Preparing and submitting Type II Plasma Master Files

A Type II PMF supports the importation of plasma for fractionation into Australia, which is processed or fractionated by a licensed manufacturer, and exported rather than supplied in Australia.

A Type II Plasma Master File is required under item 19 of Schedule 5A to the Therapeutic Goods Regulations 1990 (the Regulations). Sponsors must submit a Type II PMF for approval by the Secretary if they plan to fractionate or manufacture therapeutic goods from plasma that is sourced outside Australia at the same facility as Australian plasma.

A blood processing plant that processes plasma collected from donors in Australia for products that are or will be used in Australia (the Australian product) may only be used to process plasma collected from a source outside Australia if:

• the manufacturer of the relevant blood processing plant has submitted a Type II PMF to the Secretary, prepared in accordance with the requirements of the European Agency for the Evaluation of Medicinal Products document, Guideline on the Scientific Data Requirements for a Plasma Master File (PMF) Revision 1 (EMEA/CHMP/BWP/3794/03 Rev 1)
• after considering the Type II PMF and the plant's manufacturing processes, the Secretary has advised the manufacturer that plasma from the source outside Australia is unlikely to present a risk of contamination of the Australian product with any known blood-borne pathogens.

These requirements, together with Good Manufacturing Practice (GMP), help ensure that products manufactured from Australian plasma are not exposed to an increased risk of contamination from known blood-borne pathogens associated with overseas-sourced plasma.

A Type II PMF should contain sufficient information to demonstrate that the manufacture of human plasma and plasma-derived products consistently produces products that meet applicable safety, quality and regulatory requirements.

Sponsors should submit the Application form for a Type II Plasma Master File and provide current information, supporting data and validation evidence to justify all claims made within the Type II PMF application.

The data and format of the PMF should comply with both:

• Annex 1 to Guideline on the scientific data requirements for a plasma master file (PMF) Revision 1 (EMEA/CHMP/BWP/3794/03 Rev 1)
• Guideline on epidemiological data on blood transmissible infections (EMA/CHMP/BWP/548524/2008 rev 1)

The PMF should describe all activities from donor recruitment and selection through to the manufacture of the first homogeneous plasma pool including collection, testing, processing, storage, transport and traceability. We evaluate these activities as part of our assessment of the PMF.

Sponsors must include:

• the source of the plasma
• the location(s) where the plasma was collected
• the screening process for donors including eligibility assessment and exclusion criteria
• a description of the tests used to screen donated blood and plasma including test methods, testing sites, assay validation and acceptance criteria
• traceability from donation to plasma pool
• plasma quarantine, storage, transport and hold times
• manufacturing plasma pool size and pooling controls
• epidemiological data for relevant blood-transmissible infections
• compliance with applicable Australian standards, including TGO 102 and TGO 108.

Sponsors should ensure that the information provided is current, accurate, clearly presented and supported by appropriate evidence.

It is our preference that sponsors follow the TGA’s general dossier requirements to assist with streamlining the evaluation process. For example:

• refer to the General dossier requirements for formatting and presentation
• use the Common Technical Document (CTD) format
• be clearly organised and easy to navigate
• include 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.

We evaluate each Type II PMF to determine whether the information provided demonstrates a negligible risk to Australian plasma manufactured at the same manufacturing site and compliance with applicable standards.

When the evaluation period begins for a Type II Plasma Master File

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

• the day we receive the Type II PMF 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 working days and exclude time taken by the sponsor to respond to requests for information.

The Application form for a Type II Plasma Master File (PMF) should be submitted with all applications, amendments and annual updates to the Type II PMF. All Type II PMF applications should be submitted as per the instructions on the Application Form.

Approved Type II Plasma Master Files

Once approved, it is a mandatory requirement that sponsors submit a Type II PMF on an ongoing basis according to Schedule 5A to the Regulations. Sponsors must not make changes to an approved Type II PMF unless the changes have been notified to, or approved by the Secretary where required.

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

If you wish to extend the expiry time of an approved Type II PMF, please contact the TGA at bloodandtissues@health.gov.au to request an extension under subclause 4(2) of Schedule 5A to the Regulations.

How long an approved Type II Plasma Master File remains in effect

Approved Type II PMFs remain in effect for a defined period and are subject to ongoing maintenance requirements:

• An approval of a PMF takes effect on the day the 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 PMF. Such applications must be made within 12 months of 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.

Annual updates to a Type II Plasma Master File

Annual updates to Type II PMFs, for plasma that is processed in the same facility as Australian plasma, are required under Schedule 5A to the Regulations.

The annual update should include an updated version of the PMF documentation, detailing any changes introduced since the submission of the initial PMF or last annual update. We evaluate the updated Type II PMF to ensure the ongoing quality and safety of the plasma used in the manufacture of plasma derivatives.

An annual Type II PMF update should include:

• updated epidemiology data
• information about changes to plasma collection and screening that have occurred since the previous PMF submission
• a tracked changes version of the PMF dossier highlighting changes introduced since the last approved version of the PMF
• a list of significant updates 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 PMF
• any other significant information relevant to the PMF.

The annual update must be submitted in conjunction with the Application form for a Type II Plasma Master File (PMF) as per the instructions on the form.

The sponsor must submit annual updates after an initial Type II PMF has been approved. Sponsors should submit annual updates 3 months before their current approval is due to expire, to allow sufficient time for assessment and approval of the annual update.

We will advise sponsors in writing of the outcome of the evaluation and whether any issues require further action.

Amendments to a Type II Plasma Master File

Changes to the PMF that have the significant potential to affect the quality and safety of the Australian plasma processed at the same manufacturing site must obtain our approval before implementing these changes.

Significant updates include, but are not limited to:

• variations from a standard
• inclusion of different donor populations.

All other amendments to the PMF should be documented through the manufacturer’s quality management system and be included in the next annual PMF update.

Sponsors must submit Type II PMF applications in accordance with Schedule 5A to the Regulations. This includes:

• applications for initial approval of a Type II PMF;
• applications for approval of annual updates to an approved Type II PMF;
• applications for approval of significant updates to an approved Type II PMF (previously called Category A variations);

Current submission requirements and supporting information are detailed in this guidance.  The Application form for a Type II Plasma Master File (PMF) 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.

Sponsors should submit initial Type II PMFs, annual updates and significant updates to us per the instructions on the Application form for a Type II Plasma Master File (PMF).

Evaluation timeframes

We aim to meet the following target evaluation timeframes:

Examples of some exceptions to the target internal timeframes include:

• 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.

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

• Application for approval of a Type II PMF under subclause 2(1) of Schedule 5A to the Regulations; and
• Application for approval of an annual update of a Type II PMF under subclause 2(2)(a) of Schedule 5A to the Regulations.

The sponsor will be notified of the fee after acceptance screening of the application is completed. There is no fee for an application for approval of a significant update under subclause 2(2)(b), or for sponsors to make minor amendments to their Type II PMF.

Sponsors should refer to the Application form for a Type II Plasma Master File (PMF) on our website for current 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.