Preparing and maintaining a Technical Master File (TMF)

A TMF is a compilation of technical and scientific information relating to the manufacture and clinical use of blood, blood components, or haematopoietic progenitor cells. The TMF provides evidence that manufacturing processes, quality systems and controls are capable of consistently producing products that meet applicable safety and quality requirements. Sponsors should include sufficient information to demonstrate compliance with relevant therapeutic goods legislation and standards applicable to the products covered by the TMF.

A TMF is required under item 18 of Schedule 5A to the Therapeutic Goods Regulations 1990 (the Regulations). Human blood and blood components (including haematopoietic progenitor cells) are exempt from the requirement to be included in the Australian Register of Therapeutic Goods, provided the Secretary has approved a TMF in relation to the goods and that approval remains in effect. Sponsors of blood and blood components must apply to the Secretary for an approval of a TMF before importing, exporting, manufacturing or supplying the goods in Australia.

The TMF should:

• be clearly organised
• contain sufficient detail to support all claims made
• identify applicable standards and guidelines
• include relevant supporting data and validation evidence
• include a table of contents and appropriate cross-referencing.

The TMF should demonstrate compliance with applicable standards.

Sponsors should ensure that the information provided is current, accurate and supported by appropriate evidence. Sponsors may structure a TMF using the suggested content outlined in this guidance.

Our preference is for sponsors to follow the General dossier requirements for formatting and presentation. This includes:

• document readability, text-searchable content, folder and file naming, bookmarks, hyperlinks and security settings
• include a clear cover letter explaining the purpose of the submission and identifying the relevant master file
• provide a table of contents, where this will assist us in navigating the submission
• submit documents in PDF format where possible. Use clear file names and organise documents in a logical folder structure
• ensure PDF documents are readable and text searchable. Do not submit scanned images unless this is unavoidable
• use bookmarks and hyperlinks in longer documents to us find information efficiently
• do not apply security settings that prevent us from opening, searching, copying, printing or reviewing the documents.

Sponsors must submit applications for approval of a TMF in accordance with Schedule 5A to the Regulations. This includes:

• applications for initial approval of a TMF;
• applications for approval of annual updates to an approved TMF; and
• applications for approval of significant updates to an approved TMF (previously called Category A variations).

Current submission requirements and supporting information are detailed in this guidance.  The Application form for a TMF is available on our website. Supporting documents must be sufficient to allow determination of conformance with each standard that is applicable to the blood or blood components as in force at the time.

We aim to meet the following target evaluation timeframes:

There are some exceptions to the target internal timeframes, for example:

• when an application with a target timeframe of 45 days is complex, we may require longer than 45 working days for the evaluation and decision
• when an amendment application or annual update involves clinical evaluation of data, we may require longer than the target number of working days for the evaluation and decision
• you will be advised of a longer timeframe for evaluation of your application in the acceptance email we send to you following screening.

When the evaluation period begins

The evaluation period begins once the following conditions have been met:

• the day we receive the TMF application form;
• the day we receive the information required by the form (that is approved by the Secretary); and
• the applicable evaluation fee has been paid.

The evaluation period ends when we issue a decision regarding the submission. Target timeframes are measured in our standard working days and exclude time taken by the sponsor to respond to requests for information.

The Application form for a TMF should be used for applications for initial approval of TMFs, as well as applications for approval of significant updates and annual updates to approved TMFs. The form is available on our website at: Application for a Technical Master File (TMF). These TMF submissions should be submitted as per the instructions on the Application form.

How long an approved TMF remains in effect

Clause 4 of Schedule 5A to the Regulations specifies when an approval of a TMF takes effect, as well as how long the approval remains in effect.

• An approval of a TMF takes effect on the daythe Secretary grants the approval. The approval remains in effect until 15 months after the day it is granted.
• Sponsors must apply to the Secretary for approval of annual updates to the TMF. Such applications must be made within 12 months of the approval taking effect.
• The 15‑month approval period allows us time to evaluate an annual update while the existing approval remains in effect.
• Sponsors may request an extension of the period an approval is in effect. Such requests must be made at least 28 days before the approval ceases to be in effect.

Sponsors should refer to the Application Form for a Technical Master File (TMF) for current submission arrangements and contact details. Sponsors are responsible for ensuring that organisational and personnel contact details held by us remain current.

• If you have any questions, please contact us at bloodandtissues@health.gov.au or 1800 678 799.

We evaluate each TMF to determine whether the information provided demonstrates compliance with applicable standards and regulatory requirements. Evaluations focus on:

• product safety
• product quality
• manufacturing controls
• quality management systems
• compliance with current editions of relevant standards.

Sponsors should ensure that:

• information is current
• claims are supported by evidence
• validation studies are available where required
• scientific literature is appropriately referenced.

Approved TMFs

Once approved, it is a mandatory requirement that sponsors submit a TMF annual update on an ongoing basis according to Schedule 5A to the Regulations. Sponsors must not make significant amendments or changes to an approved TMF unless the changes have been approved by the Secretary.

Under subclause 4(1) of Schedule 5A to the Regulations, the approved TMF will expire 15 months after the approval of the initial TMF, or 15 months after the approval of the last annual update is granted. Annual updates and significant amendments must be submitted to us to be assessed and approved, to maintain the ongoing accuracy of the TMF held on file.

• If you wish to extend the expiry time of an approved TMF, please contact us at bloodandtissues@health.gov.au or 1800 678 799 to request an extension under subclause 4(2) of Schedule 5A to the Regulations.

You must submit annual updates after an initial TMF has been approved.

Annual updates to an approved TMF

You must submit annual updates after an initial TMF has been approved. This should include the following:

• sponsors may submit an annual update at any time in the period starting on the day the TMF is approved and ending 3 months before the approval is due to expire. Annual updates submitted after this period cannot be accepted.
• an annual update must be submitted using the approved form, include all required information and be accompanied by the applicable fee. Applications that do not meet these requirements are taken not to have been made
• when an annual update is approved, the period for which the TMF approval remains in effect is extended
• sponsors should submit annual updates 3 months before the expiry of the current approval period to allow sufficient time for assessment and approval
• the annual update should include an updated version of the TMF documentation, detailing changes introduced to the donor selection and testing and product manufacturing process since the submission of the initial TMF or last annual update.

We group TMF amendments into three categories.

Significant updates - Changes requiring our approval before implementation (previously Category A)

These are changes that may significantly affect product quality, safety or efficacy. Examples include:

• changes to manufacturing processes or critical manufacturing conditions
• introduction of new technologies
• significant changes to manufacturing parameters or product specifications
• new product containers
• new critical materials of human or animal origin
• changes to donor selection criteria that would permit previously excluded donors
• changes to infectious disease testing or microbial test methods used for product release.

Sponsors must obtain our approval before implementing these changes. Applications should include supporting protocols, validation reports and any other relevant evidence, and include the Application form for a Technical Master File (TMF) in the submission.

Minor amendments - Changes requiring TGA notification (previously Category B)

These are changes that may affect product quality, safety but do not require approval before implementation. Sponsors should notify us before implementation, whenever possible, by emailing bloodandtissues@health.gov.au. We may request additional supporting information, including validation reports, scientific data or risk assessments.

Examples of minor amendments include:

• a change to reagents used within an established assay
• a new infectious disease testing kit that is of equivalent or better quality than approved kit.

Minor amendments - Changes included in annual updates (previously Category C)

These are changes that are not expected to affect product quality, safety or compliance. Sponsors should document these changes through their quality management system and document them in the next annual TMF update. Examples include:

• replacement of equipment with an equivalent item where appropriate change control activities demonstrate no impact on manufacture.
• minor changes to documentation or standard operating procedures (SOPs) that do not directly impact compliance with standards or product quality, safety or efficacy.

Sponsors are encouraged to contact us if they are uncertain how a proposed change should be classified.

The applicable fees for TMFs are specified in table item 9B in clause 3 of Schedule 9 to the Regulations, and relate to:

Initial TMF application

The initial application for Technical Master File (TMF) should contain sufficient information to demonstrate that the manufacture of blood, blood components, or haematopoietic progenitor cells consistently produces products that meet applicable safety, quality and regulatory requirements.

Sponsors should submit the Application form for a Technical Master File (TMF) and provide current information, supporting data and validation evidence to justify all claims made within the TMF.

Product information

Products included in the TMF

The TMF must include each product that is subject to the same standard and is intended to be covered by or is otherwise relevant to the application. The TMF should clearly identify all products and product sub-types that are manufactured under the proposed licence. 

To assist evaluation, the TMF should provide:

• an introduction to the products being manufactured that can be readily understood by a scientific reviewer
• the intended use of each product
• the rationale for the use of the product
• information about the manufacturer and manufacturing activities.

Scientific background

The TMF should include a literature review describing the scientific basis, development and background of the product. Sponsors should include relevant references and supporting literature as an annex to the TMF.

If there is uncertainty regarding the scope of a TMF, manufacturers are encouraged to discuss the proposed scope with us before submission.

Donor selection and assessment

The TMF should describe all aspects of the donor selection and assessment process used by the sponsor, demonstrating compliance to Therapeutic Goods Order 108 and other applicable Standards. The information provided should include, but is not limited to:

• donor interview questionnaire and documentation
• donor eligibility and acceptance criteria
• donor deferral criteria
• donation quantities
• donation intervals
• follow-up testing requirements
• physical assessment process and documentation.

The TMF should describe the procedures used to:

• assess donor suitability
• ensure donor eligibility
• assess recipient compatibility where applicable
• minimise the risk of disease transmission.

Donor identification

The TMF should describe donor identification procedures and controls to ensure donors are positively identified at all critical stages of manufacture.

Donor referral

Where applicable, the TMF should describe donor referral procedures and outline how donor and recipient planning is managed.

Re-admission of deferred donors

Where applicable, the TMF should describe the criteria used to re-admit donors who have previously been temporarily deferred.

Donor testing

The TMF should describe the complete donor testing program used by the manufacturer, demonstrating compliance to Therapeutic Goods Order 108 and other applicable Standards. The information provided should include, but is not limited to:

Testing requirements

The TMF should provide:

• a list of all mandated testing including the ARTG number of all test kits
• a list of additional non-mandated testing
• the purpose of each test
• known limitations of each testing methodology
• algorithms used to determine the infectious disease status of donors if multiple and/or confirmatory tests are used in the decision-making process
• the GMP license numbers of each testing lab and associated service agreements between the sponsor and the testing labs.

Acceptance and rejection criteria

The TMF should describe:

• criteria used to accept or reject donations
• re-testing policies
• procedures for managing non-conforming test results.

Critical materials and reagents

The TMF should provide information on all critical materials used during collection, manufacture, testing and storage.

Critical materials, equipment and medical devices

The TMF should include a list of:

• critical materials
• equipment
• medical devices
• all containers, from collection to final product containers used throughout the collection and manufacturing process.

Where applicable, relevant ARTG numbers should be provided, and evidence of the microbiological quality of the materials.

Materials not included in the ARTG

Where a material is not included in the ARTG, the TMF should provide:

• the manufacturer's name
• a Certificate of Analysis (CoA)
• justification for the selection of the material.

Where applicable, evidence of compliance with relevant British Pharmacopoeia or European Pharmacopoeia monographs should also be provided.

Medicinal components

Where a material contains a medicinal component, that component should be included in the ARTG. If the component is not included in the ARTG, the TMF should provide:

• rationale for its use
• supporting justification
• a Certificate of Suitability where applicable
• evidence of the microbiological quality of the component.

Human and animal-derived materials

Where a material contains components of human or animal origin, the manufacturer should demonstrate that the material is free from potential transmissible infectious disease agents.

The TMF should include:

• source information
• screening or testing results
• supporting evidence demonstrating the negative infectious disease status of the material.

Please refer to our guidance Demonstrating the safety of adventitious agents which details the requirements for the use of human or animal materials in the manufacture of therapeutic goods.

Collection of starting material

The TMF should describe all aspects of starting material collection, handling and acceptance.

Acceptance criteria

The TMF should define acceptance criteria for starting materials, including:

• minimum collection volumes
• target cell dose where applicable
• donation intervals
• retrieval procedures
• permitted time intervals between collection and processing.

Donor treatment

Where donor treatment forms part of the collection process, the TMF should describe relevant procedures and controls. For example, where growth factors are administered to mobilise haematopoietic stem cells, the manufacturer should demonstrate compliance with relevant ethical and clinical requirements.

Any special requirements for apheresis should also be described, including:

• written requests from treating physicians
• informed donor consent processes.

Collection procedures

The TMF should describe collection procedures, including preparation of collection sites and any limits that apply to collection duration.

Collection systems and additives

The TMF should provide details of:

• additive solutions
• preservative solutions
• collection bag systems.

Details of starting materials, intermediate materials and finished products should also be provided, including transportation requirements where applicable. Details of the microbiological status of these materials should also be provided.

Materials used during collection

The TMF should provide a list of all materials used during collection and processing. This should include Certificates of Analysis (CoA) of materials or other information that demonstrates that the materials are of a sufficient quality that they do not impact the quality, safety or efficacy of the final product.

Product manufacture

Manufacturing process overview

The TMF should provide a clear description of the manufacturing process. Where possible, sponsors should include a flow diagram showing:

• major processing stages
• critical decision points
• critical control steps.

Critical control points

The TMF should identify and justify critical control points used throughout the manufacturing process. This should include:

• starting material acceptance criteria
• infectious disease testing of starting materials
• in-process controls
• finished product testing
• product release criteria
• quality control measures.

Manufacturers should state the applied specifications and justify the selection of critical process controls, operational parameters and in-process testing requirements.

Process validation

The TMF should describe the validation strategy used to demonstrate that manufacturing processes consistently produce products that meet predefined specifications.

Validation information should include:

• acceptance criteria
• process specifications
• factors used to determine acceptable and unacceptable outcomes
• in-process controls
• test methods
• rationale for acceptance limits.

Validation should address all critical manufacturing steps, including:

• processing steps that may alter product characteristics
• steps that may affect product quality
• prolonged storage steps
• any other step identified through risk assessment.

Validation data covering at least three sequential batches of product, to demonstrate the manufacturer’s ability to consistently manufacture product that meets release specifications.

Product identity, purity and safety

The validation strategy should demonstrate assurance of product identity, purity and safety. Where applicable, this may include assessment of:

• cell viability
• cell counts
• microbial contamination
• target cell populations
• product volume
• functional potency.

Prevention of contamination and cross-contamination

The TMF should describe procedures used to prevent contamination and cross-contamination. Evidence should be provided that the manufacturing process is routinely monitored, and the in-process and finished product specifications should be stated and justified.

This should include controls relating to:

• collection
• transportation
• quarantine
• testing
• manufacture
• storage
• release
• labelling
• transfusion or transplantation.

Where manufacturing facilities process different products, the TMF should describe segregation controls and other risk mitigation measures.

Pathogen inactivation

Where pathogen inactivation or bioburden reduction is performed, manufacturers should provide validation data demonstrating the effectiveness of the pathogen inactivation process.

Product testing methods

The TMF should describe all testing methods used during manufacture and release.

Scientific principles and methodologies

The TMF should describe:

• scientific principles underlying each test
• testing methodologies
• testing procedures
• testing algorithms
• validation of test methods.

Testing for transfusion-transmitted infections

The TMF should describe methods used to detect transfusion-transmitted infectious agents.

Sponsors should provide:

• a list of test kits and reagents
• verification data
• evidence demonstrating suitability for the intended use.

Out-of-specification results

The TMF should describe procedures for investigating and managing out-of-specification (OOS) test results.

Additional testing

The TMF should describe any additional testing performed under specific circumstances to improve patient safety. Examples include:

• testing for Cytomegalovirus (CMV) where clinically relevant
• Genotyping or blood typing of donor for recipient matching.

Nucleic acid amplification testing

Where applicable, the TMF should describe:

• use of nucleic acid amplification technology (NAT)
• testing protocols
• acceptance criteria
• decision-making processes.

Labelling

The TMF should describe procedures used to develop, control and validate labels. Manufacturers should demonstrate that labels are validated for their intended use and comply with all applicable standards.  Copies of all labels (collection, final product labels) and release documentation should be included.

Labelling of non-conforming products

The TMF should describe procedures used to identify, label and control products associated with confirmed infectious disease risks. This should include:

• identification of viral-positive products
• containment procedures
• quarantine arrangements
• management of non-conforming products.

Storage, stability, shelf-life and transportation

Storage conditions

The TMF should describe storage conditions for all products covered by the TMF. Where applicable, the TMF should provide validation data demonstrating maintenance of product quality and viability during storage.

Cryopreservation and transplantation products

For products intended for transplantation, the TMF should describe:

• cryoprotectants used
• cryopreservation methods
• pre-storage testing
• post-storage testing
• storage controls
• validation of cryopreservation process.

Management of non-conforming products

The TMF should describe storage controls for:

• contaminated products
• viral-positive products
• microbiologically contaminated products
• other non-conforming products.

Transportation validation

Manufacturers should provide evidence that transportation arrangements maintain required storage conditions throughout transit.  The TMF should describe:

• validated transportation protocols for all stages of product manufacture, from collection to final release (distribution) of the product
• temperature monitoring controls during transport
• anticipated transport temperature extremes and evidence that storage temperature is maintained during these extremes
• transport acceptance criteria
• if product returns are accepted, details of return process and how product quality will be ensured before product return to inventory.

Stability

The TMF should provide stability data and end-of-storage specifications demonstrating continued product acceptability throughout the proposed shelf life. If product documentation includes instructions for thawing or preparing the released product for administration to the recipient, an in-use stability study should be provided demonstrating product stability during the documented preparation process.

Disposal

The TMF should describe procedures used to:

• dispose of unused products
• management of expired products
• document product destruction.

Product release

Release criteria

Sponsors should include a tabulated list of product release specifications and associated test methods used to determine whether a product is acceptable for release. Full details of release test methods and validation of analytical methods should be included in the documentation, as well as justification of the release specifications.

Post-release test results

Where test results are unavailable at the time of release, the TMF should explain:

• reasons why release occurs before results are available
• the justification for this approach
• the timeframe for obtaining outstanding results.

Management of abnormal results

The TMF should describe procedures used to notify authorised clinicians and patients of significant abnormal results identified after release.

Returned products

The TMF should describe how the returned product is assessed before return to inventory:

• procedures for handling returned products
• acceptance criteria for returned products where applicable
• assessment and disposition procedures.

Clinical indications, outcomes and adverse events

Clinical indications

The TMF should specify the intended clinical indications for use of the product.

Clinical practice guidance

The TMF should identify relevant clinical practice guidelines that support the use of the product.

Post-release outcomes

Manufacturers should describe procedures used to collect post-release information following transfusion or transplantation.

Examples may include:

• engraftment outcomes
• product performance data
• donor adverse events
• recipient adverse events.

Adverse reaction monitoring

Where applicable, the TMF should describe procedures used to detect, investigate, monitor and manage adverse events.

Supporting documentation and appendices

Supporting documentation and appendices

The TMF may include supporting appendices and reference materials relevant to the manufacture and control of the product.

Examples include:

• validation reports
• standard operating procedures
• equipment specifications
• materials lists and specifications
• full literature references
• label registers and specimen labels
• glossary of terms
• other supporting scientific and technical information.

Annual updates - Data requirements

The annual update should include an updated version of the TMF documentation, detailing changes introduced to the donor selection and testing and product manufacturing process since the submission of the initial TMF or last annual update. This should include, but is not limited to:

• a tracked changes version of the TMF dossier highlighting changes introduced since the last approved version of the TMF
• a list of Significant and Minor Amendments submitted and/or approved since submission of the previous annual update
• details (tabulated summaries) of supporting documents, SOPs and appendices that have been updated since the last approved TMF. The updates in each document should be summarised, and the sponsor should classify the change as Significant or Minor.
• copies of new validation reports completed since the previous annual update (if applicable)
• details of product collection, manufacture and supply since the last annual update, such as
• donor numbers
• collections
• units prepared
• units released
• any other significant information relevant to the TMF.

The Annual Update should be submitted in conjunction with the Application form for Technical Master File (TMF) as per the instructions on the form.

Significant amendments - Data requirements

Significant amendment submissions should contain sufficient information for the evaluator to determine whether the proposed change will impact product quality, safety or efficacy. This should be sufficient to allow the evaluator to assess and all aspects of the proposed change and its potential impact. This should include, but is not limited to:

• details of the proposed change
• risk assessment of the proposed change
• scientific justification of the proposed change
• supporting protocols
• validation protocols and reports demonstrating no effect on product quality, safety or efficacy
• any other relevant documentation.

The data should be submitted in conjunction with the Application form for a Technical Master File (TMF) as per the instructions on the form.

Minor amendments - Data requirements

Minor amendment submissions requiring TGA notification should contain sufficient information for the evaluator to determine whether the proposed change will impact product quality, safety or efficacy. This should include, but is not limited to:

• details of the proposed change
• a self-assessment/risk assessment of the proposed change detailing the sponsor’s evaluation of the proposed change and its impact on the final product. This should include clear conclusions that there will be no adverse effects on product quality, safety and efficacy.
• any other relevant documentation.

The information should be submitted to the TGA at bloodandtissues@health.gov.au prior to implementation. Minor amendments do not require approval outside of an Annual Update, but the TGA should be informed of these changes if appropriate.