

Recommended testing

Donors of tissues not considered leukocyte-rich should also be tested for HTLV-I and HTLV-II.

Tissue that is not considered leukocyte-rich includes, among others:

Additional exclusion criteria for ocular tissue donors:

21. In assessing the suitability of an ocular tissue donor, an establishment must determine that the donor is not unsuitable to donate on the basis of the contraindications or exclusion criteria set out in sections 13.1.3 to 13.1.6 of the ocular standard.

Contraindications/exclusionary criteria

In addition to the exclusion criteria of section 13.1.3 of the general standard, donors must be excluded from donating ocular tissue on the basis of the exclusionary criteria in sections 13.1.3 to sections 13.1.6 of the ocular standard. Note that 13.1.3 (h) and (l) of the ocular standard are not intended to exclude the use of healthy tissue from a donor with intrinsic eye disease or a congenital or acquired disorder that only affects 1 eye. The contraindication only applies to the affected eye.

Note: Two new exclusion criteria have been added to section 13.1.3 of the ocular standard in the 2022 edition:

Eligibility based on HTLV and syphilis testing

Ocular tissue may be used for transplantation without having to use exceptional distribution (subject to approval by the source establishment's medical director) when testing for:

Additional requirements for organ and islet cell donors:

22. (1) In assessing the suitability of an organ or islet cell donor, an establishment must perform all of the following steps:

  1. obtain the donor information and history in accordance with sections 12.2.2.3, 12.2.2.4, 12.2.3.4 and 12.2.3.7 of the organ standard
  2. determine that the donor is not unsuitable to donate on the basis of the contraindications or exclusion criteria set out in section 13.2.2 of the organ standard
  3. perform the tests specified in sections 14.1.2 and 14.3.2 of the organ standard
  4. perform appropriate and effective tests for the diseases or disease agents specified in sections 14.2.6.3 and 14.2.6.6 of the organ standard

Exception for imported organs:

(2) Despite subsection (1), in the case of an imported organ, the transplant establishment need only have the following:

  1. documentation of the donor suitability assessment according to the requirements of the jurisdiction where the assessment was performed
  2. documentation that the tests specified in sections 14.1.2 and 14.3.2 of the organ standard have been performed
  3. documentation that appropriate and effective tests for the diseases or disease agents specified in sections 14.2.6.3 and 14.2.6.6 of the organ standard have been performed
  4. in the case of those of the tests for the diseases or disease agents specified in section 14.2.6.3 of the organ standard that must be performed before transplantation and the blood group test for ABO, a copy of the test results
Donor information and history

Section 12.2.2.3 of the organ standard requires that a donor history be taken for travel or residence outside the United States and Canada. Establishments should work with an infectious disease specialist to develop SOPs for the risk of infectious diseases that can be acquired abroad.

Travel history and timeframe of travel history along with donor symptoms, medical records and findings of the physical exam can help rule out active infections that could be acquired abroad. Travel-related diseases to consider include malaria, chagas, Zika, Ebola, dengue fever, strongyloides and West Nile virus.

Health Canada has also issued measures to address the potential risk of Zika virus transmission through human cells, tissues and organs.

Cases of donor allergies transferred to recipients have been reported for hematopoietic cell transplantation and solid organ transplantation, including potentially fatal allergies to nuts, seafood, penicillin and latex.

To address this concern, the medical social history requirements in section 12.2.2.3 of the organ standard have been amended to include information on life-threatening donor allergies. This information must be in the donor history, so that transplant establishments can take measures to address the possibility that the recipient could develop an allergy from the transplant. This is especially if the cause of the donor's death was due to an anaphylactic reaction from being exposed to an allergen.

To address the current medication requirement, establishments must assess the donor for prescribed medications and other current medications, including over-the-counter drugs or natural health products.

Contraindications/exclusionary criteria

In addition to the exclusion criteria of section 13.1.3 of the general standard, donors must be excluded from donating organs and islet cells on the basis of the exclusionary criteria in section 13.2.2 of the organ standard.

The donor's surgeon must assess the physical quality of the organ(s) being donated. The surgeon must document any abnormality or concern, such as the presence of an unsuspected infection or malignancy, and notify transplanting programs immediately.

Tests that are considered appropriate and effective

Mandatory testing

In addition to tests for the disease or disease agents specified in section 14.2.6 of the general standard, Health Canada considers the following tests to be appropriate and effective for testing organ and islet cells donors (to comply with section 14.2.6.3 of the organ standard):

Note: Results of the tests for CMV, EBV and toxoplasmosis may be reported following organ distribution.

Please refer to Table 1 for timeframes for specimen collection.

Recommended testing

Testing for WNV nucleic acid (WNV NAT) is recommended for organ and islet cell donors (section 14.2.6.4 of the organ standard). Anti-CMV IgM testing is also recommended.

An anti-viral capsid antigen IgG (anti-VCA IgG) test is recommended for detecting EBV and could be supplemented with an anti-VCA IgM test to enhance detection of recent infections. Anti-EBV nuclear antigen (anti-EBNA IgG) IgG tests should be supplemented with appropriate EBV tests for enhanced early detection of EBV infection, as EBNA IgG antibodies may not be detected in recently infected individuals.

Living organ donors should also be tested for HIV-1 and HCV using NAT, if available. In particular, NAT should be performed on organ donors (living and deceased) where it's clinically indicated. An example is if a decision is made to use exceptional distribution for a CTO from a donor with a history of high-risk behaviour and a negative serological test for HIV and HCV.

Physical exam

For conscious and competent patients, the physical examination must be performed within 30 days from the scheduled date of the medical assistance in dying procedure or when life-sustaining measures were withdrawn.

Requirements for imported organs

For imported organs from deceased donors, the source establishment would be the foreign ODO.

In some cases:

The transplant establishment and the Canadian ODO must clearly identify their respective roles and responsibilities for imported organs within their SOPs. This includes identifying the information that the ODO must obtain on behalf of the transplant establishment. This is necessary for the establishment to meet the requirements of subsection 22(2) of the CTO regulations.

Section 22(2) of the regulations provides an exception to organ standard provisions referenced in Section 22(1). Note: Section 22(2) does not exempt imported organs from general standard requirements referenced in Section 18 of the regulations, including ensuring that the testing requirements in section 14.2.6 of the general standard have been completed.

Requirements for lymphohematopoietic cells:

23. (1) In assessing the suitability of a donor of lymphohematopoietic cells, an establishment must perform all of the following steps:

  1. obtain the donor information and history in accordance with sections 12.2.2.2 and 12.2.2.3 of the lymphohematopoietic standard
  2. perform a physical examination of the donor in accordance with section 13.2 of the lymphohematopoietic standard
  3. determine that the donor is not unsuitable to donate on the basis of the contraindications or exclusion criteria set out in section 13.1.3 of the lymphohematopoietic standard
  4. perform the tests specified in section 12.2.2.4 of the lymphohematopoietic standard
  5. perform appropriate and effective tests for the diseases or disease agents specified in section 14.2.3 of the lymphohematopoietic standard

Exception for imported lymphohematopoietic cells:

(2) Despite subsection (1), in the case of imported lymphohematopoietic cells, the source establishment must:

  1. have documentation of the donor suitability assessment
  2. perform the tests specified in section 12.2.2.4 of the lymphohematopoietic standard
  3. perform appropriate and effective tests for the diseases or disease agents specified in section 14.2.3 of the lymphohematopoietic standard
  4. determine that the donor is not unsuitable to donate on the basis of the exclusion criteria set out in section 13.1.3.4 of the lymphohematopoietic standard

In the case of cord blood, the infant is considered the donor. However, transmissible disease testing and a physical exam must be performed on the person who carries the infant donor to delivery (referred to as surrogate testing).

Assessment of donor suitability

An assessment of donor suitability (section 12.2 of the lymphohematopoietic standard) is done to identify risk factors. In general, the assessment is based on medical and social history, clinical status, physical examination and tests.

Documentation of this assessment:

Donor screening

Donor screening is one component of donor suitability assessment, It's done to gather general health information and identify risk factors (such as infectious disease risks) that may impact the safety of the lymphohematopoietic cells.

The risk assessment is based on the donor's medical and social history, clinical status, physical examination and tests. Medical and social history and clinical status information can be obtained through a donor interview and a review of the donor's medical records or charts. A medical/sexual/social history questionnaire that includes the applicable contraindications/exclusion criteria and other relevant questions should be used to interview a donor. The responses should be documented in the form of a checklist so the response/outcome for each criterion can be recorded.

For a child donor, at least 1 knowledgeable person, such as the donor's parents or legal guardian, should provide the required information. The interview should be done in person or by telephone.

Donor screening should be done as close to the time of retrieval as feasible. The donor screening results should be reviewed with the donor as close to the time of retrieval as feasible, to determine if any information has changed, if:

In this cases, an abbreviated donor screening questionnaire is acceptable provided it addresses all the necessary exclusion criteria.

An establishment must develop and maintain SOPs for all donor screening steps, including those governing the donor medical/sexual/social history interview and the donor screening questionnaire(s). If a questionnaire developed by a professional organization is used, the establishment must make sure it meets the requirements of the CTO regulations for donor screening.

Cases of donor allergies transferred to recipients have been reported for lymphohematopoietic cell transplantation and solid organ transplantation, including potentially fatal allergies to nuts, seafood, penicillin and latex. We have amended the medical social history requirements in section 12.2.2.3.1 of the lymphohematopoietic cell standard to include information on life-threatening donor allergies. Except for cord blood, establishments must capture this information as part of the donor history to address the possibility that the recipient could develop an allergy as a result of the transplant.

Documentation of a donor's medical and social history must include any travel or residence outside the United States and Canada. Establishments should develop SOPs that address travel-related diseases, such as malaria, chagas, Zika, Ebola, dengue and West Nile virus.

Travel history and timeframe of travel history as well as donor symptoms, medical records and physical exam results can help rule out active infections that could be acquired abroad.

Health Canada has also issued measures to address the potential risk of Zika virus transmission through human cells, tissues and organs.

Unless tested for WNV, a donor's travel history in the past 56 days must also be obtained to ascertain if the donor had travelled to WNV-endemic areas, including those within Canada. This is to comply with sections 14.2.3 (d) (i) and (ii) of the lymphohematopoietic cell standard. A travel history within Canada is necessary when:

Contraindications/exclusion criteria

The conditions and behaviours set out in section 13.1.3 of the lymphohematopoietic standard and Annex E of the general standard may increase the risk that a donor may have and/or could potentially transmit an infectious disease to the recipient. Donors are thus excluded from donating lymphohematopoietic cells on the basis of these contraindications/exclusion criteria, except where exceptional distribution is used. For more information, refer to sections 40 to 42 of the CTO regulations.

A first-degree relative is the genetic mother, father, sibling or child of the recipient. Anyone who is not a first-degree relative must comply with the requirements of section 13.1.3.2 of the lymphohematopoietic standard. Under this section, all allogeneic donors, including cord blood donors, who are not first-degree relatives of the recipient must be screened according to the criteria specified in Annex E of the general standard.

Section 13.1.3 of the lymphohematopoietic standard gives examples of diseases that are in the exclusion criteria:

For cord blood donors, first-degree relatives include their genetic mother, father and siblings.

Section 13.1.3.3 of the lymphohematopoietic standard lists additional exclusion criteria that apply to cord blood donors, unless the risk has been excluded through either biological parent testing, donor testing or follow-up.

A cord blood unit shall not be accepted for unrelated allogeneic use if there's a first-degree relative of the infant donor with:

Examples of malignant disease with a heritable component or a genetic disorder:

If the genetic or medical history of a donor's first-degree biological relative is unknown or unobtainable, the cord blood unit is not accepted as safe for transplantation. This includes cases where the donor was conceived from a sperm or egg donation, or both.

These units could, however, be collected and banked for release under exceptional distribution.

For allogeneic donations taking place outside of Canada, donors must be assessed and accepted by the collection facility and documentation of suitability must be provided to the transplant establishment. A donor from outside of Canada must be excluded if they have HIV, HBV or HCV.

Physical examination

Donors must undergo a physical examination for evidence of:

Physical exams should be done as close to the time of retrieval as is reasonable and practical (within 30 days of the anticipate date of cell retrieval). If retrieval is postponed, the source establishment will need to determine whether a repeat physical exam or a limited repeat physical exam is warranted. Such decisions can be delegated to the physician at the collection centre.

If the donor was examined before for other reasons, such as to determine if donation is safe for the donor, the findings can be reviewed and documented in the donor's records in lieu of a new physical examination. However, this exam must have been done within the recommended timeline. Such decisions can be delegated to the physician of the collection centre.

In the case of cord blood, a surrogate physical examination of the person who carries the infant donor to delivery must be performed and the results documented. If a physical examination was previously performed while the person was pregnant, the findings can be reviewed and documented in the donor's records in lieu of a new physical examination. However, this exam must have been done within the recommended timeline.

An establishment must have SOPs describing how the physical exam of the donor is to be conducted.

Donor testing

General requirements

Donor testing includes a number of tests, such as:

The following guidance on donor testing focuses on HLA typing and lab tests for the various transmissible disease agents applicable to lymphohematopoietic cell donors.

Sections 12.2.2.4.2 (e) and (f) of the lymphohematopoietic standard stipulates that cord blood HLA typing must be done at the time of banking and before release for unrelated allogeneic cord blood. Cord blood that's reserved for and restricted to potential allogeneic use in a relative of the donor only needs to be HLA-typed before release. In this case, a second HLA typing to confirm the identity of the unit is not required if the initial HLA typing is done after a recipient has been identified and the HLA typing is of sufficient resolution.

Units that have had confirmatory HLA typing performed on a contiguous segment at some point post-freeze do not require repeat confirmatory testing before being released from the cord blood bank.

Timeframe for collecting specimens

Infectious disease tests must be performed using blood specimens taken within 7 days before or 7 days following collection of cord blood and within 30 days before other donations are collected (for example, lymphohematopoietic cells derived from bone marrow and peripheral blood). This is stipulated in subsection 12.2.2.4 of the lymphohematopoietic standard.

Collecting specimens within 30 days before the donation makes it possible to determine donor eligibility within the timeframe required for the recipient to initiate myeloablative chemotherapy. If collections from the same donor take place more than 30 days apart, the donor must be retested for infectious disease markers, unless a previously positive test result has been documented.

Health Canada considers the timeframes in Table 2 are appropriate and effective.

Table 2: Timeframe for collecting specimens for testing diseases or disease agents specified in the infectious disease testing requirements of the lymphohematopoietic standard
Type of CTO Type of testing required Timeframe
Cord blood serological screening tests and NAT for HIV-1 and HCV performed on the person who carries the infant donor to delivery within 7 days before or 7 days following collection
WNV NAT performed on the person who carries the infant donor to delivery Within7 days before or 7 days following collection*
lymphohematopoietic cells (excluding cord blood) serological screening tests performed on donor within 30 days before collection (12.2.2.4.1)
WNV NAT on donor within 30 days before collection (12.2.2.4.1)
*Given the transient nature of WNV viremia, blood samples should be tested on the day of donation or as close to the time of donation as feasible, taking into consideration WNV testing turnaround times. If this is not possible for cord blood donors and samples are collected after the donation, a WNV IgM test should be done along with the WNV NAT to detect recent WNV infection in donors with negative WNV NAT results. As with other infectious diseases, donors could become infected with WNV after sample collection but before donation if the samples are collected before donation. Additional screening and/or testing the samples on the day of donation could address this.

Establishments must have SOPs that specify the timeframes for collecting blood specimens from donors of each type of lymphohematopoietic cells.

Infectious disease testing

All source establishments are responsible for infectious disease testing, including testing that another establishment carries out on its behalf. They must have appropriate documentation (such as SOPs, agreements, contracts or audit reports) to support that testing was done as follows:

Interpreting infectious disease test results

The terms used by test kit manufacturers for interpreting serological test results are determined, in part, by the testing algorithms used. In general, the initial serological screening test is done using a single blood sample. A nonreactive sample is considered a negative test result and further testing is not required. A reactive sample is considered initially reactive instead of positive because the:

These 2 additional steps are necessary to achieve the final outcome ("positive" or "negative") in the event that a sample is initially reactive. Note: This testing algorithm is only an example. Establishments must always apply the specific testing algorithm indicated in the test kit's instructions for use.

Note also that some test kit manufacturers may also recommend confirmatory or supplemental testing with a different test kit to confirm the results of the first test kit. Confirmatory testing is necessary for patient diagnosis, but not for donor screening because false negative confirmatory test results cannot be ruled out. In these circumstances, donors must still be excluded regardless of the confirmatory test results.

Establishments that use third-party testing labs must make sure they are given the initial test kit results in cases where confirmatory testing is done for patient diagnosis. This will help them determine donor eligibility appropriately.

Instead of using "repeatedly reactive" for the final outcome of a particular screening or diagnostic test, some test kit manufacturers use "reactive" or "positive".

In this guidance document:

Donor eligibility determination must include an interpretation of the infectious disease test results as outlined:

If a donor's specimen tests positive for HIV, HBV or HCV using a required serological test but is negative using NAT, the cells cannot be distributed, unless under exceptional distribution.

Note: In exceptional circumstances, cells from the donor who is repeatedly reactive or positive for the markers of infectious disease agents, may be used under exceptional distribution. For more information on exceptional distribution, consult sections 40 to 42 of the CTO regulations.

Results of all tests, including optional tests, must be included in the donor records. Establishments must have SOPs for interpreting and handling all test results, including communicating these results to transplant physicians or to establishments to which the lymphohematopoietic cells are distributed. There must also be procedures for handling the results of optional tests that become available after the lymphohematopoietic cells have been released for distribution. The procedures must include notifying transplant physicians or establishments to which the lymphohematopoietic cells are distributed.

Archived samples

The CTO regulations do not require that samples be collected for archiving. This has no impact on the safety of lymphohematopoietic cells that meet current regulatory requirements. We recommend archiving cell, tissue, plasma or serum samples from each donor for retrospective testing of donors of lymphohematopoietic cells that are inventoried when new tests are adopted for screening donors for existing or emerging pathogens.

When to conduct retrospective testing will be based on the:

Health Canada will inform CTO establishments if retrospective testing is required.

Establishments that choose to archive samples must have SOPs for collecting and storing samples. Samples must be stored frozen and should be kept for at least 5 years. Establishments must also have documentation to show the samples are kept at the appropriate temperature while in storage.

Tests that are considered appropriate and effective

Mandatory testing

Donors of lymphohematopoietic cells must be tested for the infectious disease agents listed in section 14.2.3 of the lymphohematopoietic standard, using appropriate and effective tests. A test is considered appropriate and effective if it is:

A list of appropriate infectious disease markers is provided below. Consult the complete list of required and recommended tests as well. This list may be revised when new infectious disease tests become licensed or when new information necessitates an amendment.

Health Canada considers the following tests are appropriate and effective for testing lymphohematopoietic cell donors to comply with section 14.2.3 of the lymphohematopoietic standard:

For infant donors, the person who carries the infant donor to delivery must be tested for infectious disease agents to address vertical transmission of infectious agents to a donor who:

This is in accordance with section 14.2.6.2 of the general standard.

However, the person who carries the infant donor to delivery of an infant donor who is 29 days or older does need not to be tested for infectious disease agents if testing the infant donor includes the serological tests listed as well as NAT for HIV-1 and HCV.

In the case of donated cord blood, only surrogate testing of the person who carries the infant donor to delivery is required.

The establishments must have SOPs that describe which infectious disease tests must be performed and when surrogate testing is required for infant donors.

Lymphohematopoietic cell donors must be tested for WNV using a test kit that has been licensed to detect viral nucleic acid. Testing could be done seasonally if specific procedures are in place to determine:

Health Canada has licensed a test kit for detecting WNV ribonucleic acid in plasma specimens from both living and deceased donors.

The minimum donor testing requirements stated in section 12.2.2.4 of the lymphohematopoietic standard must be met before transplantation.

Recommended testing

Donors of unbanked lymphohematopoietic cells should also be tested for HIV-1 and HCV using NAT, if available. NAT should be performed in circumstances where it's clinically indicated: for example, for exceptional distribution for lymphohematopoietic cells from a donor with a history of high-risk behaviour and a negative serological test for HIV and HCV.

Health Canada's Medical Devices Directorate is the Canadian federal regulator responsible for licensing in accordance with the Medical Devices Regulations (MDR). The medical devices active licence listing (MDALL) database lists licensed Class II, Class III and Class IV medical devices for sale in Canada. Select "active licence search" to find a device by company name, licence name device name, company ID or licence number.

Retrieval interval for tissues:

24. An establishment that retrieves tissue from a deceased donor must carry out the retrieval within the scientifically based maximum interval between the cardiac asystole of the donor and the retrieval of the tissue.

The maximum interval between the cardiac asystole of the donor and the retrieval of the tissue is considered scientifically based if it meets 1 or more of the following criteria:

Licensed diagnostic devices:

25. (1) Subject to subsection (2), in vitro diagnostic devices that are used by an establishment in the testing of donor blood for transmissible disease agents or markers under these regulations must be licensed either:

  1. in Canada, if the testing is performed in Canada
  2. in Canada or the United States, if the testing is performed outside Canada

Exception for lymphohematopoietic cells:

(2) In the case of lymphohematopoietic cells that are imported into Canada for transplantation into a specific recipient, the in vitro diagnostic devices may be licensed in Canada or any other jurisdiction.

Under subsection 25(1) of the CTO regulations, the in vitro diagnostic devices that an establishment uses to test donors of CTO for transmissible diseases or disease agents must be licensed in Canada, if the testing is done in Canada. If the testing is done outside of Canada, the in vitro diagnostic devices must be licensed either in Canada or the United States.

Subsection 25(2) makes an exception for lymphohematopoietic cells that are imported into Canada for transplantation into a specific recipient. In this case, the in vitro diagnostic devices used in donor testing may be licensed in Canada or any other jurisdiction.

Health Canada's Medical Devices Directorate is the Canadian federal regulator responsible for licensing in accordance with the MDR.

The medical devices active licence listing (MDALL) database lists licensed Class II, Class III and Class IV medical devices for sale in Canada.

In vitro diagnostic devices for cells and tissues:

26. (1) In the case of cells and tissues, in vitro diagnostic devices that are used by an establishment in the testing of donor blood for transmissible disease agents or markers under these regulations must be licensed for screening donors.

Exception for syphilis:

(2) Despite subsection (1), in vitro diagnostic devices that are used in the testing of donor blood for syphilis may be licensed either for diagnosis or screening donors.

Donor screening test kits are licensed based on investigational testing in a population with a low disease prevalence (such as healthy blood donors). The emphasis is on test sensitivity.

Investigational testing of test kits that are licensed for diagnosis is performed in a symptomatic population. The emphasis is on test specificity. For this reason, test kits that are licensed for donor screening are considered more appropriate for screening CTO donors.

Tests that are licensed for screening donors (as opposed to tests that are licensed for diagnostic purposes) are not required for detecting the presence of a disease or disease agent in a donor that's not considered a contraindication to donation. An example is Cytomegalovirus (CMV) testing of lymphohematopoietic cell donors.

For this reason, we are amending section 26 (1) to only require assays that are licensed for screening donors for diseases or disease agents that are exclusion criteria to donation under the CTO regulations. This will allow establishments to use assays that are either licensed for diagnostic purposes or for screening donors when testing donors for diseases or disease agents that are not exclusion criteria under the regulations.

In the interim, we will assign a low priority to enforcement actions for establishments that are using assays licensed for diagnostic purposes when testing donors for diseases or disease agents that are not exclusion criteria under the regulations. Establishments will not be required to use exceptional distribution in these circumstances.

For tissues and cells, with the exception of islet cells, diagnostic devices that an establishment uses to test for diseases or disease agents that are exclusion criteria under the CTO regulations must be licensed for screening donors. Infectious disease test kits used for organ donors may be licensed for either screening donors or for diagnosis, as the timeframes for organ transplantation don't always permit the use of screening tests. The CTO regulations also indicate that test kits licensed for diagnosis can be used to test for syphilis.

Infectious disease tests are also licensed for different types of specimens. The test kit manufacturers provide instructions for how to use each test kit in the package insert.

For CTO donations, a test may be licensed for testing blood specimens obtained from live donors (for example, the blood specimen is obtained while the donor's heart is still beating) or from cadaveric donors (for example, the blood specimen is obtained after the donor's heart stops beating). For specimens obtained after the donor's heart stops beating, establishments should use a test that's licensed for cadaveric specimens, if such tests are available where the test is being performed.

Bacteriological testing of tissues:

27. An establishment that retrieves tissue, except ocular tissue, must perform bacteriological testing in accordance with section 14.3 of the tissue standard, except for section 14.3.2.8.

Source establishment requirements

The source establishment must ensure that laboratories performing microbial testing meet the applicable requirements of the authorities having jurisdiction. A copy of the laboratory's most recent certificate of accreditation would fulfill this requirement.

Testing establishment requirements

Laboratories must ensure that microbial testing is performed in accordance with validated procedures by qualified staff and that the test results are documented in the donor's record. Methods, materials and equipment must be suitable for their intended use. Lot numbers, expiry dates and other relevant information should be recorded.

Indirect or direct sampling methods may be used to obtain microbial culture test samples. Samples may be collected from each individual tissue or obtained using a sampling strategy that represents all the tissues received from a particular donor.

Indirect sampling is done by swabbing or extracting fluid. Direct sampling is done by placing samples of tissue directly into growth media.

Quality control (QC) testing must be performed for any transport medium prepared in-house to ensure both aerobic and anaerobic organisms stay viable. Growth media prepared in-house must be subject to QC testing to ensure it is sterile and can support the growth of aerobic and anaerobic organisms.

Tissue sampling and test methods must be evaluated for sensitivity and found to be appropriate and effective for each tissue type recovered and processed.

All testing methods and protocols must be documented in the establishment's standard operating procedures (SOPs).

Consult the following when reviewing or updating established microbiological sampling plans and microbiological test methods:

Packaging and labelling

Sections 28 to 33 of the CTO regulations

Packaging materials:

28. An establishment that packages cells, tissues or organs must ensure that it uses appropriate packaging materials that are free from damage and capable of maintaining the integrity of the cells, tissues and organs.

An establishment must have documented evidence that the packaging materials can maintain the integrity of the CTO. This evidence must be available upon request. Evidence could consist of specification sheets, certificates of analysis (COAs) or manufacturer's package inserts describing the packaging material.

The packaging materials must also be compatible with the CTO to prevent any interactions that may cause the package to degrade or chemicals from the packaging to be absorbed by the CTO. Only use packaging materials that have been assessed and released by quality assurance (QA) personnel or by a designated alternate. The QA personnel or designated alternate must approve any changes to the packaging materials before they are used. Materials that are outdated or rejected should be kept apart until they can be disposed. This should be recorded. All packaging materials must be visually inspected.

Language requirement:

29. All of the information that is required by these regulations to appear on a label or package insert must be in either English or French.

Cells, except islet cells:

30. (1) An establishment that distributes cells, except islet cells, must ensure that all of the applicable information, as indicated by an "X", set out in the table to this subsection is provided on the interior label, in the package insert and on the exterior label.

Pancreas and islet cells:

(2) An establishment that distributes a pancreas for islet cell transplantation, or islet cells, must ensure that all of the applicable information, as indicated by an "X", set out in the table to this subsection is provided on the interior label, in the package insert and on the exterior label.

The interior label is the label that is affixed to the interior package, which is the innermost package of a cell, tissue or organ that has a non-sterile exterior.

The package insert is the document that the source establishment prepares to accompany a cell, tissue or organ.

The exterior label is the label that is affixed to the exterior package, which is the outermost package in which a cell, tissue or organ is delivered, transported or shipped in.

Table to subsection 30(1): Labelling requirements for cells, except islet cells
Item Column 1
Required information		 Column 2 Column 3 Column 4
From retrieval establishment to transplant establishment From retrieval establishment to cell bank From cell bank to any other establishment
Interior label Package insert Exterior label Interior label Package insert Exterior label Interior label Package insert Exterior label
Information about donor and cell
1. Name of cell yes yes n/a yes yes n/a yes yes n/a
2. Description of cell n/a yes n/a n/a yes n/a n/a yes n/a
3. Donor identification code, clearly labelled as such yes yes n/a n/a n/a n/a yes yes n/a
4. Information capable of identifying the donor n/a n/a n/a yes yes n/a n/a n/a n/a
5. Donor assessment record n/a n/a n/a n/a yes n/a n/a n/a n/a
6. ABO group and Rh factor of donor, if applicable yes yes n/a yes yes n/a yes yes n/a
7. The hazard pictogram entitled "Biohazardous infectious material" set out in Schedule 3of the Hazardous Products Regulations, if applicable yes n/a yes yes n/a yes yes n/a yes
Retrieval information
8. Date, time and time zone of retrieval n/a yes n/a n/a yes n/a n/a n/a n/a
9. Information specific to retrieval procedure n/a yes n/a n/a yes n/a n/a n/a n/a
Processing information
10. Name of anticoagulant and other additive, if applicable n/a yes n/a n/a yes n/a n/a yes n/a
11. Statement "For autologous use only", if applicable yes yes n/a yes yes n/a yes yes n/a
Information for transplant establishment
12. Statement that the cell has been declared safe for transplantation n/a n/a n/a n/a n/a n/a n/a yes n/a
13. Statement "For exceptional distribution", if applicable n/a yes n/a n/a n/a n/a n/a yes n/a
14. If applicable, the reasons for exceptional distribution and a statement of how the cell does not meet the requirements of these Regulations n/a yes n/a n/a n/a n/a n/a yes n/a
15. Instructions on how to report errors, accidents and adverse reactions n/a n/a n/a n/a n/a n/a n/a yes n/a
16. Expiry date and time, if applicable n/a n/a n/a n/a n/a n/a yes yes n/a
Establishment information
17. Name of retrieval establishment, its civic address and contact information n/a yes yes n/a yes yes n/a n/a n/a
18. Name of source establishment, its civic address and contact information n/a yes yes n/a yes yes n/a yes yes
19. Registration number of source establishment, clearly labelled as such n/a yes yes n/a n/a n/a n/a yes yes
20. Name of transplant establishment, if known, its civic address and contact information n/a n/a yes n/a n/a n/a n/a n/a yes
Storage information
21. Statement "Human cells for transplant" n/a n/a yes n/a n/a yes n/a n/a yes
22. Handling instructions for storage and for storage during transportation n/a n/a yes n/a n/a yes n/a n/a yes
n/a: not applicable
Table to subsection 30(2): Labelling requirements for pancreas and islet cells
Item Column 1
Required information		 Column 2 Column 3
Pancreas: From retrieval establishment to source establishment Islet cells: From source establishment to any other establishment
Interior label Package insert Exterior label Interior label Package insert Exterior label
Information about donor and organ or islet cells
1. Name of organ or cells, as applicable yes yes n/a yes yes n/a
2. Description of organ or cells, as applicable n/a yes n/a yes yes n/a
3. Donor identification code, clearly labelled as such n/a n/a n/a yes yes n/a
4. Information capable of identifying the donor yes yes n/a n/a n/a n/a
5. Donor assessment record n/a yes n/a n/a n/a n/a
6. ABO group and Rh factor of donor, if applicable yes yes n/a yes yes n/a
7. The hazard pictogram entitled "Biohazardous Infectious Material" set out in Schedule 3of the Hazardous Products Regulations, if applicable yes n/a yes yes n/a yes
Retrieval information
8. Date, time and time zone of asystole or aortic clamping, if applicable n/a yes n/a n/a n/a n/a
9. Date, time and time zone of retrieval n/a yes n/a n/a n/a n/a
10. Information specific to retrieval procedure n/a yes n/a n/a n/a n/a
11. Name of perfusion solution n/a yes n/a n/a n/a n/a
Processing information
12. Name of storage solution n/a yes n/a n/a n/a n/a
13. Name of additives, if applicable n/a n/a n/a n/a yes n/a
Information for establishments
14. Statement that the cells have been declared safe for transplantation n/a n/a n/a n/a yes n/a
15. Statement "For exceptional distribution", if applicable n/a yes n/a yes yes n/a
16. If applicable, the reasons for exceptional distribution and a statement of how the organ or cells do not meet the requirements of these regulations n/a yes n/a n/a yes n/a
17. Instructions on how to report errors, accidents and adverse reactions n/a yes n/a n/a yes n/a
18. Expiry date and time, if applicable n/a n/a n/a yes yes n/a
Establishment information
19. Name of retrieval establishment, its civic address and contact information n/a yes yes n/a yes yes
20. Name of source establishment, its civic address and contact information n/a yes yes n/a yes yes
21. Registration number of source establishment, clearly labelled as such n/a yes yes n/a yes yes
22. Name of other establishment, its civic address and contact information n/a n/a n/a n/a n/a yes
Storage information
23. Statement "Human organ for transplant" or "Human cells for transplant", as applicable n/a n/a yes n/a n/a yes
24. Handling instructions for storage and for storage during transportation n/a n/a yes n/a n/a yes
n/a: not applicable

The donor identification code must appear clearly on the product label. Product labels must include information to make it possible to trace back to the donor.

Information capable of identifying the donor

This is information that allows the cell bank or appropriate establishment to identify the donor. It includes, among other things, the donor's name, date of birth, hospital identification number and health care number.

Information specific to the retrieval procedure

The package insert must list the following:

Biohazardous infectious materials
The following pictogram is to be used for biohazardous infectious materials:
This image indicates the package contains biohazardous materials.

This pictogram must appear on the interior and exterior labels of CTO that have tested positive for infectious disease markers that would lead to the donor being excluded. Do not use the pictogram if the tests have not yet been performed or the results are not yet known.

If a generic CTO package insert is prepared, all information specific to a CTO may be printed on a label that will accompany the CTO "standard" package insert.

If no exterior packaging is used, the establishment must include the required information for the exterior label on the interior label or package insert.

CTO should either be labelled as safe for transplantation or "for exceptional distribution" but not both.

Tissues:

31. An establishment that distributes tissues must ensure that all of the applicable information, as indicated by an "X", set out in the table to this section is provided on the interior label, in the package insert and on the exterior label.

Table to section 31: Labelling requirements for tissue
Item Column 1
Required information		 Column 2 Column 3
From retrieval establishment to tissue bank From tissue bank to any other establishment
Interior label Package insert Exterior label Interior label Package insert Exterior label
1. Name of tissue and whether left or right side, if applicable yes yes n/a yes yes n/a
2. Description of tissue n/a yes n/a yes yes n/a
3. Donor identification code, clearly labelled as such n/a n/a n/a yes yes n/a
4. Information capable of identifying the donor yes yes n/a n/a n/a n/a
5. Donor assessment record n/a yes n/a n/a n/a n/a
6. The hazard pictogram entitled "Biohazardous infectious material" set out in Schedule 3of the Hazardous Products Regulations, if applicable yes n/a yes yes n/a yes
7. Date, time and time zone of asystole or aortic clamping, if applicable n/a yes n/a n/a n/a n/a
8. Date, time and time zone of retrieval n/a yes n/a n/a n/a n/a
9. Information specific to retrieval procedure n/a yes n/a n/a n/a n/a
10. Name of storage solution, if applicable n/a yes n/a n/a yes n/a
11. Name of anticoagulant and other additive, if applicable n/a n/a n/a n/a yes n/a
12. Statement that the tissue has been irradiated, if applicable n/a n/a n/a yes yes n/a
13. Description of the disinfection and sterilization processes that were used, if applicable n/a n/a n/a n/a yes n/a
14. Statement "For autologous use only", if applicable yes yes n/a yes yes n/a
15. Tissue-specific instructions for preparation for use, if applicable n/a n/a n/a n/a yes n/a
16. Statement that the tissue has been declared safe for transplantation n/a n/a n/a n/a yes n/a
17. Statement "For exceptional distribution", if applicable n/a n/a n/a yes yes n/a
18. If applicable, the reasons for exceptional distribution and a statement of how the tissue does not meet the requirements of these Regulations n/a n/a n/a n/a yes n/a
19. Instructions on how to report errors, accidents and adverse reactions n/a n/a n/a n/a yes n/a
20. Expiry date and time, if applicable n/a n/a n/a yes yes n/a
21. Name of retrieval establishment, its civic address and contact information n/a yes yes n/a n/a n/a
22. Name of source establishment, its civic address and contact information n/a yes yes n/a yes yes
23. Registration number of source establishment, clearly labelled as such n/a n/a n/a n/a yes yes
24. Name of transplant establishment, if known, its civic address and contact information n/a n/a n/a n/a n/a yes
25. Statement "Human tissue for transplant" n/a n/a yes n/a n/a yes
26. Handling instructions for storage and for storage during transportation n/a n/a yes n/a n/a yes
n/a: not applicable

The donor identification code must appear clearly on the product label. Product labels must include information to make it easy to trace back to the donor.

Information capable of identifying the donor

This is information that allows the tissue bank to identify the donor. It includes, among other things, the donor's name, date of birth, hospital identification number and health care number.

Information specific to the retrieval procedure

The package insert must list the following:

Biohazardous infectious materials
The following pictogram is to be used for biohazardous infectious materials:
This image indicates the package contains biohazardous materials.

This pictogram must appear on the interior and exterior labels of CTO that have tested positive for infectious diseases markers that would lead to the donor being excluded. Do not use the pictogram if the tests have not yet been performed or the results are not yet known.

If a generic CTO package insert is prepared, information specific to a CTO may be printed on a label that will accompany the CTO "standard" package insert.

If no exterior packaging is used, the establishment must include the required information for the exterior label on the interior label or package insert.

CTO should either be labelled as safe for transplantation or "for exceptional distribution" but not both.

When transporting tissue from a retrieval establishment to a tissue bank, establishments can add "further processing required" in addition to the labelling requirement to state "human tissue for transplant", under item #25. This or other similar statements will show that the tissue has not yet been determined safe for transplant. Avoid using statements on the label that indicate the package contains human tissue that is not for transplant, unless further clarification is provided on the final intended purpose of the tissue.

Organs:

32. An establishment that distributes organs must ensure that all of the applicable information, as indicated by an "X", set out in the table to this section is provided on the interior label, in the package insert and on the exterior label.

Table to section 32: Labelling requirements for organs
Item Column 1
Required information		 Column 2 Column 3
Deceased donor: From retrieval establishment to transplant establishment Living donor: From retrieval establishment to transplant establishment
Interior label Package insert Exterior label Interior label Package insert Exterior label
Information about donor and organ
1. Name of organ and whether left or right side, if applicable yes yes yes yes yes n/a
2. Description of organ n/a yes n/a n/a yes n/a
3. Donor identification code, clearly labelled as such yes yes n/a yes yes n/a
4. All information in the donor assessment record that is not capable of identifying the donor n/a yes n/a n/a n/a n/a
5. ABO group and Rh factor of donor yes yes n/a yes yes n/a
6. The hazard pictogram entitled "Biohazardous infectious material" set out in Schedule 3of the Hazardous Products Regulations, if applicable yes n/a yes yes n/a yes
Retrieval information
7. Date, time and time zone of asystole or aortic clamping, if applicable n/a yes n/a n/a n/a n/a
8. Date, time and time zone of retrieval n/a yes n/a n/a yes n/a
9. Information specific to retrieval procedure n/a yes n/a n/a yes n/a
10. Name of perfusion solution n/a yes n/a n/a yes n/a
Processing information
11. Name of storage solution n/a yes n/a n/a yes n/a
Information for transplant establishment
12. Statement that the organ has been declared safe for transplantation n/a yes n/a n/a n/a n/a
13. Statement "For exceptional distribution", if applicable yes yes n/a yes yes n/a
14. If applicable, the reasons for exceptional distribution and a statement of how the organ does not meet the requirements of these regulations n/a yes n/a n/a yes n/a
15. Instructions on how to report errors, accidents and adverse reactions n/a yes n/a n/a yes n/a
Establishment information
16. Name of retrieval establishment, its civic address and contact information n/a yes yes n/a yes yes
17. Name of source establishment, its civic address and contact information n/a yes yes n/a yes yes
18. Registration number of source establishment, clearly labelled as such n/a yes yes n/a yes yes
19. Name of transplant establishment, its civic address and contact information n/a n/a yes n/a n/a yes
Storage information
20. Statement "Human organ for transplant" n/a n/a yes n/a n/a yes
21. Handling instructions for storage and for storage during transportation n/a n/a yes n/a n/a yes
n/a: not applicable

The donor identification code must appear clearly on the product label. Product labels must include information to make it possible to trace back to the donor.

All information in the donor assessment record that is not capable of identifying the donor

The donor assessment record should be redacted to remove information that could identify the donor. Do not include information that can directly identify the donor in the recipient's chart due to privacy issues. Also do not include this information on the labels that accompany the organ from the retrieval establishment to the transplant establishment.

Information specific to the retrieval procedure

List the following information on the donor's condition during retrieval of the organ (some will not apply to living donors) in the package insert when an organ is distributed from a retrieval establishment to a transplant establishment:

Additional information may not come to light until all of the organs have been retrieved. For this reason, it's acceptable to electronically transfer (by fax or email) such information when the organ is already in transport.

Statement that the organ has been declared safe for transplantation

CTO should either be labelled as safe for transplantation or "for exceptional distribution" but not both.

As an alternative to stating on the label that the "organ has been declared safe for transplantation", we will accept wording that indicates the organ has been processed according to the CTO regulations and no contraindications to donation have been identified.

Biohazardous infectious materials
The following pictogram is to be used for biohazardous infectious materials:
This image indicates the package contains biohazardous materials.

This pictogram must appear on the interior and exterior labels of CTO that have tested positive for infectious disease markers that would lead to the donor being excluded. Do not use the pictogram if tests have not yet been performed or the results are not yet known.

If a generic CTO package insert is prepared, all information specific to a CTO may be printed on a label that will accompany the CTO "standard" package insert.

Where the CTO is not packaged (for example, when organ retrieval and transplantation are done at the same time or in sequence in the same or adjacent operating room), the information that in other circumstances must appear on the interior label, package insert and exterior label must be recorded elsewhere. This could be achieved by recording the information in a document that accompanies the organ.

Additional information required:

33. A registered establishment that imports and distributes, or that only distributes, a cell or tissue must ensure that the following information is added to that required by sections 30 and 31:

  1. on the exterior label and in the package insert, the name of the establishment, its civic address and contact information
  2. on the exterior label and in the package insert, the establishment's registration number

An establishment that imports and distributes and does not take physical possession of the cells or tissues at any point (for example, the source establishment sends the cells or tissues directly to the transplant establishment) is not required to have its name and registration number on the exterior label.

An establishment that imports and distributes must provide its name and registration number to the transplant establishment so the transplant establishment can complete its records.

Quarantine

Section 34 of the CTO regulations

Quarantine of cells and tissues:

34. (1) A source establishment must ensure that cells, except islet cells, and tissues are quarantined until all of the following processing activities are completed:

  1. the donor is found to be suitable after completion of the donor suitability assessment
  2. except in the case of fresh skin, bacteriological test results are reviewed and found to be acceptable, if applicable
  3. all processing records are reviewed for completeness and compliance with the standard operating procedures

Additional requirement for live donors of tissue:

(2) In addition to the requirements set out in subsection (1), the source establishment must quarantine tissues that are retrieved from live donors in accordance with section 17.2 of the tissue standard.

Quarantine refers to the following:

Cells and tissues that are implicated in any error, accident or adverse reaction investigation must also be quarantined until the investigation has determined they are safe for transplantation.

Quarantine includes:

Quarantine does not require that these products be physically segregated if the risk of cross-contamination and improper release is managed effectively.

Exempt from this requirement are:

In cases where HIV-1 and HCV NAT will not be performed on living tissue donors, the tissue must be held in quarantine for at least 180 days. At this time the donor must be retested for the following infectious disease markers before the tissue can be released (section 17.2.2 of the tissue standard):

Tissue that is not considered leukocyte-rich include bone, cartilage, corneas, ligaments, sclera, skin, tendons and amniotic tissue.

If initial testing on a living donor blood specimen includes NAT for HIV-1 and HCV, the 180-day quarantine and testing a repeat blood sample is not required for any of the required infectious disease agents under 17.2.1 of the tissue standard.

Storage

Sections 35 to 39 of the CTO regulations

Storage limits:

35. An establishment that distributes cells, tissues or organs and that stores cells, tissues and adjunct vessels that were not used at the time of transplantation of the organ with which they were retrieved must observe scientifically based maximum storage periods.

A maximum storage period must be determined for each CTO to maintain its integrity, function and sterility throughout its shelf life. Consider the following factors when establishing the expiration date for each CTO, as applicable:

The maximum storage period is considered scientifically based if it meets 1 or more of the following criteria:

Establishments should provide instructions on corrective actions to be taken when temperatures rise or fall beyond the acceptable temperature limits.

Storage location:

36. An establishment that distributes cells, tissues or organs must store them in a location that has environmental conditions that maintain their safety and that is secure against the entry of unauthorized persons.

All CTOs must be stored under defined and controlled environmental conditions, which must be outlined in the SOP. Documentation that the CTOs were maintained under the appropriate environmental conditions must be kept and available upon request.

Environmental parameters for storage, such as temperature and humidity, must be controlled and should be monitored using calibrated monitoring devices. Evidence that these parameters are monitored must be kept. Temperature monitoring probes or devices should be located at points that represent extreme temperature areas, as determined by a temperature mapping study, if applicable. If the storage area has an alarm system with audible signals, alarm activation points should be set at temperatures that allow time for appropriate corrective actions to be taken before the CTO reach unacceptable temperatures. The alarm warning should be in a location that's continually monitored or staffed so that corrective action can be taken immediately.

There must be written procedures describing the actions to be taken in the event of deviations from established storage criteria. Such an event must be appropriately investigated and documented.

Access to storage areas must be restricted to designated personnel. Where physical quarantine areas are used, they must be marked appropriately, with access restricted to designated personnel. Where electronic quarantine is used, electronic access must be restricted to designated personnel.

Storage during transportation:

37. An establishment that ships cells, tissues or organs must ensure that they are stored during transportation in appropriate environmental conditions.

This section applies to all establishments that ship CTOs.

The appropriate environmental conditions for shipping CTOs must be defined in a procedure, along with controls for such things as temperature and light. Documentation that the CTOs were maintained under the appropriate environmental conditions must be kept and available upon request.

If an establishment accepts returns of a CTO with the intent of returning the products to inventory, there must be a process in place. This process must outline the necessary documented procedures and defined acceptability criteria that will give the establishment assurance that the CTOs have been kept under appropriate storage conditions and their integrity has not been compromised. This process must be defined in the establishment's SOP and include the following documented evidence:

An establishment cannot ship or accept any CTOs without a label.

Segregation of tissues:

38. An establishment that stores tissues must ensure that those that are intended for autologous use are segregated from those intended for allogeneic use.

Tissues for autologous use must be segregated from tissues for allogeneic use during storage to prevent the tissues from being unintentionally distributed or released. Segregation also helps to ensure that autologous tissues receive the special handling and tracking they require, as they may not have been processed under the same standards as tissues intended for allogeneic use.

Clearly label and store autologous tissues separately in restricted areas to ensure they are segregated from allogeneic tissue.

Effective segregation may be achieved by storing allogeneic and autologous tissues in different storage equipment. If they're to be stored in the same storage equipment, the storage areas for each within the storage unit must be physically separated and clearly labelled to distinguish tissues intended for autologous use from tissues for allogeneic use.

Segregation of transmissible disease agents and markers:

39. An establishment that stores cells, tissues or organs must ensure that any of them that are untested or for which the results of tests on donor blood samples are positive or reactive for transmissible disease agents or markers or are unavailable are segregated from all other cells, tissues and organs.

All CTOs must be:

Other CTOs include those that are:

The actions taken and the final status of each CTO must be recorded.

Exceptional distribution

Sections 40 to 42 of the CTO regulations

Conditions:

40. A source establishment may distribute cells, tissues or organs that have not been determined safe for transplantation if all of the following conditions are met:

  1. a cell, tissue or organ that has been determined safe for transplantation is not immediately available
  2. the transplant physician or dentist, based on their clinical judgment, authorizes the exceptional distribution
  3. the transplant establishment obtains the informed consent of the recipient

Given the urgent and life-saving or -enhancing nature of transplantations, in exceptional circumstances a CTO may be needed for transplantation and a compatible CTO may be available but has yet to be deemed safe for transplantation as required by the CTO regulations. The regulations have an "exceptional distribution" mechanism to allow CTO that may not meet all of the requirements to be distributed when there isn't a fully compliant CTO available.

These regulations are intended to maximize the safety of CTOs used in transplantation, not to determine their suitability for a specific recipient.

There are circumstances, such as using a Hepatitis C-positive CTO in a Hepatitis C-positive recipient, where a CTO may be suitable, even if this CTO has not been deemed "safe" under the regulations. Sometimes not all the information from the donor screening questionnaire is available, but the CTO is acceptable due to the direness of the intended recipient's situation. In such cases, the suitability of a CTO is a matter of clinical discretion and/or judgment.

Thus, exceptional distribution from a source establishment requires that the:

Recipient consent should be obtained according to applicable provincial laws and standards of practice.

Notice in source establishment's records:

41. (1) A source establishment that distributes cells, tissues or organs under section 40 must keep a copy of the notice of exceptional distribution in its records.

Notice in transplant establishment's records:

(2) The transplant establishment must keep a copy of the notice of exceptional distribution in its records.

Contents of notice:

(3) A notice of exceptional distribution must contain all of the following information:

  1. the name of the transplanted cell, tissue or organ
  2. the provisions of these regulations with which the cell, tissue or organ is not in compliance at the time of its distribution
  3. the justification for the distribution that formed the basis for the transplant physician's or dentist's decision to authorize it
  4. the name of the source establishment that distributed the cell, tissue or organ
  5. the name of the transplant establishment and of the transplant physician or dentist who authorized the distribution
  6. the time and date of the written authorization of the distribution and a copy of the authorization signed by the transplant physician or dentist

A source establishment must put a notice of exceptional distribution in their records when distributing a CTO that has met any of the exclusion criteria or transmissible disease testing requirements of the regulations. This notice must also be put in the transplant establishment records.

The notice of exceptional distribution must contain the information stipulated under subsection 41(3) of these regulations.

The notice must state the provisions of these regulations that were not met. Also, the source establishment must make sure that the information has been provided to the transplant establishment to obtain an informed consent from the recipient.

Follow-up:

42. A source establishment that distributes a cell, tissue or organ under section 40 before the donor suitability assessment is complete must, after the distribution, complete the assessment, carry out any other appropriate follow-up testing and notify the relevant transplant establishment of the results.

According to section 42, a source establishment that has not completed the donor suitability assessment and distributes a CTO under the conditions of exceptional distribution must:

Establishments must report the following as an accident and take the actions that are prescribed in sections 44 and 51 of the CTO regulations:

Investigating and reporting errors, accidents and adverse reactions

Sections 43 to 54 of the CTO regulations

Required action:

43. (1) Subject to subsection (2), an establishment that is not a source establishment and that has reasonable grounds to believe that the safety of a cell, tissue or organ that is or was in its possession has been compromised by the occurrence of an error or accident during processing must immediately take all of the following steps:

  1. determine the donor identification codes of all implicated cells, tissues and organs
  2. identify and quarantine any other implicated cells, tissues and organs in its possession
  3. notify the following establishments:
    1. the relevant source establishment
    2. if the cells, tissues or organs were imported, the establishment that imported them

Exception for importers:

(2) If the establishment that receives a notice under subsection (1) is the establishment that imported the implicated cells, tissues or organs, it only has to notify the source establishment.

Contents of notice:

(3) The notice must include all of the following information:

  1. the reasons for the establishment's belief that the safety of cells, tissues or organs has been compromised
  2. an explanation of how the safety of the implicated cells, tissues or organs may have been compromised, if known
  3. the donor identification codes of all implicated cells, tissues and organs
  4. the name of any suspected transmissible disease or disease agent, if known

Written notice:

(4) If the notice is given verbally, a confirmatory written notice must be sent as soon as possible afterwards.

The following requirements apply to establishments other than a source establishment that discovers or suspects that an error/accident has occurred during processing.

Under the CTO regulations, these establishments must immediately report to the source establishment and importer (if applicable) all known or suspected errors or accidents associated with the CTO that are or were in their possession if the errors or accidents took place during processing. They must:

The source establishment and the importer are identified on the exterior label as required under section 33 of these regulations.

Upon receiving the notice under subsection 43(1), the importer must notify the source establishment. The importer should send the written notice by the next business day.

Action by source establishment:

44. (1) A source establishment that has reasonable grounds to believe that the safety of cells, tissues or organs for whose processing it is responsible has been compromised by the occurrence of an error or accident during processing must immediately take all of the following actions:

  1. quarantine any implicated cells, tissues and organs in its possession
  2. send a notice described in subsection (2) to all of the following establishments:
    1. if the cells, tissues or organs were imported, the establishment that imported them
    2. any source establishment from which it received the donor referral, if applicable
    3. any source establishment to which it made a donor referral, if applicable
    4. any establishment to which it distributed implicated cells, tissues or organs
  3. initiate an investigation into the suspected error or accident

Contents of notice:

(2) The notice must include all of the following information:

  1. the reasons for its belief that the safety of the cells, tissues or organs has been compromised
  2. an explanation of how the safety of the implicated cells, tissues or organs may have been compromised, if known
  3. the donor identification codes of all implicated cells, tissues and organs
  4. the name of any suspected transmissible disease or disease agent, if known
  5. a statement requiring all implicated cells, tissues and organs to be quarantined immediately and until further notice from the source establishment and specifying any other corrective action that must be taken
The following requirements apply to source establishments:

A source establishment must take immediate action if it has reasonable grounds to believe, based on its own information and the information received under section 43, that the safety of CTO that it or another establishment processed on its behalf has been compromised by an error or accident that took place during processing. The actions it is to take are listed under subsection (1).

If a source establishment believes the CTO poses any danger to potential recipients, it must notify all known establishments that received the implicated CTO by:

The source establishment must quarantine the implicated CTO according to the requirements described in section 39 and secure it from CTOs that are in compliance.

When no investigation necessary:

45. If, on receipt of a notice under subsection 43(1), the source establishment does not have reasonable grounds to believe that an investigation is necessary, it must notify the establishment to that effect in writing and provide its reasons for the decision not to conduct an investigation.

Based on notification received under section 43 and with all available information, a source establishment must include in its records a detailed rationale if it has no reason to believe the safety of the CTO for which it's responsible for processing has been compromised by an error or accident during processing. This is set out in subsection 59 (h) of the CTO regulations. The source establishment must inform establishments that contacted it about the suspected error and accident of this decision and the actions taken for the quarantined CTO.

Action on receipt of notice:

46. An establishment that is not a source establishment and that receives a notice under section 44 or a copy of such a notice under this section must immediately take both of the following actions:

  1. quarantine all implicated cells, tissues and organs in its possession
  2. forward a copy of the notice to every establishment to which it distributed implicated cells, tissues or organs
Required action:

47. (1) Subject to subsection (2), an establishment that is not a source establishment and that has reasonable grounds to believe that an unexpected adverse reaction has occurred must immediately take all of the following steps:

  1. determine the donor identification codes of the transplanted cells, tissues or organs
  2. identify and quarantine any other cells, tissues and organs in its possession that could potentially cause an adverse reaction in the same way as the transplanted cells, tissues or organs
  3. notify the following establishments:
    1. the relevant source establishment
    2. if the cells, tissues or organs were imported, the establishment that imported them

Exception for importers:

(2) If the establishment that receives a notice under subsection (1) is the establishment that imported the implicated cells, tissues or organs, it only has to notify the source establishment.

Contents of notice:

(3) The notice must include all of the following information:

  1. a description of the adverse reaction
  2. the donor identification codes of all implicated cells, tissues and organs
  3. the name of any suspected transmissible disease or disease agent, if known

Written notice:

(4) If the notice is given verbally, a confirmatory written notice must be sent as soon as possible afterwards.

Establishments other than source establishments that discover or suspect an unexpected adverse reaction has occurred must immediately report to the source establishment and the importer (if applicable) all suspected or known unexpected adverse reactions associated with a CTO. To comply with this requirement, the establishment must:

After receiving the notice under subsection 47(1), an importer of a CTO must notify the source establishment of the adverse reaction.

An unexpected adverse reaction following the transplantation of a CTO includes:

These must be reported to the source establishment and importer, if applicable.

Under subsection 47(3) of the CTO regulations, the notice must:

The reporting of unexpected adverse reactions suspected to be associated with an CTO is time-sensitive. For this reason, the initial notice may be provided verbally. A written notice must be issued as soon as possible, preferably by the next business day.

Note: Reporting is not required when the transmission of a disease/disorder is expected (for instance, when it's known the infectious disease or disease agent was present in the donor before transplantation). An example is if a bilateral lung recipient develops Mycoplasma hominis pneumonia and the donor's tracheal/bronchial aspirate was known to contain Mycoplasma hominis. The Mycoplasma hominis was a known respiratory commensal in the donor, which means that the resulting pneumonia in the immunocompromised recipient was not unexpected an adverse reaction. If the donor's tracheal/bronchial aspirate was not tested or not found to contain Mycoplasma hominis (it's a difficult organism to culture), it would be an unexpected adverse reaction and subject to reporting and investigation.

Adverse reaction reporting applies to all CTOs, including those distributed by exceptional distribution. The requirement to report an adverse reaction for an exceptionally distributed CTO depends on whether the reason for exceptional distribution would lead someone to expect the adverse reaction. In other words, is it considered an unexpected adverse reaction.

For details on the unexpected serious adverse reactions that the source establishment must report to Health Canada, consult section 51 of the CTO regulations.

Action by source establishment:

48. (1) A source establishment that has reasonable grounds to believe that an unexpected adverse reaction has occurred that involves cells, tissues or organs for whose processing it is responsible must immediately take all of the following actions:

  1. quarantine any implicated cells, tissues and organs in its possession
  2. send a notice described in subsection (2) to all of the following establishments:
    1. if the implicated cells, tissues or organs were imported, the establishment that imported them
    2. any source establishment from which it received the donor referral, if applicable
    3. any source establishment to which it made a donor referral
    4. any establishment to which it distributed implicated cells, tissues or organs
  3. initiate an investigation into the adverse reaction

Contents of notice:

(2) The notice must include all of the following information:

  1. a description of the nature of the adverse reaction
  2. an explanation of how the safety of the implicated cells, tissues or organs may have been compromised, if known
  3. the donor identification codes of all implicated cells, tissues and organs
  4. the name of any suspected transmissible disease or disease agent, if known
  5. a statement requiring all implicated cells, tissues and organs to be quarantined immediately and until further notice from the source establishment and specifying any other corrective action that must be taken

Source establishments that discover or suspect that an unexpected adverse reaction has been associated with a CTO must take action, as outlined in section 48 of the regulations. The source establishment must:

The source establishment must investigate the unexpected adverse reaction. At a minimum, it should include the information being requested in the notice. Refer to section 51 of the regulations for more information.

An unexpected adverse reaction following the transplantation of a CTO includes:

It does not include the expected transmission of an infectious disease or disease agent. An example is the transmission of HCV from a donor who was known to be HCV-positive before transplantation to an HCV-negative recipient. This is an expected outcome as the organ was known to be HCV-positive. It would be an unexpected adverse reaction if the recipient develops HCV following transplantation of an organ that was not known to be HCV-positive.

Under subsection 48(2) of the CTO regulations, the notice must:

The reporting of adverse reactions suspected to be associated with an CTO is time-sensitive. For this reason, the initial notice may be provided verbally. A written notice must be issued as soon as possible, preferably by the next business day.

For details on the unexpected serious adverse reactions that the source establishment must report to Health Canada, consult section 51 of the CTO regulations.

Action on receipt of notice:

49. An establishment that is not a source establishment and that receives a notice under section 48 or a copy of such a notice under this section must immediately take both of the following actions:

  1. quarantine all implicated cells, tissues and organs in its possession
  2. forward a copy of the notice to every establishment to which it distributed implicated cells, tissues or organs

These requirements apply to establishments other than a source establishment that receive a notice under section 48 of the CTO regulations. Section 49 states that an establishment that is not a source establishment and that receives a notice under section 48 must quarantine all implicated CTOs over which it has control. A copy of the notice received must be sent to all establishments to which it has sent the implicated CTOs.

Requirement to cooperate:

50. An establishment must provide the source establishment that is conducting an investigation with any relevant information in its possession with respect to cells, tissues or organs that it distributed or transplanted.

All establishments contacted by a source establishment conducting an investigation must help in the investigation and provide all relevant information to the source establishment immediately. This includes, among other things:

Requests for information made to establishments by the source establishment often reflect requests that are made to the source establishment by Health Canada.

Reports to Minister:

51. (1) A source establishment that is conducting an investigation into either of the following subject-matters must provide the Minister with the reports described in subsection (2):

  1. a suspected error or accident that is identified after distribution of cells, tissues or organs that could lead to a serious adverse reaction involving the transmission of an infectious disease or disease agent
  2. an unexpected serious adverse reaction that is thought to involve the transmission of an infectious disease or disease agent

Contents and timing:

(2) The reports must include the following information and be provided at the following times:

  1. within 24 hours after the start of the investigation, a preliminary report that includes all relevant information that is available at that time
  2. within 15 days after the start of the investigation and every 15 days after that until the final report is made, an update on any new information about the suspected error or accident or serious adverse reaction, on the progress made in the investigation during those 15 days and on the steps taken to mitigate further risks
Reporting errors, accidents and adverse reactions

For these regulations, the Minister is represented by the following Health Canada branches:

Source establishments must provide all available information to Health Canada within 24 hours for:

They must report errors and accidents to Health Canada by email that they identify after the affected CTO has been distributed: bpcp-pcpb@hc-sc.gc.ca.

Include the following information in this report:

This requirement to report to Health Canada does not supersede the establishment's requirement to report designated infectious diseases to public provincial/territorial health authorities.

During the course of an investigation into an adverse reaction or unexpected serious adverse reaction, the source establishment must also report to the following:

Clarification on accident reporting

The following are circumstances under which certain test results that are received post-transplant must be reported to Health Canada as an accident:

The source establishment must forward all test results to:

In another example, bacteria or fungi found in the blood of a donor could be clinically significant to the health of the recipient and should be reported as an accident to Health Canada. The source establishment should report all unexpected positive blood cultures (received post-transplant) if it doesn't have a protocol in place to determine clinical significance. This reporting could be reduced if the establishment has a protocol that:

The source establishment must report to Health Canada as follows:

Regardless, the source establishment should immediately report all positive blood culture results, received post-transplantation, to the transplant establishment. The transplant establishment will then be able to assess the clinical significance to the organ recipient and provide timely medical treatment, if necessary.

Tissue transplant establishments that perform microbial testing before transplantation must inform source establishments if the culture results indicate an active/acute infection of clinical significance. This is outlined in section 43 of the CTO regulations.

Not all situations must be reported:

Error and accident reporting (directed to BPCP)

Email your reports to BPCP: bpcp-pcpb@hc-sc.gc.ca.

Use the following error and accident report form to report:

Investigation

During an investigation, a source establishment must determine:

Source establishments must:

Any documentation on the investigation must be available for Health Canada to review when we request it.

Reports

Every 15 calendar days after an investigation begins and until the final report is submitted, the source establishment must update BPCP on the following:

The updates must include information on the number of:

The Minister may ask an establishment to recall a product based on this information. A recall is a set of actions that an establishment takes to remove a product from the market if the product:

At any time during the investigation, Health Canada can ask for more information, as set out in section 14 of the CTO regulations.

A source establishment does not need to report an error or accident to the Minister if it can determine before an investigation starts that no CTOs exported to Canada were affected. However, the establishment should inform the Minister of any errors, accidents or adverse reactions involving a CTO not exported to Canada, to avoid miscommunications.

If it's determined during the course of the investigation that a CTO involved in the error or accident was exported to Canada, the establishment must provide to the Minister all reports described in sections 51 and 54 of the CTO regulations.

Reporting unexpected serious adverse reactions

Source establishments that suspect an unexpected serious adverse reaction involving the transmission of an infectious disease or disease agent from a donor to a recipient by transplanted CTO has occurred must:

We encourage source establishments to voluntarily report other unexpected serious adverse reactions that are thought to originate from the donor of the transplanted CTO. These include the transmission of:

Information on preliminary (initial), follow-up and final reports

Use the following form for your preliminary (initial) report and any follow-up reports to MHPD:

Preliminary (initial) report

The source establishment must provide MHPD with the following within 24 hours of an investigation into an unexpected serious adverse reaction:

This requirement is outlined in to section 51(2)(a) of the CTO regulations.

This information should include the:

We require 1 reporting form for each affected recipient. Each affected recipient should have a unique source establishment report number.

15-day update (follow-up) reports

The source establishment must provide MHPD an update on the status of the investigation and any further risk mitigation measures taken:

This is outlined in section 51(2)(b) of the CTO regulations.

This update should also include:

Clearly mark all updated information on the reporting form and present the steps taken as part of the investigation in chronological order. You may attach additional pages to the Mandatory Adverse Reaction Reporting Form for Industry if you need more space.

MHPD may ask for more information after receiving the adverse reaction report. The type of information requested is outlined in section 14 of the CTO regulations. If an establishment other than the source establishment has this information, it must cooperate with the source establishment. This is outlined in section 50 of the regulations.

Contact us

Source establishments should send adverse reaction reports covered by this guidance document by fax to:

Canada Vigilance Program
Marketed Health Products Safety and Effectiveness Information Bureau
Marketed Health Products Directorate
Tunney's Pasture
Address Locator: 1908C
Ottawa  ON  K1A 0K9
Fax: 613-957-0335
Email for enquiries: canada.vigilance.cto@hc-sc.gc.ca

When investigation shows no contamination or compromise:

52. (1) If the results of the investigation show that the implicated cells, tissues or organs are not contaminated or compromised, the source establishment must notify every establishment that was notified under section 44 or 48 to that effect in writing and that they may be released from quarantine.

Forwarding of copies of notice:

(2) On receipt of a notice under subsection (1), an establishment that is not a source establishment must forward a copy of the notice to every establishment to whom it distributed implicated cells, tissues or organs.

Implicated CTOs that are determined to be not contaminated may be distributed. The source establishment:

When investigation inconclusive or shows contamination or compromise:

53. (1) If the results of the investigation show that some or all of the implicated cells, tissues or organs are contaminated or compromised, or the results are inconclusive, the source establishment must notify every establishment that was notified under section 44 or 48 to that effect in writing and that they may not be released for distribution.

Forwarding of copies of notice:

(2) On receipt of a notice under subsection (1), an establishment that is not a source establishment must forward a copy of the notice to every establishment to whom it distributed implicated cells, tissues or organs.

Implicated CTOs that are determined to be contaminated or where the results are inconclusive must be destroyed or reserved for distribution under exceptional distribution. This is outlined in section 40 of the CTO regulations.

The source establishment must:

All establishments that receive a notification must follow the directions on handling the implicated CTOs.

Final report to Minister:

54. (1) On completion of an investigation, the source establishment must submit a detailed final report to the Minister that contains at least all of the following information:

  1. the results of the investigation
  2. the final disposition of the cells, tissues and organs that were the subject of the investigation and the reasons for that disposition
  3. any corrective actions taken

Summaries of final reports:

(2) The source establishment must send a summary of the final report to every establishment that was notified under section 44 or 48.

Forwarding of summaries:

(3) An establishment that receives a summary under subsection (2) must send a copy of it to every establishment to which it distributed implicated cells, tissues or organs.

Once the source establishment has finished its investigation, it must notify and provide a final report to BPCP or MHPD, whichever is appropriate. The final report must contain enough details and indicate the results of the investigation. It

should also:

Other requirements

The source establishment must investigate and document all errors and accidents and adverse reactions regardless of the reporting obligation to Health Canada.

Under subsection 59(h), a source establishment must keep the following records:

Under subsection 60(f), a transplant establishment must keep records of any errors, accidents and adverse reactions associated with CTOs it has transplanted, and any corrective action taken.

Furthermore, establishments are required under subsection 74(2) to review any SOP based on the receipt, from the source establishment, of a summary report of an error, accident investigation or a follow up report to an adverse reaction investigation that revealed a deficiency.

Records

Sections 55 to 63 of the CTO regulations

Record quality:

55. Records kept by an establishment must be accurate, complete, legible and indelible.

Except for distribution records, all records must identify the person who is doing the activities and the dates of the various entries.

Establishments must have a system in place to ensure the accuracy of their records, including transcribing test results manually. Transcribed data must be independently verified.

Records must be understood and made accessible. Use indelible ink for handwritten records and cross out text that's corrected in a paper document. Also, initial or sign any correction, entry or notation made after the record was completed. Date these so the reader can distinguish which information is original and which is changed.

Use a standardized format for dates (for example, YYYY/MM/DD or MM/DD/YY) for all records.

Records must be preserved to ensure they remain complete and accurate over time and accessible when needed. Establishments may use microfiche, microfilm or other ways to keep permanent records. A person other than the person who transferred the information must verify what media has been used to hold this information.

Guiding principles for transferring to secondary medium and destroying original records

Transfer

The source establishment should validate and document the transfer process in appropriate procedures, and ensure that:

For records that are copied off-site, a contract signed by the establishment and the service provider must describe the requirements in detail, for example:

Electronic or other system

We recommend that you validate the format and system where documents are retained for their intended use. Include the following:

Destroying original records

It may be acceptable to destroy original paper records after they have been transferred to a secondary medium if the principles discussed in this document are in place. You should document the process used to destroy the original paper records in appropriate procedures. Additional requirements that may apply to the destruction of personal/confidential information should also be considered.

Other considerations

Other requirements may apply to the transfer, storage and destruction of records, including:

Donor identification code for source establishment:

56. (1) A source establishment must assign a donor identification code to each donor of a cell, tissue or organ for which it has responsibility.

Donor identification code for all establishments:

(2) Every registered establishment and transplant establishment must ensure that the donor identification code is a component of its records system.

The source establishment assigns the donor identification code. This is a unique identifier. It corresponds to all CTOs from that donor processed by or on behalf of the given source establishment. The donor identification code will associate the CTOs with information about the donor from which it was retrieved.

Depending on how many CTOs were retrieved, a donor may have more than 1 donor identification code associated with them. This is because the source establishment may be different for various types of CTOs retrieved from the donor.

All source establishments must assign a donor identification code to every donor it is responsible for processing.

For example, in the case of a multiple tissue/organ donor, where bone, ocular tissue, kidney and liver were to be retrieved from the donor, an organ donation organization (ODO) would be the source establishment responsible for the processing and safety of the organs. The source establishment would assign a donor identification code to the organs.

Similarly, the tissues might be sent to a comprehensive tissue bank for processing. This tissue bank would assign a donor identification code to the tissues that it processes from that donor. Thus, the donor would be associated with 2 different donor identification codes. If, however, the bone and ocular tissues were sent to a bone and an eye bank rather than a comprehensive tissue bank, each of these establishments and the ODO would assign a donor identification code. The donor would then be associated with 3 different identification codes.

We recognize that 1 identification code per donor may be preferable. However, there are generally different source establishments for each of the different types of CTO, located in different provinces, regions and countries. The logistics of having 1 identification code for each donor would be very difficult. It would require all of the individual programs to collaborate to create a single donor coding system or the establishment of a single national organ and tissue donation body.

Although it's not possible to have a single identification code for every CTO donor at this time, it's still necessary that each CTO be associated with information about the donor from which it was retrieved and any processing activities that it underwent. For this reason, subsection 56(2) of the CTO regulations requires that the donor identification code be a component of the record-keeping system used by all registered and transplant establishments.

A source establishment may assign other numbers or codes to a CTO in addition to the donor identification code to help with their own record-keeping. However, all identifiers must be traceable to the original donor. Likewise, other establishments involved in processing a CTO may also assign their own numbers or codes to that CTO for their records.

Under sections 30 to 32 of the CTO regulations, the donor identification code must be clearly labelled as such. This will ensure that everyone who handles a CTO will be able to identify and record the donor identification code that was assigned by the source establishment.

Requirement:

57. An establishment's records must contain information with respect to all cells, tissues and organs that it processes, distributes, imports or transplants that identifies:

  1. the establishment from which it receives the cells, tissues and organs
  2. all establishments to which it distributes the cells, tissues and organs

Records must contain information about the establishment from which CTOs are received and establishments to which CTOs are distributed. Requiring each establishment to record this information makes it possible to trace the CTOs throughout the chain of distribution.

In addition to the name of each establishment, records should include the:

Shipping documents:

58. An establishment's records must include all shipping documents with respect to cells, tissues and organs that it ships to another establishment.

Source establishment records:

59. The source establishment must keep records with respect to cells, tissues and organs that it processes that contain at least all of the following information:

  1. the donor identification code
  2. documentation showing completion of the donor suitability assessment
  3. a description of the cells, tissues and organs retrieved from the donor
  4. if applicable, the name of any source establishment from which it received a donor referral or to which it made a donor referral
  5. the name of the retrieval establishment
  6. documentation of all processing activities
  7. the notice of exceptional distribution, if any
  8. documentation of any reported errors, accidents and adverse reactions and their investigation, if any, in connection with cells, tissues or organs retrieved from the donor that it banked or distributed and any corrective action taken

Information on traceability does not need to be in the donor chart. But it must be in the source establishment's records.

Records are a critical component of any quality assurance (QA) system. They are documented evidence of compliance. Source establishments must keep these records along with the performance of each significant step when processing, importing, storing, distributing (including exceptional distribution), transplanting and investigating errors, accidents and adverse reactions for each CTO. All steps must be clearly associated with the person, time/date and location of such activities.

Aside from other recording requirements that are covered under various sections of this document, the following requirements are specific to processing activities.

Processing equipment records

Source establishments must keep records for each piece of equipment that could affect the quality and the safety of the CTO. These records must include, at the least, the:

The records should be readily available for the lifespan of the equipment. Each item of equipment should be uniquely labelled, marked or otherwise identified.

Testing records

Source establishments must have records for all laboratory tests of transmissible disease markers. The tests must be done in accordance with the corresponding test kit manufacturer's instructions.

Where applicable, records of written agreement between the source establishment and any testing laboratory should be in place to provide relevant information. There should be records showing agreements for the following:

Testing laboratories should make available to the source establishment its detailed testing records, logs and other supporting documents. These documents should include the:

Critical supplies records (such as devices, instruments, reagents, containers)

Records must be kept for each critical supply item that is used during processing and that could affect the quality and the safety of the product. These records must include:

Where applicable, records of written agreement that show relevant information such as roles and responsibilities between the source establishment and the retrieval establishment must be kept. The written agreement should also attest that the records are in compliance with the CTO regulations.

If an error, accident or adverse reaction occurs, a report must be written that describes the incident, the investigation, corrective actions taken and any follow-up activities required.

In addition to the donor identification code, other attributes such as a description of the CTO must be unique to avoid identity mix-up (for example, Achilles Tendon L and Achilles Tendon R).

In cases of exceptional distribution, source establishments must keep in their records:

Transplant establishment records:

60. The transplant establishment must keep records with respect to cells, tissues and organs that it transplants that contain at least all of the following information:

  1. a description of the transplanted cells, tissues or organs
  2. the donor identification code
  3. the registration number of the source establishment
  4. the notice of exceptional distribution, if any, and confirmation that the donor suitability assessment was completed as required by section 42
  5. information that allows the identification of the recipient
  6. documentation of any errors, accidents and adverse reactions and their investigation in connection with those cells, tissues or organs and any corrective action taken

The recipient's chart does not have to keep information on traceability. This information must be in the transplant establishment's records, however.

In addition to the donor identification code, other attributes such as a description of the CTO must be unique to avoid identity mix-up (for example, Achilles Tendon L and Achilles Tendon R).

For exceptional distribution, the transplant establishment's records must contain the following:

Establishments to cooperate:

61. An establishment must provide the source establishment and the transplant establishment with all of the information described in sections 59 and 60, respectively, that it possesses to complete the establishment's records.

When 2 or more establishments are involved in CTO-related activities, each establishment must:

Establishments that are contacted by a source establishment or a transplant establishment for any information described in sections 59 and 60 of the CTO regulations must provide that establishment with all the information requested.

Retention: 10 years after transplantation:

62. (1) An establishment must keep the following records for at least 10 years after the date of transplantation, if known, or for at least 10 years after the date of distribution, final disposition or expiry of the cell, tissue or organ, as the case may be, whichever is the latest:

  1. the records described in section 57
  2. the records described in section 59, except paragraph (h)
  3. the records described in section 60, except paragraph (f)
  4. the record of destruction or other disposition of the cell, tissue or organ, if applicable

Retention: 10 years after record creation:

(2) An establishment must keep the following records for 10 years after the date of their creation:

  1. the records described in paragraphs 59(h) and 60(f)
  2. reports of audits conducted under section 76, if applicable

Retention: employee records:

(3) An establishment that distributes cells, tissues or organs must keep records of the qualifications, training and competency of its employees for 10 years after the time an individual ceases to be an employee of the establishment.

Retention: standard operating procedures:

(4) An establishment that distributes cells, tissues or organs must keep a copy of every version of its standard operating procedures for 10 years after they are superseded by a new version.

With the exception of subsections 59(h) and 60(f), processing activity records, as well as records of importation, distribution and transplantation of the CTO that the establishment has in its possession must be kept as follows:

Under subsections 59(h) and 60(f), records must be kept for 10 years from when they are created. Other records described in section 62 of the CTO regulations are to be kept for 10 years from when the employee left the establishment [subsection 62(3)] or the date that a new version of the SOP came into effect [subsection 62 (4)].

Storage of records:

63. An establishment that distributes cells, tissues or organs must store records in a location that has appropriate environmental conditions and that is secure against the entry of unauthorized persons.

Storage areas for records must maintain the integrity of the records and access must be restricted to designated personnel.

For records stored off-site, an SOP must outline specific requirements, such as for:

Personnel, facilities, equipment and supplies

Sections 64 to 69 of the CTO regulations

Sufficient number and qualifications:

64. (1) An establishment that distributes cells, tissues or organs must have sufficient personnel who are qualified by education, training or experience to perform their respective tasks to carry out the establishment's activities.

Competency:

(2) An establishment that distributes cells, tissues or organs must have a system for the orientation and training, both initial and ongoing, of personnel and for the evaluation of their competency.

Not enough or underqualified staff increases the risk of errors and accidents. There must be a sufficient number of qualified personnel to perform the tasks required.

An establishment should prepare and keep a current organizational chart that shows lines of responsibility. Job descriptions must describe the qualifications and functions of each staff position.

Personnel must receive initial and ongoing training appropriate for their duties.

Training programs must be available and must include an assessment of competency that may include the following:

Personnel affected by a new or revised SOP must receive training before performing any tasks associated with a new or revised SOP. Training records must confirm when training took place, include information verifying this, such as the employee's signature, and indicate if technical or competency testing is required.

The medical director or scientific director may delegate responsibilities to qualified persons within the establishment, in accordance with the SOP.

Establishments that distribute must keep records of the qualifications, training and continuing competency of individuals.

Requirements:

65. The facilities of an establishment that distributes cells, tissues or organs must be constructed and maintained to permit all of the following:

  1. the carrying out of all of its activities
  2. the efficient cleaning, maintenance and disinfection of the facilities in a way that prevents contamination and cross-contamination
  3. environmental and microbiological monitoring and control appropriate to the areas where its activities are carried out
  4. controlled access to all areas where its activities are carried out

Premises must be:

The sanitation program should include:

Access to areas where aseptic activities are conducted and where products and samples are stored must be controlled.

Establishments should have microbial and environmental monitoring procedures, with alert and action levels set for areas where aseptic activities are conducted and susceptible products are processed or packaged.

There must be no direct access from the areas where processing is carried out to the exterior of the building, except in emergencies.

Requirements for equipment:

66. An establishment that distributes cells, tissues or organs, in carrying out its processing and storage activities, must use equipment that is cleaned and maintained and, whenever applicable:

  1. qualified for its intended purpose
  2. calibrated
  3. disinfected or sterilized before each use
  4. requalified or recalibrated, as appropriate, after any repair or change is made to it that results in a change to its specifications

Establishments must ensure that all equipment can be easily cleaned and maintained. Cleaning schedules must be established and followed to prevent contamination, cross-contamination or spread of infectious diseases. The cleaning procedure must be validated to ensure that contaminants and cleaning product residues that could interact with the CTOs are removed.

Equipment must be:

For more information on equipment, refer to section 5.3 of the general standard.

Requirements for storage equipment:

67. An establishment that distributes cells, tissues or organs that uses equipment to store cells, tissues or adjunct vessels that are not used immediately in organ transplantation must ensure that the equipment maintains appropriate environmental conditions.

Establishments must:

Environmental parameters for storage, such as temperature and humidity, must be controlled and should be monitored using calibrated monitoring devices.

Establishments must:

Establishments should:

Procedures describing the actions to be taken in the event of deviations from established criteria must be written. Such events must be appropriately documented and investigated.

Processing supplies:

68. An establishment that processes cells, tissues or organs must use qualified supplies for those activities that could affect the safety of the cells, tissues or organs, and must store solutions, reagents and other supplies under appropriate environmental conditions.

The person responsible for the establishment's QA (medical director, the scientific director or designate) must establish acceptance criteria for the supplies used to process CTOs.

Supplies should be quarantined until the person in charge of QA finds each specific lot is acceptable for use. The conditions of use and storage of each supply must be appropriate as instructed by the manufacturer. The expiry dates of supplies and ongoing storage conditions must be strictly observed.

Cleaning supplies:

69. An establishment that processes cells, tissues or organs must ensure that it uses supplies for cleaning, maintenance, disinfection or sterilization that do not react with, or that are not absorbable by, the cells, tissues or organs.

The choice of cleaning supplies used in the processing areas should be reviewed to ensure that they do not negatively impact the quality and safety of the CTOs they come in contact with. The cleaning supplies must be of the appropriate grade and quality.

Cleaning supplies that could affect the safety of the CTOs must:

The name and the lot numbers of supplies that are used to clean, disinfect or sterilize equipment and instruments should be recorded and the expiry dates must be strictly observed.

Quality assurance system

Sections 70 to 76 of the CTO regulations

Application:

70. Sections 71 to 76 apply only to establishments that distribute cells, tissues or organs.

Under these regulations, all registered importers and establishments that distribute as intermediaries and source establishments must have a QA system (refer to the following section 71 for details). This includes source establishments that are also transplant establishments for lymphohematopoietic cells that are not banked and organs from living donors.

Quality assurance system required:

71. An establishment must ensure that it has a quality assurance system in place that complies with the requirements of these Regulations for all activities that it carries out.

A QA system must be established to ensure the maximum quality and safety of the CTOs distributed by the establishment. Quality assurance consists of all the organized arrangements made and the measures taken to reach this objective.

The QA system must have the following elements.

Management requirements (sections 71 to 76):

Documentation system (sections 72 to 75):

Other systems:

Computer systems/data processing control used to process and distribute CTOs and other regulated activities:

Process control:

Quality control:

Suppliers for critical supplies and services (section 68):

Reporting and investigating errors, accidents and adverse reactions (sections 43 to 54):

Audit program (section 76)

The QA system should have the following elements.

Preventive action:

Customer complaints and corrective actions:

Standard operating procedures required:

72. An establishment must have standard operating procedures with respect to the safety of cells, tissues and organs for all activities that it carries out.

An establishment must also:

For example, such SOPs could be in place for:

SOPs contains instructions or directions so that personnel can perform activities and document consistently and ensure they're in compliance with regulatory requirements.

Requirements:

73. The standard operating procedures must meet all of the following requirements:

  1. be in a standardized format
  2. be approved by the medical director or scientific director
  3. be available for use at all locations where the relevant activities are carried out
  4. have any changes to the procedures approved by the medical director or scientific director before being implemented
  5. be kept up-to-date

For the format of each SOP, indicate, at a minimum:

SOPs (and changes to these) must be kept in a document control system that ensures they are current and authorized by the medical director, scientific director or designates. In an urgent situation, a change to a current operating procedure is allowed if the medical director or scientific director approve, sign, date and document the reason for the change. Invalid or obsolete documents must be promptly removed so they're not used in error.

Routine review:

74. (1) An establishment must review its standard operating procedures every two years and again after any amendment to these regulations.

Supplementary review:

(2) An establishment that receives a summary of a final report of an error, accident or adverse reaction investigation or the report of an audit either of which reveals a deficiency in a standard operating procedure must review that procedure.

SOPs must be reviewed and/or revised every 2 years at a predetermined period, by a knowledgeable person(s). The review must be documented. SOPs must also be amended to reflect changes to the CTO regulations. The medical director, scientific director or their designates must approve and document the changes, including the reason for the changes.

Keep all SOPs for 10 years after they have been superseded by a new version (subsection 62(4) of the CTO regulations).

Records of compliance:

75. An establishment must keep records that demonstrate that it has implemented its standard operating procedures.

Records must indicate the dates when SOPs and their revised versions are implemented.

Audits:

76. An establishment must conduct an audit every 2 years of the activities that it carries out to verify that those activities comply with these regulations and with its standard operating procedures, by a person who does not have direct responsibility for the activities being audited.

Audits ensure that all regulated activities are performed according to the CTO regulations and the establishment's SOPs. They must address regulated activities that have an impact on CTO safety. All the activities that need to be audited must be reviewed at a minimum every 2 years and there should be an SOP written for these audit activities.

Management must document and review the audit findings and follow-up actions/corrective actions should be implemented in a timely manner. If your establishment has arranged with another establishment to perform any regulated activity on your behalf, you should verify that those activities are being conducted appropriately and comply with the CTO regulations. This should be done every 2 years. For example, you may assess a contractor's compliance by auditing the contractor on-site or remotely or by reviewing audit reports provided by the contractor or by a third party that has audited the contractor.

An establishment should audit all establishments performing regulated activities on its behalf. An establishment contracting another establishment to conduct transmissible disease testing is not required to audit the testing facility if:

Personnel responsible for carrying out the QA system requirements should conduct the audits. They must know the subject matter and the process being audited. Management must define the responsibilities and who is responsible for and has the authority to conduct the audit. Also, personnel auditing an activity must not be directly responsible for that activity. For example, a supervisor responsible for donor screening must not audit any donor screening activities done in its own facility.

The living donor organ programs should work together to develop standardized SOPs and questionnaires to ensure donor screening and testing practices are consistent among the different organizations.

Powers of inspectors

Section 77 of the CTO regulations

Taking photographs:

77. An inspector may, in the administration of these regulations, take photographs of any of the following:

  1. any article that is referred to in subsection 23(2) of the act
  2. any place where the inspector believes on reasonable grounds that any article referred to in paragraph (a) is processed
  3. anything that the inspector believes on reasonable grounds is used or is capable of being used in the processing of any article referred to in paragraph (a)

An inspector is a person designated under section 22(1) of the Food and Drugs Act to enforce the act and regulations. Once designated by the Minister, an inspector will carry out his/her responsibilities according to the guiding principles of transparency and fairness, as described in Health Canada's compliance and enforcement policy. Inspectors' regulatory powers are described under section 23 of the act.

Learn more:

Section 23 authorizes inspectors to examine and make copies of documents and records, even if they contain personal medical information. Inspectors review these documents to verify compliance with the CTO regulations. Health Canada handles all information in accordance with applicable laws on privacy, confidentiality and access to information.

Learn more:

Transitional provisions

Section 78 of the CTO regulations

Processed within 5 years before registration:

78. (1) Subject to subsection (2), the following establishments may import, distribute or transplant, as the case may be, cells and tissues that were processed within 5 years before the day on which these regulations are registered:

  1. a registered establishment
  2. a transplant establishment that does not distribute cells or tissues

Prohibition:

(2) An establishment may not import, distribute or transplant, as the case may be, cells or tissues under subsection (1) unless the requirements of subsection 56(2) and section 57 are met.

Coming into force

Section 79 of the CTO regulations

Six months after registration:

79. (1) These regulations, except subsection 26(1), come into force 6 months after the day on which they are registered.

Exception:

(2) Subsection 26(1) comes into force 1 year after the day on which these regulations are registered.

Transitional provision:

(3) Section 78 ceases to be in force 5 years after the day on which these regulations are registered.

Page details

Date modified: