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Proposed standards for human blood and blood components, human tissues and human cellular therapy products

Consultation

26 July 2011

This consultation closed on 2 February 2011.

Interested parties were invited to provide comment on the proposed ID Order, the four product-specific Orders, and the labelling Order.

The TGA reviewed comments received as they relate to each consultation document.

Documents

Written submissions were invited on the following documents:

How to access a pdf or Word document

Draft Therapeutic Goods Order: Standards for minimising infectious disease transmission via therapeutic goods that are human blood and blood components, human tissues and human cellular therapy products

Draft Therapeutic Goods Order: Standards for human cardiovascular tissue

Draft Therapeutic Goods Order: Standards for human musculoskeletal tissue

Draft Therapeutic Goods Order: Standards for human ocular tissue

Draft Therapeutic Goods Order: Standards for human skin

Draft Therapeutic Goods Order: General requirements for the labelling of biologicals

In addition, the following documents are also available for information:

Information paper – Consultation on proposed standards for human blood and blood components, human tissues and human cellular therapy products

Draft Australian Code of Good Manufacturing Practice for human blood and blood components, human tissues and human cellular therapy products

Background

In December 2009, public consultation invited comment on a revised Code of Good Manufacturing Practice for human blood and blood components, human tissues and human cellular therapies (Code of GMP), and five proposed Therapeutic Goods Orders: Standards for minimising infectious disease transmission via therapeutic goods that are human blood and blood components, human tissues and human cellular therapies (ID Order), and product-specific standards for biologicals that are musculoskeletal tissue, cardiovascular tissue, ocular tissue and skin.

Feedback from the consultation informed significant changes to the five proposed Therapeutic Goods Orders. These changes included revision of requirements, reformatting, and development of a separate labelling Order for biologicals.

The Code of GMP has only required minor amendments as a result of this process, and therefore the revised Code of GMP is provided as information only, to support the second round of stakeholder consultation.

Further background information and context for the consultation is provided in the above Information paper.

Enquiries

Enquiries should be directed via email to bloodandtissues@tga.gov.au or by telephone to 02 6232 8443.

Public submissions

25 July 2011

All submissions received during the consultation period are published below, unless they were marked as confidential.

The comments received have been reviewed by the TGA and the six orders have subsequently been revised.

Also provided below are tables, categorised by the standard, summarising stakeholder comments and TGA responses pertaining to those comments. These documents were used to inform discussions leading the revision of the order. Please note, where the table refers to 'TGC Subcommittee', these issues were presented to the Therapeutic Goods Committee (TGC) Subcommittee on Biologicals at their meeting on 10 March 2011.

Submissions on the proposed standards for human blood and blood components, human tissues and human cellular therapy products

How to access a pdf document

Summary of stakeholder comments: Standards for musculoskeletal tissue

Reference Issue Stakeholder comments TGA comment
4 (2) microbial definition. Current methodologies do not routinely include mycoplasma and rickettsia. Suggest that this is qualified and covers known pathogenic microorganisms that affect donations encountered within the limits of the standard detection methods for bioburden testing. Can the term specified microorganism of clinical significance be used? Noted without change. As part of product dossiers, manufacturers will be required to submit a list of specified microorganisms of clinical significance, which, if tested and found to be present, will require rejection and discard of the tissue. The list and list justifications will be determined by experts within the TGA.
4 (2) minimal manipulation (f)any similar thing to a thing mentioned in paragraph (a),(b),(c),(d) or (e) Suggested to include tissues processed in high concentration of glycerol (i.e. >75%) - e.g. fascia

Noted without change. Regulations are not within the scope of this consultation. Suggest submitting request for consideration to the TGA.

Preservation using high concentration glycerol is consistent with the revised definition of minimal manipulation (see (g)) in the Regulations. Definition of minimal manipulation updated in all orders/glossary.

6 (1) Suggest to add "autologous tissue to be used in the same procedure" An autologous graft used in the same surgical procedure e.g. iliac crest from the patient used as graft for a knee revision or tendon for a knee ligament reconstruction in the same surgical procedure (i.e. not temporarily stored) should be exempt. Noted without change. The scenario given includes medical practice that is akin to the Excluded Goods Order. These products will not be therapeutic goods and as such will not be under TGA oversight.
6 (1)(c) Tissues processed beyond minimal manipulation not included in this order Query if appropriate to exempt from order "tissue that is processed beyond minimal manipulation. Such tissue start materials still need to comply to this order + further processes to have distribution approved (e.g. dossier)

Noted without change. Class 3 and 4 products that are exempt from compliance with the Order will still be required to comply with other regulatory requirements, and may choose to comply with the MS Order if appropriate. The dossier will include the starting material specifications for TGA evaluation.

Exemptions specified in (c)(i)-(ii) removed from order, to be put in Guidelines.

7 (1) Are MS tissues included in the term critical materials?

Defining design and composition of human tissues will be problematic.

In the definition for critical materials include 'does not included MS tissues'.

Agree to clarify. Tissue is not a critical material. Consider for Guidelines.
7 (2) (a) Transport Identify more clearly that this refers to transport of musculoskeletal tissue that has been collected, and is in transit from the collection facility to the Bone Bank. Agree. Order updated to clarify where transport refers to starting vs finished product.
7 (2) (a) Maintaining tissue at or below 8° C prior to and during shipment.

We currently require tissue to be shipped at 10° C or below in accordance with the State of New York regulation (section 52-5.5(c)) and AATB standards (12th Edition, section D5.800).

Tissue shipped at 10°C or below prior to and during shipment is safe; tissue does not need to be maintained at or below 8°C prior to and during shipment.

b) to be deleted and 7. (2) to be worded:

"Musculoskeletal tissue that is to be transported to the manufacturing facility must be packaged using aseptic technique with at least one moisture impermeable barrier and maintained at or below 10 DC prior to and during transportation."

Noted with change. This paragraph has been updated for consistency across all orders.
7 (2) (b) Tissue sampling pre-processing

If the tissue is subjected to processing then a sample using a validated technique is taken at the end of processing (not the beginning) and this test is the release test. There should not be a requirement for a pre-processing test to occur unless perhaps antibiotics are used during processing. Strongly request that this requirement is removed or re-worded.

It was agreed that given the pre-processing sample was the release test for unprocessed tissue, the sampling technique & test method had to be validated.

The Banks were invited to provide objective evidence to justify why a validated pre-processing sampling technique and test method should NOT be a requirement for processed tissue. These comments are to be provided by the individual Banks for consideration by the TGA.

Noted with changes. MS Order requirements (2)(3)(4) have been reworded to clarify
7 (2) (b) Addition "...bioburden determination when no further processing is to be undertaken prior to release"

Samples taken at retrieval of tissue that is processed prior to release are of less value to final product release determination. The information from this can be used as a potential early indicator for discard. The most important sample for release purposes is the final sample taken prior to final packaging of the tissue.

".....bioburden reduction process must demonstrate no microbial growth when final prepackaging representative samples are tested."

7 (2) (a) & (b)
7 (4) Does this requirement make post irradiation sampling mandatory? Provided the irradiation process has been validated and conducted to requirements post irradiation sampling should not be required.
7 (4) Specified microorganisms.

Will the auditors accept each bank's determination of the specified microorganisms of clinical significance?

It was suggested that the ATBF undertake to prepare a list of specified microorganisms of clinical significance for each tissue, including justifications, for submission to the TGA for approval. These standardised lists could then be made available to ATBF members for inclusion in their product dossier. This proposal will be discussed at the next ATBF Executive meeting and presented to ATBF members.

As part of product dossiers, manufacturers will be required to submit a list of specified microorganisms of clinical significance, which, if tested and found to be present, will require rejection and discard of the tissue. The list and list justifications will be determined by experts within the TGA.
7 (4);
7(6)(a)
specified microorganism - clarify How and by whom will 'Specified' be determined? Will this follow the British or European pharmacopeia lists of organisms? Or will it be at the manufacturer's discretion?
7 (4) Bioburden reduction

[We use] a chemical flushing and washing process that was developed to render allograft tissue sterile and [our] tissue sterilization process is validated to sterilize tissue.

The Standard should allow for the possibility of validating a bioburden reduction process to reproducibly reduce or eliminate microorganisms of clinical significance. Musculoskeletal tissue for bioburden determination (as required in 7(2)(b)) is sufficient to screen incoming tissue bioburden to detect the presence of microorganisms which fall outside the validated sterilization process.

Testing may not be mandatory where validated bioburden reduction processes are used.

Representative samples of MS tissue must be validated to have no microbial growth.

7 (5) Neutralisation of antimicrobial agents "neutralisation of the antimicrobial agents. "This is difficult to achieve as there is no agreed pathway of neutralisation. It is highly dependent on which antimicrobial agents are used and in what concentrations, and often this information is not available or known. Noted with changes. The requirement to neutralise antibiotics has been removed. This forms a part of the validated bioburden test as required by the Order.
7 (6) (b) repeat sampling and testing for bioburden where tissue is subjected to further processing; If tissue is treated by gamma radiation and this is considered processing by definition, what would be the value of retesting a sample post irradiation be, if the pre irradiated samples showed no presence of specified organisms? Noted with change. Validated bioburden techniques will not necessitate further bioburden sampling. Requirements reworded to clarify.
7 (6) (c)

Does this requirement make post irradiation sampling mandatory where the irradiation process has been validated?

Is the intent of this requirement to allow tissue with a positive micro test result to be released provided a sample tested post terminal bioburden reduction is negative?

7 (6) (c) Media rather than tissues tested These samples tested may be fluids (bathing solutions), which are also indicative of the tissue environment. Suggest to change from "...representative samples of musculoskeletal tissue must have..." to: "...samples representing the musculoskeletal tissue must have..."
7 (6) (c) Clarification - micro positive tissue. Is the intent of this requirement to allow tissue with a positive micro test result to be released provided a sample tested post terminal bioburden reduction is negative? The addition of 'These samples may be representative of pre and / or post bioburden reduced tissue' will avoid auditors interpreting that testing is required both pre and post terminal bioburden reduction for tissue with a negative pre bioburden reduction test result.
7 (6) (c) Re-word as follows: "Musculoskeletal tissue that has not been subject to a validated terminal Bioburden reduction process must be sampled post-process, the samples taken must show no microbial growth when tested with a validated sampling method."
7 (8) (b) Storage conditions

Because cellular viability is not necessary for safe and effective use of transplanted musculoskeletal tissue, it can be stored without a cryoprotectant at less than minus 40°C for up to 5 years. [We] and other AATB-accredited tissue banks have a long history of distribution of musculoskeletal tissue which has been frozen at less than minus 40°C without a cryoprotectant with a shelf life of 5 years.

Recommendation: modify the text of 7(8)(b) to read "frozen and or cryopreserved at less than minus 40°C for no more than 5 years"

Noted without change. (c) and (d) indicate alternative temps can be validated.
7 (8) (d) Storage temperatures must be maintained during transport. Some tissues processed by [us] are stored at room temperature (e.g., following lyophilization). Tissues labelled for storage at ambient temperatures may experience higher or lower temperatures during transport. [Our] experience is that tissues stored at room temperature are not harmed by the temporary increases or decreases associated with transport.
7 (8)(b) Requirement to establish storage conditions even though meeting TGO specified storage conditions.

The 'must be established' should apply where implementing conditions other than those stated.

As this is about storage conditions it the commencement date should be specified as being from date of retrieval.

  1. Substitute "or" for "and", or
  2. Remove "cryopreserved"
Agreed with change . Clause modified to include 'or'.
7 (8)(b) Shelf life timeframe - clarify.

"Frozen and cryopreserved ..." could be interpreted that a cryoprotectant is required when tissues are frozen at less than minus 40°C.

Requirement (b) should include a commencing date. Is this about the final packaging or life of tissue from date of retrieval?

Noted with change. Requirement reworded to add 'after packaging'. Clarify in Guidelines
7 (8) Neutralisation of antibiotics Validated test methods must include antibiotic neutralisation – this is not necessary to state explicitly.

Noted with changes. Remove (8)

Clarify in Guidelines

Donor Interview Identify in this Tissue specific TGO that the timeframe for donor interview can be 30 days prior and 30 days after bone collection.... which allows the use of authorised people in the Pre Operative clinics to conduct questioning while the patient is in the hospital for the surgery workup. Noted with change. Interview timeframe in ID Order for TGC subcommittee consideration.
6(d) Terminal sterilisation reference to Annex

May not be applicable to these tissues, e.g. irradiation is not covered by the Annex.

SAL may be determined in consultation with the regulator, prescriptive levels are not mandated - e.g. for implantable devices (10-6) greater than non-implantable devices (10-3). Noted with change.

Removed Annex 1 reference, insert 'sterility assurance level' as in consultation with the Regulator.

Summary of stakeholder comments: Standards for cardiovascular tissue

Reference Issue Stakeholder comments TGA Comment
4 (2) Inclusion of mycoplasma and Rickettsia in the definition of "microbial"

[See full comment in Infectious Diseases TGO]

See comment for 7. (2) (d) below

How and by whom will 'Specified' be determined? Will this follow the British or European pharmacopeia lists of organisms? Or will it be at the manufacturer's discretion?

As part of product dossiers, manufacturers will be required to submit a list of specified microorganisms of clinical significance, which, if tested and found to be present, will require rejection and discard of the tissue. The list and list justifications will be determined by experts within the TGA.
4 (2) Suggest add glycerol to definition of minimal manipulation minimal manipulation (f) any similar thing to a thing mentioned in paragraph (a),(b),(c),(d) or (e) Suggested to include tissues processed in high concentration of glycerol (i.e. >75%) - e.g. vascular conduits

Noted. Definition of minimal manipulation updated following Regulations consultation.

Preservation using high concentration glycerol is consistent with the revised definition of minimal manipulation (see (g)) in the Regulations. Definition of minimal manipulation updated in all orders/glossary.

7 (2) (a)
&
7 (4) (a)
Transport temperature of heart/ cardiovascular tissue to manufacturing facility (2-8°C) too restrictive.

Transport of the product starting material (i.e. cardiovascular tissue – heart or heart block*) at the temperature range indicated (i.e. 2-8°C) is not critical to the safety or quality of the final product [as demonstrated by] validated transport procedures.

The temperature of hearts retrieved from deceased or domino donors can be close to body temperature. Placing the heart into a temperature-conditioned & validated transport container even with the addition of a litre of refrigerated solution (e.g. Hartmanns) to the primary heart container, can result in a temperature reading of >8°C for a period of time during transport, depending upon the size/volume/starting temperature of the added heart.

Transport temperatures of up to 10.2°C for 15-55min have been recorded for a substantial number of hearts transported for processing. Valves processed from hearts transported at these temperatures do meet release criteria and demonstrate competency and efficacy when implanted into recipients.

Restricting the transport temperature of the product starting material to the indicated temperature range will result in the un-necessary discard of generously donated and extremely limited tissue.

*Eastern State Banks retrieve and transport starting cardiovascular tissue as "heart blocks". Retrieval of heart blocks is not allowed in WA. Rather, the entire heart is retrieved from deceased donors with the remains of the heart returned to the body following valve retrieval at the manufacturing site. Whole hearts are also retrieved from domino donors and transported for processing to CTTWA.

Agreed with changes. Modified to reflect either stated temperatures or alternative conditions validated by the manufacturer to maintain product safety and integrity
7 (2) (a)
7 (4) (a)
Transport temperature - change to wet ice (or equivalent) The lower limit is to prevent ice crystal formation as a result of dropping below 0°C. The limit of 0°C with wet ice is acceptable, and is the option/preferred method of transportation e.g. organs packed in wet ice for transplant. - Suggested change from: "transported at 2°C to 8°C" to: "transported refrigerated (2°C to 8°C) or in wet ice (0°C-8°C) to the..." Noted with change. These paragraphs have been updated for consistency across all orders.
7 (2) (a) (i)
and (ii)

Timeframe to processing - Suggest increase to 36 hours

(i.e. 12 hours for transport until manufacture)

The time frame of 30 hours is challenged as this may preclude transfer of tissues collected at 24 hours across the country (e.g. heart blocks from Tasmania retrieved at 24 hours asystole needing to be transported interstate). Agreed. Timeframe to beginning of processing extended to 36 hours in 7(2)(a)
7 (2) (a) (i) & (ii) Timeframe to processing – request extend hours to 48

Depending upon when the heart is retrieved (up to 24hr of asystole) and worst-case scenarios for transport to the manufacturing facility (up to 10hr), it may not be possible for processing and treatment with antimicrobial agents to commence within 30hr of asystole or 30hr collection from a living donor.

Outcomes have demonstrated that as long as cryopreservation is initiated within 48hr of death (asystole), the valves meet release criteria and demonstrate competency and efficacy upon implantation.

Suggested modification of reference:

Cardiovascular tissue that is subjected to a bioburden reduction process must be:

  1. (a)transported to the manufacturing facility .... where cryopreservation must commence:
    1. (i) within 48hr of asystole; or
    2. (ii) within 48hr of collection from a living donor; and

This proposed change is also required to allow 7. (5) (b) to be feasible.

Noted with change as above.

TGA agreed to consider proposed reference modification i.e. cryopreservation must commence within 48hr of asystole rather than processing and treatment with antimicrobial agents must commence within 30hr of asystole.

Antimicrobial treatment is included in the scope of processing - consider revising to collection within 24 hours (specified in the ID order), and

Commencement of cryopreservation within 48 hours in 7(4)(a).

7 (2) (d) Assessed for microbial growth

1. Is "assessed for microbial growth" referring to bioburden determination? Does "must demonstrate no microbial growth when cultured" mean when "tested"?

2 Does the "must demonstrate no microbial growth" only apply to samples tested POST incubation with antimicrobial agents or does it cover all samples taking for bioburden determination throughout processing? Pre-treatment samples may demonstrate microbial growth that is removed via anti-microbial treatment.

Suggested modification of reference: "(d) assessed for microbial growth. Post anti-microbial treated samples must demonstrate no microbial growth when...OR (CTTWA)

"(d) assessed for microbial growth as defined in the product dossier. Post anti-microbial treated samples must demonstrate no microbial growth when...

2. Agreed. Order changed to 'bioburden'

TGA agreed to clarify that (d) refers only to post-antimicrobial treated samples (see above).

2. Agreed. Order changed to 'when tested'

7 (2) (d) Suggest adding 'Final' to '...samples must demonstrate no growth' 3. Samples prior to decontamination may have non pathogenic flora present that are removed as a result of the bioburden reduction process which may be acceptable for release. Noted without change. 7(2)(c) specifies there must be NO growth following bioburden reduction
Additional General Requirement Specified microorganisms of clinical significance

To standardise requirements between product specific TGOs the following reference should be added to the cardiovascular TGO possibly as 7. (2) (e) so that other reference numbering does not have to be changed:

"Cardiovascular tissue subjected to a bioburden reduction process must be sampled for bioburden determination to exclude tissue contaminated with specified microorganisms of clinical significance".

Noted without change. 7(2)(c) specifies there must be NO growth following bioburden reduction
7 (3) Validating neutralisation of antibiotics. "neutralisation of the antimicrobial agents." is difficult to achieve. Validation of bioburden test. Instead of [a negative test] a better indication of effectiveness of bioburden reduction (by antimicrobial treatment) is to ensure that methods are able to detect organisms when antibiotic treatment has been omitted or ineffective. i.e. recovery of organisms indicates a problem. Noted without change. For clarification in Guideline.
7 (10) Transport on dry ice at ‑80°C Short term storage at ‑80°C and transport on dry ice is accepted international practice. Additional text..."to be transported at or below minus 100°C, or in dry ice (‑80°C) in a validated container system." Noted without change. International standards recommend that transport conditions should maintain storage temperatures as specified.

Summary of stakeholder comments: Standards for ocular tissue

Clause Issue
(TGA summaries)
Stakeholder comments TGA comment
No information regarding transport temp of tissues There are no requirements for transport temperatures when tissues are transported between collection and transfer to processing Bank; and/or from Bank to end-user as in other Orders. Noted without change. Product specific Orders only specify if requirements differ from the ID Order.
4 (2) microbial definition By defining Microbial in this way, an unrealistic and unachievable standard is being set as it is not the aim of bioburden testing to ensure that the product is free of every known microorganism that may exist. Current methodologies do not routinely include mycoplasma and rickettsia. Suggest that this is qualified and covers known pathogenic microorganisms that affect donations encountered within the limits of the standard detection methods for bioburden testing. Can the term specified microorganism of clinical significance be used?

Noted without change.

As part of product dossiers, manufacturers will be required to submit a list of specified microorganisms of clinical significance, which, if tested and found to be present, will require rejection and discard of the tissue. The list and list justifications will be determined by experts within the TGA.

6 (1) (d) Amniotic membrane used for therapeutic ocular procedures This is not included in any of the TGOs. Where does it fit? Amniotic membrane will be regulated as a biological. Currently no product-specific Order applies to amnion. Requirements of the ID Order and cGMP will apply.
7 (2) & (3) Flexibility for changes in technology or practice Replacing the word "must" with "should" provides a good practice standard without imposing unreasonable restrictions on practice - as long as validity testing showed the practice to be acceptable Noted with changes. Order modified to increase timeframe for collection.
7 (2) Requirements restrictive - Viability could still be demonstrated if the time was exceeded. ... Any time limits placed on retrieval in these instances are internal benchmarks used by the Eye Bank to improve efficiency e.g. to go beyond 24 hours means that the discard rate of corneas (once viability tested) will be higher than those under 24 hours. In Europe where normothermic storage of corneas is widespread it is not unusual for Eye Banks to accept eye donation beyond 48 hours and even out to 72 hours. Indeed, in some countries it is unusual for eye donation to occur inside of 24 hours1.
7 (3) A change is necessary to ensure that the application of future technologies is not prevented.

The draft TGO states: "Ocular tissue must be stored as follows:........(a), (b), (c)..."

This section, like (2) above, relates to maintaining the viability of the cornea during storage for a particular transplant purpose and using a particular storage technique.

...other temperatures and time frames are already suitable for Optisol storage (for example) – the manufacturers have published data to show that 48 hours at room temperature provides good storage. Cycles of cooling and warming a hypothermically stored cornea to enable specular microscopy viewing of the endothelium has also been shown to have no adverse affects on the cornea and could be considered an important element in determining the likely efficacy of the cornea for transplantation.

Noted with change. 7 (3) (e) modified to permit justification of alternative conditions for storage of any type of ocular tissue with validation.
7 (6) Clarification –transport or storage medium.

Subsection 7 (5) refers to transport medium not storage medium.

Evidence of any microbial contamination after testing of the storage medium under subsection 7(5) must result in discard of tissue that has not been released for supply to a recipient.

Noted with change. Requirements rephrased and formatted for clarity.
7 (9) Terminal sterilisation This section does not apply to ocular tissue and could be removed. It implies that corneas can remain viable if sterilised. They cannot. Noted without change. Scope of Ocular Order is beyond corneas. Retained for consistency.
8 (1) External reference documents There needs to be a mechanism (policy) on how the most up-to-date and relevant documents can be readily incorporated as required. This is necessary to ensure that the TGA standards do not lag behind changes in practice, many of which may be changes to address risk reduction as new risks are identified or emerge.

Noted without change. It is necessary to specify a version of the mandated document. The Order will be updated after consultation when the referenced standard is updated.

Discussed in liaison meeting with EBAANZ. EBAANZ agreed to inform TGA early in the review stage of the Order.

Summary of stakeholder comments: Standards for skin

Ref Issue Stakeholder comments TGA Comment
4 (2) specified microorganism definition How and by whom will 'Specified' be determined? Will this follow the British or European pharmacopeia lists of organisms? Or will it be at the manufacturer's discretion? As part of product dossiers, manufacturers will be required to submit a list of specified microorganisms of clinical significance, which, if tested and found to be present, will require rejection and discard of the tissue. The list and list justifications will be determined by experts within the TGA.
4 (2) minimal manipulation (f)any similar thing to a thing mentioned in paragraph (a),(b),(c),(d) or (e) Suggested to include tissues processed in high concentration of glycerol (i.e. >75%) –

Noted. Definition of minimal manipulation updated following Regulations consultation.

Preservation using high concentration glycerol is consistent with the revised definition of minimal manipulation (see (g)) in the Regulations. Definition of minimal manipulation updated in all orders/glossary.

6 (1) Suggest include 'skin grafts for autologous use used in the same surgical procedure' It is commonplace for split thickness skin to be taken from e.g. the patient's thigh to be used on the patient's burnt hand in a single procedure (i.e. not stored). These should be exempt. These products will be excluded by other regulatory mechanisms.
6 (1)(c) Human skin processed beyond minimal manipulation should not be exempt Why include this as exemption as must comply with Order + additional dossier? Class 3 and 4 products that are exempt from compliance with the Order will still be required to comply with other regulatory requirements (cGMP and ID Order), and may choose to comply with the MS Order if appropriate. The dossier will include the starting material specifications for TGA evaluation
7 (2) and
7 (10) (b)
Clarify time frames and the intent of the clauses.

It is stated in 7 (2) Collected skin must be maintained at 2°C to 8°C during storage or transport for a period of no more than 72 hours prior to processing or banking."

Also in 7 (10) "Storage conditions for each type of skin must be established. Conditions for storage of skin must be (b) 2°C to 8°C for no more than 14 days "

Storage is defined as maintaining a substance, material or product under appropriate controlled conditions"

7 (2) implies transport and storage before processing or banking and (10) (2) appears to refer to a period after the tissue has been banked? Can the tissue therefore be transported and stored for 72 hours, then stored for a further 14 days?

Agreed with changes. Transport conditions prior to processing have been removed as these are now consistent with ID Order (72 hours, <10°C), and storage conditions rephrased to clarify.
7 (2) (a) Maintaining tissue at or below 8° C prior to and during shipment. We currently require tissue to be shipped at 10° C or below in accordance with the State of New York regulation (section 52-5.5(c)) and AATB standards (12th Edition, section D5.800). Tissue shipped at 10°C or below prior to and during shipment is safe; tissue does not need to be maintained at or below 8°C prior to and during shipment. Agreed. Refer to ID Order. Requirement now below 10°C.
7 (5) Specified microorganisms Who will determine what organisms will be included on the list is and what will it be based on, British/ European pharmacopeia. How specific and all inclusive will it be? As part of product dossiers, manufacturers will be required to submit a list of specified microorganisms of clinical significance, which, if tested and found to be present, will require rejection and discard of the tissue. The list and list justifications will be determined by experts within the TGA.
7 (7) Validation of bioburden test to include neutralisation of the antimicrobial agents present in the sample.

"...neutralisation of the antimicrobial agents." This is difficult to achieve as there is no agreed pathway of neutralisation.

Validation of bioburden test: It is not possible to recover Antimicrobial sensitive organisms that have been killed or inactivated by antimicrobials, even after the antibiotic has been neutralised. Organisms do not recover and do not grow once they are already dead The only way to recover antibiotic sensitive organisms from tissue is not to use the antibiotic. This would significantly compromise the product and is NOT the best practice when patient care and safety is a top priority.

Noted with change. Validated bioburden techniques will not necessitate further bioburden sampling. Requirement reworded to clarify.
7 (10) Requirement to establish storage conditions of processed tissue

Again, as with the musculoskeletal TGO, given the storage conditions stated are a "must be", there is no reason why the conditions "must be established".

Suggest deleting the first sentence, with 7 (10) to read: Conditions for storage of processed skin must be....

Agreed with changes.
7 (10)(a) Storage temperatures Consider review. Usually (international practice) temperature is below ‑100°C to secure 5 years and/or ‑80°Cto‑100°C for 06 months Noted without change. Requirement consistent with AATB skin storage conditions. More stringent conditions may be applied by the manufacturer.
7 (10) (d) Storage temperatures must be maintained during transport. Some tissues processed by [us] are stored at room temperature (e.g., following lyophilization). Tissues labelled for storage at ambient temperatures may experience higher or lower temperatures during transport. [Our] experience is that tissues stored at room temperature are not harmed by the temporary increases or decreases associated with transport. Requirements of (c) allow for manufacturer to validate alternative practices and provide evidence in product dossier.

Summary of stakeholder comments: General requirements for the labelling of biologicals

Ref Issue Stakeholder comments TGA comment
4 (2) sponsor name and address Option to provide company website in lieu of PI. We wish to raise the option of providing reference to a company website for access to product information (PI, CMI) Noted without change. Definition consistent with TGO 69. Sponsor may include additional website information however the specified information must be supplied with the product, on the label or where permitted on accompanying documentation.
4(2) definitions Distributor information rather than sponsor. In situations where the product is not marketed by the sponsor but is distributed by a third party, there should still be the option to include the distributor details on the labelling instead of the sponsor details Noted without change. The sponsor is responsible for the supply of the approved product in Australia and must appear on the label. The sponsor may opt to include distributor information in addition.
4 (2) Definition of container as 'immediately covering the goods' Immediately covering suggests the container that is in immediate contact with the tissue (according to the TG Act definition). Tissues are usually double (or triple) 'wrapped' with the label (not sterile) on the outer wrap. In inner most wrap cannot be easily labelled as the label would need to be sterile. It is presumed (although not clear) that the 'immediately covering' could be interpreted as the 2nd or 3rd level of sealed 'wrapping'. An exclusive (from Act) definition may be required. Provisions as per new 6(5) permit labelling on second-layer if required.
6 (2) Clarify - do requirements apply to sample vials? Do the requirements stated in 6. (2) apply to labels used on any sample collected for a product or just for the containers used for collection and/or release of the product Label requirements are only applicable to the biological (starting or finished product). Samples not intended for therapeutic use are not within the scope of the Labelling Order.
6 (2) (c) However, this letter height cannot be accommodated on cryovials used for product aliquots collected and stored for internal testing purposes. The intention is to label these vials with a 2D bar code containing the required product information.
6 (2) (c) Restricting letter height to > 1.5mm - conflicting views.

Requiring the letter height to be >1.5mm is not an issue for product containers and primary pack labels used at collection and/or release.

Hospital labels which are often used on collection containers are not standardised and not all the information provided on these labels meets the letter height requirement (i.e. >1.5mm).

Noted without change. The 1.5mm requirement applies to the particulars required by the Order. Hospital labels typically inform of donor details, which will be required to be >1.5mm. Exemptions may be granted through application to TGA.
6 (2) (c) [page 4] General requirements for label letter height of not less than 1.5 mm
  • Please confirm that abbreviated labelling for small containers are still applicable per TGO 69
  • We wish to raise for consideration, the need for labelling exemptions to allow use of letter height < 1.5 mm in certain circumstances where the container is small and cannot accommodate all of the required labelling text at 1.5 mm (even if using abbreviated text on the label)
Noted without change. The requirements allow for small labels by permitting substantial information to be in accompanying documentation if required. Exemptions may be granted through application.
6 (3) [label requirements should only apply to outer container]

Re-write paragraph as follows:

"When using multiple container collection systems the following information must be included on the outer container containing the blood, cells and tissue:..."

Noted as above. Consideration to review how to best apply the label at collection.
6 (3) General requirements In general, Hospital labels are used on collection containers. These labels provide at least two identifiers including a unique identification number linked to the donor, but do not contain the information listed in b-e. These details are provided with the product as accompanying documentation. Agreed with change. Provided the unique identifiers is non-repeatable and linked to the other required information that will accompany the product after collection, and is traceable to the product from collection and all stages of manufacture.

6 (3) (c)

6 (4)

Recording time and date of tissue collection on the container.

1. In relation to musculoskeletal tissue collection – deceased donor:
The time of musculoskeletal tissue collection would be an estimate given that the procedure can span a number of hours, therefore this is not meaningful information nor critical. This information is recorded on the documentation.

2. In relation to musculoskeletal tissue collection – living donor:
Femoral head collection kits are manufactured by a third party as a sterile item and there is no provision to determine the date and time of tissue collection at the time of kit manufacture. This information is recorded on the accompanying documentation, which is linked by a unique identification number to the tissue.
In general, Hospital labels are used on collection containers. These labels provide at least two identifiers including a unique identification number linked to the donor, but do not contain the information listed in b-e. These details are provided with the product as accompanying documentation. Whilst having to write femoral head on a jar containing a femoral head is a case of stating the obvious we can instruct these jars to be labelled femoral head by the third party manufacturer. The jar will then have two labels.

Noted without change. Guideline to specify that completion of collection is the time.
6 (3) (c)
and (d)
Collection time and facility on label vs accompanying

Requires the date and time of collection to be recorded on the container. For blood components, the collection date is recorded on the container but not the time. This information is contained in a linked donor record.

Similarly the standard requires that the collection facility is recorded on the container. It is not feasible to individually record the facility name on the blood component.

It has been a long standing agreement with TGA that the name of the individual collection facility is not required on the component label, but that this information must be recorded and be completely traceable..

It is suggested that there should be scope within the labelling standards to permit the collection (and manufacturing facility information where appropriate) to be either recorded on the label or captured in records linked uniquely to the individual component, in such a way as to enable complete traceability

Noted without change. Guideline to specify that completion of collection is the time
6(4) Sponsor name and address".

Is it really necessary to have the full address on the primary container if it is on accompanying information? What is the need for this? Suggest leaving name but remove address from primary container label, but having both these items on the accompanying information.

Suggest requiring instructions for thawing and instructions for return only must be on accompanying documentation.

Noted. Agreed. Name/ address divided

Paragraph (6) specifies that (e) to (r), which includes thawing instructions, are not required to be on the container if there is insufficient space.

6 (5) Requirement (a) & (d) combined in automated labelling system. 1. Some validated labelling systems (e.g. Stemsoft) identify a product/donor by a unique identification number (5a), which incorporates the sponsor name and address (5d). The product type/name (5c) is also included, whereas the batch number (5b) is not applicable. The remaining information (5 (e)-(r)) will be included on the documentation accompanying the released product. Will this labelling system be acceptable? For clarification: Yes. Provided all information is maintained and fully traceable, the described label would meet the requirements.
6 (5) AUST R number There is no mention in the document regarding the inclusion of the AUST R number on the label – please clarify The inclusion of an ARTG number will not be required for biologicals, as the supply and use of biologicals is predominantly within healthcare settings and limited batch sizes enable greater traceability than for other consumer goods.
6 (5) (g) storage conditions Please add option of including other storage conditions e.g. excursion / home use situations, and storage after product reconstitution (if applicable) Noted without change. The requirements do not preclude additional information being included on the packaging or documentation.
6 (5) (d) Information on the label on the container and primary pack

2. As container is the cover that immediately covers the goods, this requirement will have a significant negative impact for unprocessed products. E.g. the packaging supplied to hospitals for FH collection is obtained sterile (ARTG listed) from a third party, having the third party put these details onto the container (a plastic bag or jar) is not practical (e.g. donor I.D. is unknown). This requirement would prohibit the provision of non-irradiated and whole FHs and put an end to the non-processing FH collection banks.

For MS tissues that are wrapped in a number of sterile layers (to facilitate unwrapping and handing across the sterile field in theatre) the relevance and wisdom of putting a label on the final sterile layer was questioned. Suggest labelling be restricted to the wrap covering the sterile layers

Provisions as per new 6(5) permit labelling on second-layer if required.
6 (5) (c)(d) Address and product type on accompanying documentation

With a small container (e.g. 1 mL syringe) there is limited space, unless the label is folded back on itself. Folding the label makes it more difficult to read and can reduce the contact area with the container, resulting in a less securely attached label.

It would be preferable if (c) and (d) are also included in the exclusions listed in 6 (6).

Noted with change. Order has been amended to allow sponsor address (formerly d) to be moved to information if required. Subsection 6 (7) allows for most other information to be provided in accompanying documentation.
The need to allow for an absolute minimum for product identification on the container and primary pack label is paramount when one considers export requirements when multiple languages may also have to be allowed for on the primary and secondary labels. Noted without change. Products for export, which are not supplied in Australia, will not be required to meet Australian labelling requirements. The label presentation should be acceptable to TGA. To clarify in Guidelines.
Primary pack versus container The requirement as written does not distinguish between primary pack and container. Splitting these requirements would permit different minimum requirements for each type of label. Noted without change. Both container and primary pack must be labelled unless inner container is required to be sterile.

Summary of stakeholder comments: Standards for infectious disease minimisation

Ref Issue Stakeholder comments TGA comment
3 Typo? Should be plural Instead of "...therapy product." Should be "...therapy products." Noted without change – sentence is singular ("a particular... product").
4 (2) Definition of risk of Prion disease There is still inconsistency with the definition of 'UK' against EU recommendations for residency.

Noted without change.

Consistent with current TGO wording (TGO 81)

EU definition of UK is England, Northern Ireland, Scotland and Wales. The Isle of Man is not considered as part of the UK or EU.

Countries listed do not include all BSE countries. Countries listed are not all countries with BSE risk.
4 (2) prion disease, risk of

(1) The definition of environmental and iatrogenic risks in the TGO only addresses exposure to the putative causative agent(s) of variant CJD, and not any other form of prion disease. This needs to be addressed so that appropriate risk factors are included and non-significant risk factors are excluded. Thus,

1.1) the exclusions as listed in the TGO for ocular tissue to address vCJD are not warranted on the basis of a risk versus benefit analysis and should be removed as ocular tissue donor criteria. See Hogan et.al.1, Hirst et al.2 and Chu3.

1.2) Risk factors for other forms of prion disease which have a higher risk profile should be included as they currently are in the professional standards. See Hogan et.al.1 and EBAANZ Medical Standards4.

For TGC Subcommittee Consideration

Cornea is classified as Category B tissue (lower infectivity tissues) similar to liver, kidneys and heart.

Consideration to be given whether the degree of donor deferral (potentially 19%) is appropriate given the risk of transmission.

4 (2) Definition: Prion disease, risk of

The wording for risk of iatrogenic transmissible spongiform encephalopathies differs slightly from the current wording in Therapeutic Goods Order 81 (TGO81), which refers to "blood and blood products"[vs] "blood and blood components", which according to the definition on page 3 would exclude fractionated products.

It is the view of the Blood Service... that fractionated product should be included in the iatrogenic risk statement, as per TGO81, but that this restriction should be limited to processed plasma products provided prior to 31 December 2001.

For TGC Subcommittee consideration

Interpretation of TGO 81 to be reviewed.

Microbial definition, Page 4 Inclusion of mycoplasma and Rickettsia in the definition of "microbial"

It is unclear why these organisms are specifically identified in the "microbial" definition? The current validated and approved test methods (e.g. BactAlert/BacTec) used to identify bioburden or microbial contamination do not detect either of these organisms. In addition, there is only one laboratory in Australia licensed to test for mycoplasma and I am not aware of any testing laboratories whose licensed test methods detect Rickettsia. Therefore, criteria for acceptance and release of products cannot be based on microbial specifications if the definition of "microbial" includes mycoplasma and Rickettsia.

Suggest that this is qualified and covers known pathogenic microorganisms that affect donations encountered within the limits of the standard detection methods for bioburden testing. Can the term specified microorganism of clinical significance be used?

Noted without change.

As part of product dossiers, manufacturers will be required to submit a list of specified microorganisms of clinical significance, which, if tested and found to be present, will require rejection of the tissue from therapeutic use. The list and list justifications will be reviewed by experts within the TGA.

Guidelines to provide further clarification

4 (2) blood products and blood components Definition of "Blood Products" (referred to in Table 1) [Blood product definition] should be included, specifically to distinguish the difference between "Blood", "Blood Components" and "Blood Products". The definition of "blood component" includes "plasma for fractionation" and could theoretically include plasma derivatives, however the reference to "blood products" in Table 1 confuses the definition. The best solution is to include "blood product" as a specific term for plasma derivatives.

Noted with change

Definition of blood products reviewed. WHO definition: "Any therapeutic substance derived from human blood, including whole blood, blood components and plasma derived (medicinal) products"

Order updated to remove 'blood products' from deferral criteria in table 1.Consistent with EC Directive and consistent with TGA approach (it is not intended to defer recipients of plasma derived products)

4(2) and Part 3 8(1)(a) and Definition of 'Trained Interviewer'

We request that the definition of 'trained interviewer' be further clarified.

Is there any associated certification, qualification for this role? What kind of evidence is required to demonstrate that the interviewer is trained? Who is deemed adequately qualified to perform this training?

Noted without change. Following 2009 consultation, 'trained' replaced 'qualified' – amended to allow manufacturer to determine suitable qualifications and method of training.
5 (1) "Allogeneic use"

This implies intended for transfusion i.e. removed from one person and applied to another person?

Suggest change to:

  1. a deceased human donor and intended for allogeneic use; or
  2. a living human donor and intended for further manufacture.

Noted without change.

Subsequent to "further manufacture", product is still for allogeneic use....

5 (1) Exemptions for medical practitioners not clear in ID Order.

Suggested addition and reason(s):

The intent of the Biologicals Framework is that "that registered medical practitioners will be exempted where they take a biological from their patient and return the biological unmodified to the same patient during the same clinical procedure". Presently this intent is not clear in the wording of "5. Application of this order" or in "section 6. Exemptions".

Although one could interpret that "6. Exemptions" are intended to include a medical practitioner single surgical procedure it is still not clear and should be directly stated.

"Registered medical practitioners will be exempted where they take a biological from their patient and return the biological unmodified to the same patient during the same clinical procedure", should be stated under in this, and other applicable TGOs.

Noted without change.

Exemptions regarding medical practice will be included in another applicable TGO/ legislation which will take precedence over Section 10 Orders.

6 (3)(b) Exemptions - clarify

1. Clarification sought. Does this mean that all blood, blood components and HPC manufactured within hospitals are exempt from this order?

2. Autologous Skull Flaps are not identified as exempt. Our understanding is that this will be in the Excluded Goods Order.

1. Correct – provided criteria are met.

2. Correct. The ID Order (or any Section 10 Order) will not specify goods that are covered by the Excluded Goods Order.

6 (3)(b) Exemptions for HPC

We support the exemption applied to donors of haematopoietic progenitor cells (HPC) from complying with this draft Therapeutic Goods Order.

[seek clarification of scenarios where unrelated allogeneic, related allo from separate facilities]

Noted. The HPC scenarios provided exhibit sufficient clinical oversight to be in compliance with the exemption under (b). Collection of HPC from external facility is prescribed by the treating physician (including prescription for cell count based on recipient weight/ clinical indication).
6 (3)(b) and (c) add "applicable for autologous use only" There is room for interpretation that unregulated banking for allo-donation can take place. Noted without change. The exemptions specified are only applicable to ID Order . Other regulatory requirements, including product specific standards and Code of GMP will still apply. The exemption is intended to apply to products with a high degree of clinical oversight, whether autologous or allogeneic.
6 (4) "a product in relation to which an exemption from compliance with this Order has been granted by the Secretary in accordance with section 14 and 14A of the Act" The Process for applying for a S14 exemption needs further explanation and definition for Plasma Master Files, particularly for 'export only' products. Noted without change.
8 (1)(a) remove to 'face-to-face' interview requirement. There are circumstances where a telephone interview is appropriate e.g. the donor guardian and/or next of kin representing the donor due to age or consciousness will not be available for face-to-face interview within timeframes for donation e.g. NOK abroad. More specific follow up issues on the medical history may also be followed up with the donor by the tissue bank by telephone after donation to clarify statements made prior to donation. Mandating face to face interview will preclude donation unnecessarily. A well performed phone interview is no greater risk than a well performed face to face interview.

Noted without change.

Face-to-face interview is not mandatory. Interview requirement has been revised to state 'should' be face-to-face, following 2009 consultation.

8. (1) (b) Interview timeframes – too stringent for MS tissue

1. What is the rational to limit the interview to 7 days prior or 30 days post collection. The period of time stated in the TGO should represent the default time period if the manufacturer did not wish to assess the risk.

2. 'The interview must occur no more than 7 days prior to or 30 days after collection......'

The Musculoskeletal Tissue specific TGO could identify the expanded 30 day prior to and 30 days after collection timeframe for these donors for the donor interview. Quite often, potential donors are interviewed at pre-admission clinics which are undertaken 2-3 weeks pre surgery (donation). If surgery is postponed, a repeat interview is likely to be required with little or no benefit to reducing the risk of capturing additional exclusion information.

For TGC Subcommittee Consideration: Item 3.2.

Interview timeframe harmonised with international standards and was endorsed by TGC Subcommittee. It is recognised that 30 days as a minimum requirement may be suitable for reasons of logistical (e.g. pre-operative interview) or clinical reasons (e.g. patient myeloablative conditioning).

(c) Aligns with EC directive for blood donors (permanently ineligible)

(d) Aligns with EC directive for blood donors (permanently ineligible)

(e) Aligns with EC directive for blood donors (permanently ineligible)

(g) Aligns with EC directive for blood donors (permanently ineligible). This is also a permanent deferral in the USA

(AABB Medication Deferral List (pdf,102kb))

(m) Aligns with EC directive for blood donors (permanently ineligible)

8 (1) b) The interview timeframe does not allow time to find an alternative [HPC] donor

This is important as the recipient would have usually commenced conditioning prior to this timeframe and must proceed with an infusion.

We request that that the donor interview occur within 30 days prior of collection

This paragraph clearly relates to cord blood NOT donors but clarification is needed.

[The difference between interview and testing timeframes] contrasts both currently applicable standards

... We propose that this TGO be harmonised with the FACT International standards.* [30 days prior for both]

Interview timeframe Internationally inconsistent. There is no time limit in the USA for when this interview can occur. A 7-day time limit presents an unreasonable and unnecessary burden.
Interview timeframes to wide The Blood Service does not believe it is appropriate to interview prospective blood donors 7 days prior to, or 30 days post collection, as risk may have been incurred in the intervening period.

Noted without change. The ID Order contains the minimum requirements for all human blood and blood components, human tissues and human cellular therapy products. A manufacturer may choose to impose more stringent requirements if deemed appropriate and/or informed by risk assessment of individual products.

It is intended that the standard for blood and blood components/ products will remain tighter than the ID Order. Consider including restricted timeframe in future revision of TGO 81 (if CoE insufficient as above).

8 (1) and
8 (2)
Clarify donor status for timeframes. Sub-titles are required for each of the two sections for clarity – (1) referring to living donors and (2) referring to deceased donors. This is required for reasons of clarity. Requirements currently include sufficient detail of donor status. Living/ deceased is explicitly stated.
8 (2)

"and/or examination of the medical documentation..."

Emphasis importance of interview.

Place time restriction on review of medical documentation

Does this mean that an examination of the medical documentation alone is sufficient even if an interview is possible?

Suggested rewording:

An interview with the next-of-kin/guardian or other knowledgeable historian of a deceased donor and examination of the [pertinent, available] medical documentation to obtain and record the medical and social history of the donor must take place and be recorded at the time of, or no more than 7 days prior to or following collection. If an interview is not possible, examination of the medical documentation may be sufficient.

ADD to 8 2 (a): "examination of the medical documentation .... or no more than 7 days prior to collection. This must be completed before release of tissues from quarantine

Agreed. ID Order rephrased to emphasise importance of interview.

This statement was written to provide an option for donor acceptance in the event an interview with a next-of-kin or other knowledgeable historian was not available. It was not intended for examination of medical documentation to replace an interview if available.

8 (3) Requirement for Table 1 unclear

This is currently ambiguous. The intent is - that donor medical and social history needs to be evaluated, including those responses given at interview if appropriate – but this is not clear.

Medical and social history information for cadaveric donation will be derived from a number of sources that will vary for each individual case.

A simpler requirement would be to omit the words "and responses at interview" to "Donor medical and social history criteria as set out in column 1 of Table 1 must be reviewed and evaluated using these criteria"

Agreed with changes suggestion – to broaden in absence of interview but using medical documentation as per (2)
8 (3) Periods of ineligibility [Table 1] – autologous donor questions 'burdensome'

The periods of ineligibility specified in Table 1 apply only to allogeneic donors, but all questions must be asked for autologous donors as well, even though there are no periods of ineligibility.

This is a burdensome requirement for autologous donors, and, in settings where this is no doubt that the intended procedure would go ahead, raises questions of compliance with patient privacy requirements. It would be hard to justify this approach for an autologous product that is manufactured in isolation and released fresh (without storage).In the autologous setting, a risk-based approach would allow a subset of these questions to be asked.

For TGC Subcommittee consideration Item 3.3

oted. The information specified informs a risk-based approach to collecting, processing or storing autologous as well as allogeneic products. TGC to consider options for autologous donor interview criteria.

8 (4) Typo "...prior to donation are as set out in..." Agreed with change.
8 (4) Table 1 Table 1 sections (d) to (s). This list is overly restrictive for islet allotransplantation.

Given that the donor pool is already small, adherence to this protocol which is based on blood donation will eliminate highly desirable donors without any real reduction in risk.

Donor pancreases for islet transplantation should adhere to the same criteria as whole organ donors. Given that these donors have been in ICU it is often not possible to wait until they are infection free.

Most will have had a blood transfusion during ICU and many have lived in the UK or a Malaria prone area. Experience with organ donors has shown that the risk to the recipient of disease transmission is minimal in these circumstances. Even when including recent tattoos and past drug behaviour. Especially when compared to the substantial risks involved with immunosuppression and the transplant procedure itself.

We propose the donor pancreases for islet transplantation conform to the same infectious disease standards as other solid organs.

Noted without change.

Degree of processing with islets precludes similar regulation as whole organs. Allogeneic islet transplantation is considered as a procedure which enhances the quality of life of the recipient. Current TSANZ criteria specifies: "where transplantation is not life saving but aims to improve the quality of the recipient's life, a greater margin of safety is appropriate"

"Background medical history" states that specific attention be paid to "intravenous drug abuse, tattoos and body piercing" etc for organ donors.

Exemptions from particular requirements within the ID Order will be considered on application to the TGA. Written justification for an exemption must be supplied with the application.

8 (4) Table 1 Donor deferral as applicable to Cadaveric eye donation

The time periods of ineligibility listed within the Table are inconsistent and seem not to relate to risk assessment, virology testing window periods, current industry standards or harmonisation with international standards.

... there are requirements where the authors have confused those questions asked during the medical and lifestyle interview with exclusion criteria. The question asked initially at interview is often a broad question that is then used to elicit further information upon which a decision can be made i.e. the interview question itself is not an exclusion criteria (e.g. the interview question ever used I.V. drugs being applied to mean a permanent ineligibility to donate).

Noted with change.

Additional requirement inserted to exempt ocular tissue from specific malarial deferral criteria.

Ineligibility periods are informed by EC directives and other industry standards.

International (US) standards for eye banking do include deferrals from donor ineligibility.

8(4) Table 1 Periods of ineligibility prior to donation do not agree with USA

(c) In the USA it is not possible to accept a donor known to be infected with HBV, even if they are HBsAg negative persons who are demonstrated to be immune. We recommend you remove this exception.

(d) In the USA, a donor is ineligible if they have injected any drug for a nonmedical reason in the past 5 years. Because of the incubation period associated with diseases transmitted by drug injection, it is not necessary to make donors ineligible if they have done so more than 5 years ago.

(e) In the USA, a donor is ineligible if they are a recipient of human derived clotting factors within the past 5 years. Because of the incubation period associated with diseases transmitted by human derived clotting factors, it is not necessary to make donors ineligible if they received them more than 5 years ago.

(g) This is no longer a deferral in the USA. It has been determined there is no risk associated with receiving human pituitary derived growth hormone.

(m) AATB states persons who are known to have malaria or to be at risk for malaria & FDA does not address malaria

As per 8(1)(b) Above – For TGC Subcommittee Consideration – Item 3.3

(c) Aligns with EC directive for blood donors (permanently ineligible)

(d) Aligns with EC directive for blood donors (permanently ineligible)

(e) Aligns with EC directive for blood donors (permanently ineligible)

(g) Aligns with EC directive for blood donors (permanently ineligible). This is also a permanent deferral in the USA (AABB Medication Deferral List)

(m) Aligns with EC directive for blood donors (permanently ineligible)

Table 1 (a) Table 1 - autologous blood products.

The period of ineligibility prior to donation outlined in Table 1 does not apply to autologous donors.

The Blood Service has commented previously that acceptance of autologous blood donors without the donor ineligibility periods that apply to homologous blood donors could potentially introduce risk to the Blood Service where both autologous and homologous donations are collected and processed.

The inclusion of the requirements for adequate segregation of autologous units is however noted as a positive improvement to the document.

The current Blood Service eligibility criteria for autologous donations are more stringent than those proposed in the new standard.

Impact :

  • If autologous donors are permitted to donate without the donor eligibility periods applicable for homologous donors, there will be increased risk to staff required to handle these positive or potentially positive units.
  • Impact on improving the quarantine and storage facilities for such units (if collected).
  • Increased risk to the blood supply by having positive units released for autologous transfusion – potential for mix ups during shipment, or at hospitals.
  • Potential risk of autologous donor backlash if deferred on basis of more stringent Blood Service criteria.

Noted without change.

The TGA support the need for more stringent criteria for autologous blood donors. However, the ID Order contains the minimum standards. A manufacturer may decide that increased risks associated with specific types of product may warrant additional criteria or processes to be established.

Table 1 (d) Permanent ineligibility if non-prescription drug injection It appears that the Draft has confused the interview question with the period of ineligibility. The question is whether a person has ever used drugs, and a "yes" is then questioned further to determine when, where, how and the likelihood of drug use still occurring. For example, a single use 30 years ago should not make the donor ineligible but a long history of drug use may be considered for ineligibility.

For TGC Subcommittee consideration – Item 3.3: Deferral timeframes

See 8(4) above

Note:

Aligned with EC directive for blood (permanent deferral)

EC directive for tissues makes no mention.

TSANZ says (Background medical history, p25):

"The donor's medical history must be known and recorded in the hospital records. Specific attention must be paid to... intravenous drug abuse..."

pp 24-25 section D of AATB states "Prior to the Recovery of tissue from a potential deceased donor, a Physical Assessment shall be performed...If any of the following signs are observed ... then the tissue shall be rejected: ...Physical evidence of non-medical percutaneous drug use such as needle tracks (and/or non-medical injection sites), including examination of tattoos [which may be covering needle tracks]"

EBAA (November 2003 Revision) D1.120 A. 24. a.: "Persons who have injected drugs for a nonmedical reason in the preceding 5 years including intravenous, intramuscular, or subcutaneous injection of drugs." (this in turn references FDA guidance from 1997...)

table 1 (d)

The proposed permanent ineligibility if the donor discloses any episodes of injecting non-prescription drugs may exclude the only suitably matched HPC donor for patients with life-threatening diseases.

Since comprehensive infectious disease testing is performed in all donors, we propose that an appropriate and safe approach would be to render such donors ineligible if evidence of risk behaviour within the past 12 months.

Table 1 (d) Injection of drug for nonmedical reasons

Request revision of the wording as it is currently restricted only to injection of drugs by the donor, and would not identify a donor who had been injected by another individual.

The following wording (from the current approved Donor Declaration applicable to all blood donors) is suggested: Ever "used drugs" by injection or been injected, even once, with drugs not prescribed by a doctor or dentist"

Agreed with changes.

Modified wording to include injection by another person

Table 1 (e) Recipient of human derived clotting factors/ viable animal tissues

Without this change a recipient of an animal cell or tissue (e.g. a porcine heart valve) which had been provided in accordance with this order, would be permanently ineligible to donate.

If provided in accordance with this order the risk is no greater than that of a recipient of human derived clotting factors.

The criteria should be re-worded to: If not in accordance with this Order, recipient of (i) human derived clotting factors (ii) viable animal cells or tissues

The ineligibility should be 12 months.

Noted without change.

This criteria applies to viable animal cells and tissue only.

Porcine heart valve is a non viable animal product.

Table 1 (e)

Recipients of human derived clotting factors that are not in accordance with the Order are permanently ineligible. Recipients of clotting factors that conform to the requirements would therefore be considered eligible.

Impact :

Difficulty in distinguishing the difference between eligible and ineligible products (would be date dependent and would be reliant upon donor memory). Potential for confusion in donor assessment.

Noted with changes.

ID Order updated with changes to (e) and (i).

Clotting factors removed from (e) and relocated to (i) with deferral period consistent for blood and blood components (6 months). Consistent with current Australian practice.

Clotting factors are not subjected to the same degree of pathogen inactivation as other blood products, and as such a deferral period is warranted for clotting factors.

Transition arrangements to be clarified, as TGC Subcommittee item 3.1. and within Guidelines.

Table 1 (e) Permanent ineligibility if given human Derived clotting factors The proposed permanent ineligibility for donors treated with given human derived clotting factors may exclude the only suitably matched HPC donor for patients with life threatening diseases. Although the requirement specifies clotting factors not in accordance with the Order, no explanation of this could be located within the document. A rational approach would be to accept if no risks in past 12 months and NAT not indicative of HIV, HCV or HBV.
Table 1 (f) and (g) Permanent ineligibility if prion disease risk or if given human pituitary derived growth hormone

The proposed permanent ineligibility for prion disease risk and recipients of human pituitary derived growth hormone may exclude the only suitably matched HPC donor for patients with life-threatening diseases. This requirement would exclude many (possibly the majority) of donors on marrow donor registries in the UK, and is likely to significantly impact many donors on European as well as Australian registries.

Although there is no current testing for prions available, we propose that the risk be disclosed to the Transplant Physician & consent obtained from the patient for use of such a donor, since the benefit of HPC transplant generally far exceeds the risk of prion disease.

An HPC donor for direct donor to host transplantation would be excluded from the operation of this Order (medical practice)
Table 1 (g) Recipient of human pituitary derived growth hormone The permanent ineligibility status for recipients of human pituitary derived growth hormone should be limited to receipt of the hormone prior to 1986 (as practices changed post this date to mitigate the risk)

Noted without change.

It is appreciated that Human derived pituitary hormone has not been used since 1986, and synthetically derived product is now used. 'Human pituitary derived' provides sufficient distinction (receipt of synthetic hormone is subject to deferral)

Table 1 (h) Remove 'deceased' The requirements should be the same for both living and deceased donors

Noted without change.

Requirement for living donors is covered in (i).

Table 1 (h) & (i) The ineligibility for allogeneic organs deceased and living, should align There is no reason for a discrepancy between a deceased donor and a living donor. Death per se does not increase the risk for transmission of disease (especially for eye donation).

Agreed with change.

Add exclusion period to specify 'before asystole'

In addition, 12month lead time is retained (rather than 6 months as per (h)) to allow margin for deceased donors.

Table 1 (h) & (i) Donors who have received blood, cells or tissue 1. A deceased donor who has been a recipient of allogeneic organ(s), cells, or tissues and a recipient (presumed although not stated to be a living person) of allogeneic blood, blood components or blood products, organs, cells or tissues that are not in accordance with the requirements of this Order are ineligible permanently or for 12 months. This is interpreted to mean that recipients are accepted only if tissues received are banked after the date that the Order comes into effect. Could the TGA please clarify if this is the correct interpretation – i.e. if a person is a recipient of tissue from a TGA licensed tissue bank prior to the date this Order comes into effect, would this render the person ineligible?

For TGC Subcommittee consideration – Transition Item 3.1

Including: products collected prior to the implementation of this Order.

'Blood products' has been removed to be consistent with current international approach, acknowledging the degree of pathogen inactivation applied to plasma-derived blood products (excepting clotting factors).

Table 1 (i) P7 Donor eligibility – outside Australia

'.......... recipient of allogeneic organ(s) cells or tissue that are not in accordance with the requirements of this order': Does this mean recipients of these graft items outside of Australia are ineligible as donors?

'.......... recipient of allogeneic blood, blood components or blood products, organs, cells or tissues that are not in accordance with the requirements of this order': Can this be translated to if the recipient was a recipient of the listed items in Australia, there is no ineligibility as a donor?

Please clarify whether these donors are permanently ineligible, ineligible for 12 months unless (f) or (g) apply, or have no ineligibility as a donor?

Noted with changes.

Correct interpretation that recipients of products outside Australia are ineligible unless compliance with the requirements of the ID Order can be demonstrated.

Transition arrangements will apply to products collected prior to implementation of the ID Order –TGC Subcommittee Item 3.1 (Transition arrangements). Refer to Guidelines. Provided that the products are compliant with the requirements of this Order.

Deferral time amended to 6 months for living donors to align with CoE, and 12 months prior to asystole for deceased donors.

Table 1 (i) Period of ineligibility EU only requires 6 months deferral.
Table 1 (i) Recipient of allogeneic blood, blood components or blood products

Recipients of allogeneic blood, blood components or blood products that are not in accordance with the Order are ineligible for 12 months.

Issue 1:

Definition of "blood products" is required in this context of a 12 month ineligibility period because the assumption is that "blood products" are plasma derivatives (as blood and blood components are listed separately). However, recipients of blood products (e.g. clotting factor) would also be subject to category (e) of Table 1, which requires permanently ineligibility.

Issue 2:

Recipients of blood, blood components or blood products that conform to the requirements of the Order would therefore be considered eligible immediately. The Blood Service currently applies an ineligibility period to these donors

Noted with changes.

Issue 1: 'Clotting factors' has replaced 'blood products' in (i) to align deferral criteria and international practice.

Issue 2: More stringent criteria may be applicable for certain product types, and this can be applied by the manufacturer. The ID Order is a minimum standard.

T8(4) Table 1 (j) Donor sexual practices It is not necessarily the donor's sexual practices that are the issue but with whom he/she entertains the practice (i.e. MSM and prostitutes). Eliciting a donor's sexual practices may be inappropriate the way the criteria is worded e.g. a risk associated with MSM is anal intercourse, hence the requirement would suggest eliciting from a donor whether he/she entertained (amongst other more risky sexual practices) anal sex (either hetero or homosexual) – although it could be argued this is indeed a risk that should be excluded. It is however proposed this line of explicit questioning could be deemed by the donor population to be inappropriate.

Noted without change.

This is intentionally left broad.

Section 8,
Table 1 (k)
Criteria and period of ineligibility

The question of imprisonment is not required by EU regulations, and it is therefore not asked in EU blood centres. Only source plasma centres have adopted the question as part of the voluntary industry standards.

Currently none of [our] EU based blood centres include this question in their donor interview process.

Noted with change.

The requirements are aligned with current Australian practice, e.g. ARCBS GSBD and TSANZ, however this is not necessary for fractionated plasma products.

Exemption for plasma derivatives in 8 (5) to include (k)

Table 1 (l) This should be deleted or specifically not apply to eye donors. The interview question is designed to determine if there could be some more insidious and contra-indicated disease process occurring such as HIV infection. A positive answer to the question "did the donor have any unexplained fever or infectious illness?" is not an exclusion in itself.

Noted with change.

Amended to deferral for "unexplained" illnesses

Table 1 (m) A donor who has lived in a malarial area within the first five years of life

Donors who have lived in a malarial area within the first 5 years of life are ineligible for 3 years from last visit, or 4 months if malarial testing is negative. Plasma collected from such individuals should be considered suitable as plasma for fractionation, yet this requirement is not included in the exemptions for plasma for fractionation listed on Page 8 (5).

It is requested that section (m) is added to the list of exemptions recorded on page 8 in PART 3 – Specific requirements, 8. (5).

The stated ineligibility period for donors living in malarial areas is inconsistent with the malaria strategy previously agreed with TGA and inconsistent with the requirements contained in the currently mandated COE 14th edition.

The TGA and Blood Service made a joint submission to the Council of Europe to change the malaria deferral strategy several years ago. The submission was successful and the revised wording from that submission appears on page 68 of the 14th edition.

The revised strategy was subsequently implemented, on approval by TGA, into Blood Service practice.

This strategy requires that donors who have spent a cumulative period of 6 months in malaria endemic area(s) at any time during their life may be accepted as a blood donor if the result of a validated immunological test for antibodies to the malaria parasite, taken at least 4 months after the last visit to a malaria area is negative.

It is requested that the donor ineligibility statement be amended to reflect the above 6 month cumulative period at any time during the donor's life.

Noted with changes. For TGC Subcommittee consideration – Deferral Item 3.3

This currently Aligns with the EC directive (2004)...

CoE 14th ed states:

"Persons who have lived in a malaria area for a continuous period of 6 months or more at any time in life" Deferral given is "May be accepted as blood donor if the result of a validated immunological test for antibodies to the malaria parasite, taken at least 4 months after the last visit to a malaria area is negative

"If the test is positive the donor should be permanently deferred "If a test is not performed the donor should be permanently deferred

CoE 14th ed states

"Persons who give a history of malaria

"Should be deferred until asymptomatic and off treatment

"May be accepted as blood donor if the result of a validated immunological test for antibodies to the malaria parasite, taken at least 4 months since cessation of last treatment/last symptoms is negative

"If the test is positive the donor should be deferred and may be re-evaluated after 3 years

"If a test is not performed the donor should be permanently deferred"

Table 1 (o) Format: An asymptomatic visitor to endemic malarial areas. Suggest revision of wording to be consistent with the wording of (m) and (n), i.e. "Ineligible for 6 months after leaving the endemic area. This may be reduced to 4 months if an immunologic or molecular genomic test is negative at donation."

This currently Aligns with the EC directive (2004)...

CoE 14th ed states:

"All other persons who have visited a malaria endemic area

"May be accepted as blood donor if the result of a validated immunological test for antibodies to the malaria parasite, taken at least 4 months after the last visit to a malaria area is negative

"If the test is positive the donor should be deferred and may be re-evaluated after 3 years

"If a test is not performed, the donor may be re-accepted once a period of 12 months has elapsed after last return from a malaria area"

Agreed. Order updated to align with CoE

Table 1 (o) 6 month ineligibility is too restrictive This is too radical for living tissue donors. Consider: review of donor status 06 months post visit in terms of symptoms and/or possible release of irradiated tissues where the dose would kill the parasite. See comment above.
table 1 (m), (n), (o), (p) These should be deleted or specifically not apply to eye donors. Transmission of malaria by corneal transplantation is highly unlikely because of the vector of transmission (erythrocytes), and there is no evidence of this ever having occurred. While an eye donor is likely to be rejected if active infection with malaria was established, the requirement to screen for malaria based on risk factors of travel and time, without confirmation of actual infection, is not warranted on the basis of risk.

TGC Subcommittee to note – Item 3.2.

Agreed. New 8 (6) inserted to apply specific deferrals for ocular tissue.

EBAA standard does not contain these requirements. Insert paragraph excluding donors of cornea [or eye] from m,n,o and p (mirror PFF). Note cornea and sclera are both.

Table 1 (m), (n), (o), (p) Molecular genomic test for Malaria

Remove the reference to a "molecular genomic test" for malaria because a negative test result in a molecular genomic test would not necessarily accredit the donation due to the low likelihood that the test sample would contain actual malaria parasitic DNA .

Accreditation of the donor status via testing should be limited to Immunologic testing.

Agreed with change.

While this currently Aligns with the EC directive (2004), the CoE only states the immunological test be used.

Order amended to align with CoE (molecular test removed)

Table 1 (q) Ineligibility should be consistent. The increase in ineligibility would be consistent with risk of blood borne infections acquired by any other means. If ineligibility is for six months and 4 months for a NAT HCV result, the same criteria should be applied to all other ineligibility for risk of acquiring a blood borne transmissible infection.

Noted, with change.

This currently Aligns with the EC directive (2004)

Inconsistent with (i) which does not align with EC, but with current Australian Practice.

Order amended to harmonise deferrals for (i) and (q) with CoE (i.e. 6 months)

Table 1 (q) Does not acknowledge the 6 months retest period for a living donor.

1. "A donor with exposure to risk of acquiring a blood borne transmissible" is "ineligible for 6 months from the time of exposure, or for 4 months provided NAT test for HCV is negative"

As the period of ineligibility does not acknowledge the 6 months retest period for a living donor, can this be amended to "ineligible for 6 months from the time of exposure, to collecting blood for screening for HIV, HCV, HBV, or for 4 months provided NAT test for HCV is negative"?

2. States ineligible for 6 months from the time of exposure. If patient is a live donor, can this be the 6 months that the tissue is in quarantine prior to 180 day testing, as is the case often at present?

A period of 6 months is required from the time of exposure to collecting blood for screening for HIV, HCV, HBV, or for ......

For TGC Subcommittee consideration

Considered substantially. These exclusions do not intend to negatively impact on the number of potential donors.

While the concept for the purpose of product release is logical, there is a risk in allowing collection and banking of these products in quarantine pending 180 day result.

Managing inventory to segregate varying levels of risk is another potential risk.

The concept is inconsistent with the intention of table 1 and risk-based donor selection. These donors are not tested by NAT and as such window periods are greater.

For TGC Subcommittee consideration

Table 1 (q) A donor with exposure to risk of acquiring a blood borne transmissible infection Is electrolysis no longer considered a risk of acquiring a blood borne transmissible infection? Electrolysis not considered to be a risk of acquiring a blood borne transmissible infection
Table 1 (s) "Exposure to particular epidemiological situations" This requirement is far too generalist to be of any practical use. Who determines the epidemiological situation? Who decides if it is relevant to the tissue donation e.g. a flu outbreak for eye donation is irrelevant to the risk of donation for corneal transplantation.

The reference is intended to apply only to alert situations (e.g. Hep A). It will be the responsibility of the Banks to be aware of alert situations and to establish deferral parameters consistent with the situation and in consultation with the TGA .

To be clarified in Guidelines

"A donor with exposure to particular epidemiological situations"

This is very open ended to auditor interpretation can it be

1. Deleted, or

2. only apply where alerts have been issued for an epidemiological situation that is of concern.

Reword? "A donor with exposure to particular epidemiological situations (e.g. disease outbreaks) subject to formal alert."

8 (5) Suggest rephrase The testing and deferral period requirements of Table 1 (a)(iii), (b)(iii), [(i) (h)], (m), (n), (o), (p), (q) are not required to be met when the donation is to be used exclusively for plasma for fractionation. Agreed. Order changed to add (m) to list (see ARCBS comment)
8 (5) Testing and deferral requirements of Table 1 The requirements of Table 1 not required to be met when the donation is to be used exclusively for plasma for fractionation should include (m) and should NOT include (q).

Agree to add (m) (see previous)

(i) And (q) go together, either both in or both out.

8 (5) Testing and deferral requirements for plasma for fractionation

Criterion (m) from Table 1 is not included in this subsection paragraph as not being required for 'plasma for fractionation'. In the EU/USA, source plasma donors (for fractionation only) are not asked/deferred for Malaria risks.

This criterion would have an impact on [our] ability to supply products to Australia as currently none of [our] EU or US based source plasma suppliers defer such donors (for plasma for fractionation only).

Agree to add (m) to list (see previous)
8 (6) Vertical transmission – where Baby donor has eaten donor milk Include possibility of baby donor receiving milk from a Milk Bank; whereby the milk donor may need to be evaluated.

Noted without change. Guidelines to provide further information.

Milk donors are not currently within the jurisdiction of the TGA however do have a degree of self-regulation. The likelihood of this scenario is low, and as such it would be appropriate for manufacturers in these situations to have risk-mitigating procedures (in accordance with Section 7(1)(a)) As milk is regulated as a food, it would be product

Table 2 "Sera of animal origin" is not well defined.

This requires some better qualifying or descriptive guidelines. Why is the period for "vaccines unknown" 12 months?

Further clarification of this type of vaccine is requested, as it is unclear which vaccines may fall within this category. Provision of an example would also be of assistance.

Noted without change. "vaccines unknown" is 12 months based on precaution for unknown risk.

Further clarification, including examples, to be provided in Guidelines.

8 (10) (a) A product must not be manufactured from a donor who is known to have a disease or condition.....

This presents difficulty in patients receiving an autologous cellular therapy who have received radiation therapy or high dose chemotherapy e.g. patients who develop EBV driven tumours as a result of poor immune function induced by the therapy they have received. These patients should not be excluded as there limited risk in receiving their own cells.

We propose an additional requirement (c) be included exempting cells to be used in an autologous setting.

Noted.

Clarification: This requirement is intended to allow for clinical judgement.

8 (10) (b) Use of ineligible allogeneic donors This caveat allows the acceptance of a donor who would otherwise be excluded if the donor is accepted by the "manufacturers medical officer" or "evidence supports quality, safety and efficacy of the product". We suggest that a more reasoned approach for use of "ineligible donors" would also include a statement from the recipient's physician of urgent medical need & approval for use, in addition to written informed consent from the recipient to demonstrate that they are aware of relative risk from the product. This would avoid exclusion of a related donor where they are the best (or only) possible donor while making explicit transplant physician and recipient consent and maintains the current system of donor assessment by an independent physician (thereby improving safety by limiting conflict of interest issues).

Noted without change.

Suggested changes are beyond the scope of the Order.

8(11) Age requirements [We have] advanced past the arbitrary use of age as an indicator for tissue acceptability. For tissues requiring mechanical strength, for example, tissues from multiple donors are tested after being subjected to [our] processing to verify sufficient biomechanical strength is retained. For some tissues in which age may affect its utility (e.g., osteoinductivity of demineralised bone matrix), quality tests are performed with tissue from each donor. Clarification: This requirement allows a manufacturer to choose age limits subject to other criteria, such as biomechanical testing.
8 (11) (b) Validation of Donor age range

The intent of this requirement is understood – i.e. to prevent tissues being collected from an obviously unsuitable age group.

The age range of donors of certain tissues can be determined from historical experience, physical assessment of the tissue or user specifications. This information however cannot necessarily be "validated" (i.e. confirmed that it consistently fulfils the requirements for a specific use) other than in the absence of adverse event reports.

Agreed. Wording changed to reflect this.
8 (11) (a & b) Age of donor & safety and efficacy of product

1. It is not clear how these requirements relate to minimising infectious disease transmission.

The requirements have the potential to limit the accessibility to life-improving or extending treatments in patient cohorts that are already under represented in clinical trials.

2. There should be a simple mechanism for allowing medical justification by a treating physician in cases where the product represents the best option for treatment, especially when the condition is life-threatening or life-disabling.

1. Noted with changes. Title of the Order amended to reflect scope, which includes elements of product quality and safety.

2. Noted. This requirement requires the manufacturer to set age criteria – this is consistent with current clinical trial eligibility criteria.

9 (1) Aseptic blood collection Where blood collected prior to autopsy was not of sufficient volume to perform both serology and NAT. In these instances, blood may be collected directly from the heart post-autopsy for serology testing. Aseptic collection of these samples cannot be proven with the risk being a false positive not a false negative result. The scope of the ID Order includes both living and deceased donors, therefore aseptic practice is essential, noting the aseptic sample collection is unlikely to affect a deceased donor. Agree to rephrase
9 (2) (a) Donor sampling

1. What objective evidence or rational supports limiting the window period to 7 days post donation and what is the management strategy of material being collected beyond this time period i.e. what is the difference between 7 days versus 8 days post donation? Again, the blood sampling range would be better served to represent the default range applied to manufacturer if they did not wish to undertake an assessment to determine an appropriate blood sampling range for the manufacturing process (and operator), preparation and assembly of the final product and donor (recipient).

2. If blood sampling of a living donor must occur no more than 7 days prior to or 7 days after collection of the tissue, it does not allow for recollection if a sample is then identified as haemolysed or insufficient for testing purposes. The graft would have to be discarded. A longer time frame would be beneficial. Ability to obtain a repeat sample within 7d for logistically impossible (e.g. overseas or fly-in/fly-out client) [for autologous chrondrocyte donors].

1) Noted without change. 7 days is consistent with international practice, with the exception of HPC in cases where myeloablation precludes a small window. Where samples are collected outside this window, and it is not specified in a product-specific order, the manufacturer is responsible non-compliance with the legislated standard.

FDA CFR 1271 Timing of specimen collection. You must collect the donor specimen for testing at the time of recovery of cells or tissue from the donor; or up to 7 days before or after recovery, except [HPC].

2) Noted without change. Manufacturers may apply for an exemption or alternative to a specific requirement in the Order by providing objective evidence to justify an exemption for TGA review.

9 (2) (a) Blood sampling of a living donor must take place 7 days prior to or 7 days after collection of blood, blood components, cells or tissues. This specification if accurate is far too restrictive. The requirement to test 7 days prior to collection has potential to compromise patient assessment and product quality especially in situations where patient preconditioning occurs in the week preceding administration. In the allogeneic setting donor suitability must be established prior to commencing conditioning – the 7 day timeframe in many cases would be insufficient. The product specific Order takes precedence - in the case of non-cord HPC this is currently BP and it is the intention of the TGA to harmonise with NPAAC in future. Note that HPC used by a medical practitioner in the course of patient treatment is currently exempt from the ID Order.
9 (2) (a) Donor sampling and test management Blood samples cannot be taken "no more than 7 days prior to or 7 days after collection...." For the reasons described above [See 8 (1) (b)]
9 (2) a) Blood sampling of a donor must take place no more than 7 days prior to or 7 days after collection of blood, blood components, cells and tissue.

A number of our collections are received by through the Westmead Bone Marrow Transplant Service which is NATA accredited and soon will be FACT accredited. The timeframe stipulated in the TGO does not align with the serology testing requirements to be met by the service which are specified in following documents i.e. tested within 30 days before collection:

B6.6 Foundation for Accreditation of Cellular Therapy (FACT) International Standards for Cellular Therapy Product Collection, Processing and Administration (4th Edition)

S2.4 Requirements for Procedures Related to the Collection, Processing, Storage and Issue of Human Haemopoietic Progenitor Cells (Third Edition 2009)

We request that the TGA review the timeframe for collection to align with these recognised national and international standards.

Noted without change. It is acknowledged that industry standards for non-cord HPC allow samples to be taken 30 days before or after collection, as does legislation in Europe and USA.

Most non-cord HPC are exempt from the requirements of this Order under Section 6 or excluded under the Excluded Goods Order.

The TGA intends to mandate a TGO for non-cord HPC that is harmonised with NPAAC (and FACT-JACIE) as the HPC product specific Order in future. Until this time, non-cord HPC that are regulated may require section 14 exemption from some requirements of the ID Order – this can be determined in consultation with the TGA.

9 (2) (a) Blood sampling...no more than 7 days prior to or 7 days after collection...

Although it is noted that the requirements in the order are minimum standards and that more stringent requirements may be applied, the Blood service does not believe it is appropriate to sample blood donors up to 7 days prior to their donation as risk activity may occur in the intervening period. For blood donation, the sample which is used to perform the mandatory screening testing should be collected AT the time of the blood donation.

The option for a blood sample for donor testing to be collected 7 days prior to blood donation is inconsistent with the requirement for the timing of collection of a sample for testing archive (refer page 11, 9. (8)), which must be taken "at time of collection..."

Noted without change.

It may be appropriate for products to have more stringent requirements as determined by a manufacturer. The ID Order is a minimum standard.

Noted with change. 9 (8) has been clarified to align sample collected under timeframes specified in 9 (2) or (3).

9 (3) This requirement needs to be rewritten both for 1) clarification of the reasons for the restriction and 2) to ensure that samples taken after 24 hours are still considered suitable for mandatory testing for Eye Donors.

Why is there a 24 hour restriction on blood sampling? If it relates to validation of the blood test in regards to sample viability then the sampling time should be that defined by the test validation.

For eye donation NAT testing (which has tighter requirement for the blood specimen samples) is not required, and a sample taken more than 24 hours after death is still valid for serological testing. In Europe where normothermic storage of corneas is widespread it is not uncommon for more than 24 hours to have passed before blood sampling and retrieval of eyes is performed. Indeed, some countries such as Denmark restrict access to coronial donors until after 24 hours has elapsed5. A restriction of 24 hours unreasonably restricts access to this valuable donor pool for eye tissues.

Noted with changes.

For deceased donors, sample is likely to be unsuitable for testing after 24 hours: 1. Changes to blood, 2. Microbial issues 3. Blood samples should be collected no later than collection of tissue. There may be an option to allow testing of samples taken beyond 24 hours, provided that the test is validated/licensed for an extended time period. Suggest modify 9(3) of the ID order as follows:

'Blood sampling for testing of a deceased donor should take place no later than 24 hours after asystole. If samples for testing are taken more than 24 hours following asystole, the testing methodology must have been validated for cadaveric samples to include the relevant time period.'"

9 (4) Format

Format of item

Parts (a) and (b) relate to initial sentence. Part (c) should be a stand-alone sentence. E.g. The results of such testing must be evaluated prior to release......

Agree. Amended to be consistent format with 4. (1) (a) and (b) and (2)
9 (4) (a) all donors must be tested by serology at the time of collection and (b) NAT testing for HIV, HCV and HBV must be performed at the time of collection to exclude a window period infection. Once again the 30 day rule applied for HPC is more compatible with patient treatment and product manufacture. To meet these requirements processing could not commence until donor testing is complete thereby compromising product quality by extending the period between collection and processing. Alternatively processing could commence under quarantine - which is never guaranteed 100% effective - until test results are complete. Either scenario severely compromises product quality in direct contrast the aims of these standards.

Noted without change

Practicable interpretation to allow for 9(2)(b)

Evaluated as part of dossier. Further clarification to be provided in Guidelines. Lab needs to validate kit for use.

9 (6)(a) The test kits/methodologies

How and by whom will "most appropriate technology/ methodology" be determined? Who will define appropriateness? The manufacturer or the auditor?

If the methodology has current approval by the relevant regulatory authority as in point (b) should not an "appropriate" status follow?

Noted. Further clarification to be provided in Guidelines.
9 (6) (a) and (b) Requirements in relation to donor blood sampling

Who determines most appropriate kits for the samples being tested?

(b) be approved by the relevant authority in the country in which the testing is performed, or, performed in a facility approved by the same authority to perform such testing.

Where the tests are TGA approved is it possible that we can now use a non-TGA licensed lab for the mandatory screening, and confirmatory micro and virological provided the lab meets cGMP requirements 905 and 909? cGMP 905 requires a competent laboratory unless legislation requires otherwise. We have not found this requirement in the Act. Is this TGO the only relevant legislation for this requirement?

(b) is not an "or" statement. The TGA will require the test kits/methodologies to be approved by the relevant authority in the country in which the testing is performed, AND performed in a facility approved by the same authority to perform such testing. (b) the "or" should be changed to "and" given this is the requirement.

Noted. Requirements for in vitro diagnostics being reviewed with OMQ and IVD sections within TGA
9 (8) "...expiry date of products..." What is the definition of 'products' in this instance? If this is defined as finished product e.g. Albumin, this period of archival could imply up to 10 years! Would this be applicable to 'export only' plasma who have their own local regulatory requirements and may not have the required resources to accommodate this Australian requirement?

Noted with changes. For TGC Subcommittee to note.

ID Order updated with new requirement to exempt PFF samples from the archive requirement

BP monograph for PFF does not include a requirement for sample archive time.

9 (8) Expiry date- clarification

Request clarification of the term "products" as it appears in the requirement for retention of samples for 2 years post expiry. Although the term "blood product" is often used to refer to fractionated product, it is the Blood Service understanding that in this context, the "product" is the blood component (i.e. plasma intended for fractionation) and is not the finished (fractionated) product.

Impact : Significant financial and operational impact would result if the term "product" is extended to include finished (fractionated) product, particularly in regard to the duration of sample retention.

i.e. 2 years post expiry of the manufactured product could potentially require a 10 year archive duration if fractionated product is included in the scope of the requirement.

9 (8) Requirement is too long

Sentence too long and therefore ambiguous Simplify by using shorter sentences separating the requirements for living and deceased donors

Living donors: If there is a 180 day post collection sample is there a need to store the time of collection sample? 180 days post collection samples must be stored. Deceased donor.: the time of collection sample must be stored

Agreed. Requirement amended to clarify.
9 (8) Suggest adding "...taken from living donors at 180 days minimum post collection This will allow for over 180 days. Agreed with change.
9 (8) Archive samples

It is possible to archive only if a sample is available.

Recommend changing the wording to "Dedicate samples... must be archived, if available, at or below minus 25°C..."

Noted without change. It is a requirement that a sample is archived from the donor
9 (8) Sample archive The Blood Service does not currently have a sample archive in place, and this is a pre-existing gap of which TGA are informed. The Blood Service is in the process of closing this gap. Noted without change. Transition arrangements will be in place following implementation of the ID Order.
9 (9) "Archived samples must be retested"

1. Archived samples are not always suitable for use in new screening test protocols (e.g. NAT testing).

Suggested modification of reference:

"Where possible, the donor's archived sample is to be retested with the new screening test protocol prior to release of the product ...."

2. Can where practicable be included re the testing of archived samples in the event of a screening protocols change?

Noted with changes. ID Order updated to include 'where possible' – it may not be a possible requirement to undertake repeat testing in some circumstances such as suitability of assay for archive samples. This will be determined by the manufacturer as described, after consultation with the TGA.
9 (9) we would suggest that wording be amended to remove "must" and replace with "should be retested". If the word "must" remains even though a Manufacturer can determine otherwise based on formal risk assessment this matter will become contentious between Manufacturers and Auditors.
9 (9) Requirement to test archived sample if screening protocols change during the life of a product

Where screening protocols change during the life of a product in storage, the donor's archived sample MUST be retested (based on risk and in consultation with regulator).

Impact: Direct costs of retesting archive on introduction of new screening protocol could be considerable. These costs would need to be incorporated into the risk-benefit analysis and considered in consultation with the regulator.

9 (9) "Where screening protocols change ..."

Screening protocol is a vague term and need clarification. Does this imply a change is test protocol, or does it mean a change in testing platform or test method or kit?

Does a "protocol" here cover test algorithms and/or methods? Is it inferring a previous test method constitutes an increase in risk – or does this point only refer to new algorithms which may include additional tests?

Noted without change.

Further clarification to be provided in Guidelines.

The requirement intends to apply where the method or algorithm of a screening test, thus protocol.

10 (2) Physical assessment

The amendments made to this requirement from the previous draft are a positive improvement, however the Blood Service would like to see further refinement to ensure that healthy blood donors are not unnecessarily subjected to physical examination as part of the mandatory criteria for routine blood donation.

Suggest replacement of existing requirement with the following;

"Assessment of the suitability of the donor, which may include a physical assessment, where appropriate must be conducted by a trained assessor and, must take place..."

Noted without change.

The term physical assessment was amended after the previous consultation in order to indicate that it did NOT mandate a physical examination in all patients, but an assessment based on relevant clinical criteria of risk adapted to the particular cell/tissue being collected. The definition of 'physical assessment' reflects that. The current practice includes a degree of physical assessment as is consistent with TGO 81 CoE 14 ed and

Guidelines for the Selection of Blood Donors (GSBD, ARCBS) (section 1.5.6 "Medical Assessment and General Advice to Donors" p8): "The Donor Assessment should conclude with a basic medical assessment to determine the donor's: Age, haemoglobin level, current state of health, weight, blood pressure, pulse (for apheresis donors)"

10 (2) (a) Physical assessment of the donor must take place at the time of donation This is clearly impractical. At the time of HPC donation is clearly far too late to assess an HPC donor physically Noted. Product specific order will apply for HPC where the HPC are not subject to exemptions.
10 (2) (a) Physical assessment of a living donor at the time of donation may not be possible.

3. As it is written, this requirement requires a physical assessment of the donor to be conducted during the operation (i.e. "at the time of donation" for a live femoral head donor) so this would have to be undertaken by a medical officer or nurse in the Operating Theatre.

It then follows that tissue bank staff would have to train these health professionals in assessing their patients (i.e. the assessment must be conducted by a "trained assessor"). This would appear to be inappropriate imposition on the Operating Theatre staff.

A physical assessment of a living donor at the time of donation is difficult as the Donor Consent/Medical History is frequently conducted in a Pre Operative clinic prior to the donation day. This should read that the assessment may be conducted when the interview is completed.

Noted with changes. TGC Subcommittee to note.

MS Order has been updated to include a product-specific requirement for donor physical assessment 30 days prior to collection.

10 (2) (b) The 24 hour limit for physical inspection should be removed. The reference to 24 hours in (b) should be deleted or specifically exclude eye donors from this requirement. Under part (b) - It is unclear why 24 hours restriction should apply, and it does not seem to be related to risk. Because of rigour mortis physical assessment may sometimes be more appropriate after 24 hours. Agreed with change. ID Order updated to remove the time constraint, permitting physical assessment at the time of collection for deceased donors.
10 (3) (a) (i) Donor test results

... the test must demonstrate that the samples tested are non-reactive.

Why must we fail for results other than non-reactive that are assessed as being clinically negative? e.g. living donors retested at 180 days, where the donation results are assessed as being clinically negative and the retest results are negative?

Noted without change. Further clarification to be provided in Guidelines.

Laboratory policy should determine whether duplicate confirmatory testing overrides the 'reactive' test – the result as determined by the manufacturer testing policy must be compliant.

10 (3) (c) "Cornea" or "corneal donor" The word "cornea" in both (3) (c) and Table 3 needs to be changed to "ocular tissue" or "eye tissue". Certainly whole eyes should be processed with the same exclusion criteria as corneas, rather than those that are more exclusive.

Noted without change.

Cornea allowances consider that cornea is avascular and based on evidence of reduced infectious disease transmission provided for cornea.

Table 3 Donor resting requirements

Syphilis and HTLV-1/2 testing at donation

Syphilis and HTLV-1/2 both have window periods. The alternative to perform these tests at 180 days should be allowed, provided the donated tissue is not handled prior to receipt of retest results. This request is particularly relevant for HTLV1/2 due to its low prevalence.

Noted without change.

Collection of tissue without full panel of initial testing introduces potential risk into the bank, even if the product is quarantined. Manufacturers may wish to undertake additional testing at 180 days, the ID Order specifies the minimum standard.

It is noted that the HTLV window period is not well established, and that transmission generally vertical or via transfusion

Table 3 HBcAb testing The requirement for HBcAb testing has been removed from the previous draft of this TGO (Dec 2009). Current literature indicates that HBcAb testing (and subsequent HBsAb and HBV NAT in HBcAb positive donors) in addition to HBsAg is required to fully determine HBV status (Transfusion 2008; 48: 1001-26).

Noted without change. NAT has demonstrated high accuracy at the time of collection with minimum window period for HBV.

Alternatively , with 180 day serology is not precluded. HBcAb is not of added informative value when NAT HBV or 180d HBsAg is tested.

Table 3 Serology testing for autologous use following islet auto transplantation. Islet autotransplantation should be exempt from the regulatory requirements.

Noted without change.

The scenario of autologous islet transplantation described is intended be excluded from TGA oversight upon commencement of the framework based on medical practice exemptions.

10 (4) (a) and (b) Testing of HPC donors

The move to NAT testing for HIV, HCV and HBV will have large cost implications on a sector facing a number of new cost requirements with licensing etc.

We request scientific and literature evidence detailing the risk with current serology testing practices and need to also perform NAT testing?

We also request that the TGA ensure that laboratories performing NAT testing for blood from donors that have been mobilised have their procedures validated for blood with high white cell counts.

Noted without change.

Currently HPC are subject to specific exclusions from regulation or exemptions from licensing when manufactured under medical supervision, and are subject to the ID Order exemption under section 6. Where products are not manufactured for medical practice, requirements of the ID Order apply.

The manufacturer may submit justification for exemption from specific requirements for TGA consideration.

Validation of NAT for mobilised donors noted – this is within the scope of audit of testing laboratory.

10 (4) (a) and (b) Testing of HPC donors At the time of HPC donation is clearly far too late to perform serology and NAT testing
10 (4) (b) Donor testing requirements Inconsistent with 9 (2) (a) These requirements requires serological and nucleic acid testing to be performed at the time of collection to exclude a window period infection however this is not consistent with 9 (2) (a) which states that blood sampling of a living donor must take place no more than 7 days prior to or 7 days after collection.

Agreed with change.

10 (4)(a) and (b) amended to be consistent with 9(2)(a) – testing at time of collection but within 7 days.

Clarify application to living/ deceased donors

Do (a) and (b) therefore refer only to deceased tissue donors? This is not clear as (c) then goes on to refer to living donors.

  1. refers to all donors (Table 3)
  2. NAT is a must for deceased, non-ocular tissue donors and living, allogeneic, plasma donors for fractionation (Table 3).

Clarity of wording sought.

Noted without change.

Compliance with 10(4) is required for all donors. Where requirements are not applicable to deceased donors (e.g. 180 day testing) a suitable alternative is provided (e.g. NAT)

10 (4)(d) Address feeding from Milk Bank and milk donor screening. This requirement does not clearly capture babies that may have [received] donated milk Noted without change (see comment for 8 (6)). General risk management principles of 7(1)(c) apply. Breast milk is regulated as a food and thus not currently regulated by the TGA.
11 The requirement for microbial control varies between product i.e. It is product-specific.

Those aspects of microbial control that may be appropriate for one tissue are not appropriate for another tissue. In addition, microbial control is not a standard for minimising infectious disease transmission and thus should not be included in an infectious diseases TGO.

This section should be removed, rewritten to be product-specific, and the appropriate re-write placed in the Product-specific Therapeutic Goods Order.

Noted without change.

Microbial contamination of a cell or tissue product is transmissible to the recipient through the use of that product, and results in infection.

The microbial control measures required by this Order are minimum requirements that are applicable to all human cell and tissue products, to minimise proliferation of potential intrinsic contamination, and to minimise introduction of extrinsic contamination through manufacturing processes. Where specific products may warrant differing requirements from the ID Order, product-specific orders will specify alternative requirements.

11 (1) risk assessment for microbial control A strategy for the minimisation of the intrinsic and extrinsic microbial contamination in a product must be established based on a risk assessment considering the nature and intended use of the product. Who performs the risk assessment the manufacturer, supplier or laboratory? Noted. The manufacturer is required to develop and implement the strategy for microbial control
11 (2) "Human cells & tissues" Does the term tissue include ocular tissue. If so, this requirement is more restrictive than the requirements in the ocular TGO. Agreed with changes. Amendments in ID Order 11(2) to include (c) with reference to product specific order.
11 (2)(a) Collection timeframe unclear – commencement or completion within 24 hours?

Would suggest re-writing this paragraph as follows:

"as soon as possible after asystole and commence within 24 hours of asystole provided" etc. Refer to AATB Standard (12th Edition P.38) which states the same; no time for completion is given.

Should it be necessary for TGA to include a "completion time" Australian Biotechnologies suggests that it be at each collection centres discretion based on Risk Assessment performed for each individual case.

Agreed with changes. ID Order requirement amended to specify cessation time, MS Order modified to extent timeframe for tissue harvest.

The requirement intends for "completed" within 24hr of death. Following substantial justification from Bone banks, noting that retrieval can routinely take many hours, it is agreed that the MS order should be updated to extend the completion time for MS tissue to 36 hours.

11 (2) (a) and (b)

It is not clear from this requirement whether collection of tissue from a deceased donor must commence within 24 hours of death or be completed within 24 hours of death.

Should tissue retrieval have to be 'completed' within 24 hours of death, there is genuine concern that this will severely limit the number of tissue donors in many jurisdictions.

11 (2) (a) and (b) Currently the policy for the NSW Bone Bank is to have 'Knife to skin' (i.e. making the first incision) within 24 hours of asystole if the body was refrigerated within 12 hours of death or within 15 hours of asystole if the body was not refrigerated. Whilst keeping in mind that a full retrieval can take up to 10 hours (especially if the technicians are in training) but that there should also be a time limit we suggest that the statement be adjusted to
11 (2) (a) Remove specific temperature requirements

The USA requirement is tissue excision shall commence within 24 hours of asystole if refrigerated or cooled (i.e., without specifying a temperature range).

Recommend changing the wording to "...provided the body has been refrigerated or cooled within 12 hours of asystole; or"

Noted without change. These cited requirements from the AATB standard are broader than is appropriate. This standard is a legislative instrument and the subject of evaluation and audit for compliance.
11 (3) "...should be no more than 72 hours in duration" EP/BP monograph for Plasma for Fractionation states that "the total period of time during which the temperature exceeds -20C does not exceed 72 h". The proposed TGO appears to be more stringent than the monograph in that it states that transport (of plasma for fractionation) should be no more than 72 hours in duration. This wording should be consistent. Noted. Product specific order requirements will take precedence over ID Order requirements, where they are specified.
11 (3)

Transport temperature conditions

Storage conditions

1. For bone, the industry follows a maximum of 72 hours of refrigerated temperature before freezing occurs. The draft TGO does not need a 72 hour limit if freezing of bone has already occurred. Suggest the refrigerated range be changed to less than 10°C, or if this is critical for other tissue groups, then identify the storage ranges in the MS TGO.

2. See comment also for the Cardiovascular TGO, 7. (2) (a). [Temperature of 10°C does not compromise tissue safety or quality]

Agreed. Manufacturer validation will be allowed in product specific Order regarding time and temperature for transport and storage.

Temperatures for transport and storage revised as per considerations below.

11 (3) (a) (a)if refrigerated 2°C to 8°C This is inconsistent with Council of Europe, 15 Ed section, Chapter 5, Section 4 for storage of plasma (2-6 C) and shipping/transport of plasma (2-10 C). Noted without change. Product specific order takes precedence as stated.
11 (3) (a) Temperature

AATB refrigerated temperature range is defined as 1-10 C, not 2-8 C.

Recommend changing the temperature range to "1°C to 10°C" [as per current practice and AATB standard].

Agreed with changes.

Temperature requirements for transport and storage have been revised to less than 10°C, which is consistent with current practice, international tissue bank standards and Council of Europe. It will be the responsibility of the manufacturer must use an appropriate lower temperature limit based on the effect of temperature on the quality of the tissue.

Transport time of 72 hours is consistent with BP monograph 0853 (PFF) where the temperature exceeds -20°C.,

Manufacturers will be able to provide validation of alternative transport timeframes and temperatures if required, as a part of the product dossier or TMF.

11 (3) (a) transport conditions of human blood and blood components

Transport temperature requirement of 2 degrees C to 8 degrees C is more restrictive than the Council of Europe Guidelines (2-10 degrees C). It is our understanding that for blood components, the Council of Europe Guide to the Preparation Use and Quality Assurance of Blood Components would be designated as the product specific Standard and would therefore take precedence over this requirement.

The 72 hour limit in transport duration is inconsistent with the BP requirements for plasma for fractionation.

Impact: Significant impact if 2-8°C must be met, as transport would require re-validation and possible change in shippers.

11 (3) (c) change -40°C Query whether temperature for cryoprotected should not be stated as -70°C as purpose of practice is for longer term storage and hence need for lower temp.

Noted with changes.

Transport temperatures in 11(3) (b) refer to collection material and thus freezing is unlikely. Transport for final product comes under 11(4) and is responsibility of manufacturer to determine appropriate temperature for transport and storage of the product.

11 (3) Microbial control Please note that international transplant centres will wish to transport the product for their patient at the temperature they desire or that they are regulated to do according to their own regulations. If this is mandated it has the potential to stop international export of products from Australia. Noted. Products for supply in Australia are required to meet Australian standards.
11 (3)

Microbial control

Transport conditions

Time and temperature requirements

  • The relevance of 72 hours as a maximum transport duration is not clear. (e.g. frozen product being shipped overseas in a mechanical freezer).
  • 3 different temperature ranges are specified.
    Are these the only temperature ranges within which product can be transported?
    Or, does the 72 hour maximum apply only to these ranges and not to product that can be transported at ambient temperatures?
  • The temperature ranges are not necessarily relevant to many products which may have broader or narrower ranges, or indeed, combined ranges.

Noted – amendments made to clarify:

11(3) refers to starting material

Final product requirements to (4) with storage and temperature

11 (3) transport conditions

Historically Musculoskeletal tissue has been transported at "wet ice temperatures" with those temperatures recorded as between 0°C - 10°C for the past 30 years here in Australia with no detriment to the tissue.

Can the TGA provide data/rationale to support the change to transport temperatures?

For musculoskeletal tissue the temperatures as given are too narrow and should be opened to 0°C - 10°C. This statement should be placed in the tissue specific Standard and should be subject to validations as performed by individual manufacturers.

Noted with change. Temperature revised to be 10 degrees as consistent with AATB, CoE and current industry practice for tissue banks.
11 (4) Validated Temp

Storage conditions ... validated by the manufacturer. Not all tissue banks in the USA will have this information, and most go by the AATB temperature requirements. Differences between temperature ranges listed in product specific Orders and those listed in AATB Standards may preclude import of those tissues from the USA.

Recommend changing storage condition temperature ranges in product specific Orders to match those developed by the AATB. The AATB standards have a long history of use in the USA.

11 (5) Product release specifications Results of microbial testing will not necessarily be known before the product is released in the unrelated HPC setting. Again logistically impossible to provide these results at release. Noted without change. For all product types, compliance is required with one (or more) of the options provided. Requirement specified in 11(5)(c) does not mandate microbial testing results to be available at release, and requires that measures in place during manufacture minimise the risk extrinsic contamination.
11 (5) Bioburden specifications

It is unclear which of the stated bioburden release specifications (a or b or c) would be required to apply for blood and blood components.

Impact: It is the position of the Blood Service that (c) would be the applicable criteria for blood components, however if (a) or (b) apply then there will be considerable cost and resource impact on the Blood Service to implement these requirements.

Noted. Interpretation is correct that 11(5)(c) is appropriate for blood and blood components.
11 (5) Ocular tissue is not subject to bioburden testing and therefore this section must exclude ocular tissue. This section concerns bioburden testing. The eye is naturally colonised and bioburden testing is unwarranted. Tests are not performed and there is doubt what would be regarded as clinically significant. It would appear that this section should not apply to eye tissue. Noted without change. For all product types, compliance is required with one (or more) of the options provided. Requirement specified in 11(5)(c) does not mandate microbial testing results to be available at release, and requires that measures in place during manufacture minimise the risk extrinsic contamination.
11 (5) (b) specified microorganism means a microorganism which, if isolated from the tissue, necessitates discard of the tissue.

How and by whom will 'Specified' be determined? Will this follow the British or European pharmacopeia lists of organisms? Or will it be at the manufacturer's discretion?

Suggest Each manufacturing facility must have a list of microorganisms of clinical significance which must be developed using a risk assessment process to specify those microorganisms that, if detected on the sampled tissue specimens when tested for bioburden, will result in discard of the tissue.

Noted without change.

Where applicable, manufacturers will be required to submit (in the product dossier) a list of specified microorganisms of clinical significance, which, if tested and found to be present, will require rejection of the tissue from therapeutic use. The list and list justifications will be reviewed by experts within the TGA.

Guidelines to provide further clarification.

12 This section relates to Good Manufacturing Practice not "minimising infectious disease transmission" Should be removed from this TGO and incorporated into the relevant cGMP using terminology and language that is consistent with the cGMP.

Noted without change.

Critical materials requirements specified in the TGO as relevant to transmission of infectious disease. QMS requirements are retained in cGMP.

12 (1) "pathogenic bacteria" or other "infectious agents".
  • Pathogenic bacteria is not listed in the definitions, but is a much more appropriate term than microbial or specified organism which are used

Suggest a general revision of all 3 terms.

  • Infectious agent is not defined
Agreed. ID Order updated to remove 'pathogenic'. It is the intention to ensure that materials do not introduce any bacteria.
12 (2) (a) To ensure the continued viability of normothermic storage of corneas, solutions used in this process must be excluded from the requirement to demonstrate sterility.

Suggested change and reason(s):

Any standard or requirement must (i) significantly reduce risk, (ii) add value (iii) be enabling.

The requirement to "test for and satisfy sterility requirements in accordance with an approved pharmacopoeial test for sterility" provides none of these principles in regard to normothermically stored corneas. While the solutions used for normothermic storage are put through a sterilisation process, its purpose it to reduce the likelihood of microbial contamination which would otherwise grow and multiply in a nutrient enriched environment.

The corneas placed in storage are not sterile, yet microbial contamination testing during normothermic storage ensures that any clinically significant degree of contamination is detected and the corneas not used for transplant surgery. Therefore it is not necessary to demonstrate sterility at the level required by this standard. Demonstration of sterility to the levels required by the TGO 1) adds no value, 2) does not reduce risk, 3) is costly and inefficient (and could reduce the efficacy) of this process.

Noted without change.

Microbial control requirements for ocular tissue have been discussed with EBAANZ: Principles of Good Manufacturing Practice are to ensure extrinsic contamination is not introduced to the tissue. A full validation of the aseptic process used to manufacture the solution may be acceptable.

12 (2) (c) This Part references specific external documents that are likely to be updated with new versions or addition with time. ...there needs to be a mechanism (policy) on how the most up-to-date and relevant documents can be readily incorporated as required. This is necessary to ensure that the TGA standards do not lag behind changes in practice, many of which may be changes to address risk reduction as new risks are identified or emerge. Noted without change. Where the requirements of an externally published document are adopted by legislation, it is required that specific revisions are included. This minimises any ambiguity associated with compliance, and ensures full transparency of the regulation. When the cited documents are updated, it will be necessary for the TGA to evaluate the changes and if required, consult on any modification to the requirements (as is the process for all mandatory standards). If appropriate, the Order would then be updated with the new version of reference. Where the reference is a TGA policy or requirement, equivalent principles would apply.