Guidance 9: Therapeutic goods that contain or are produced from human blood or plasma
Guidance on the regulatory requirements for therapeutic goods that contain, or are produced from, human blood or plasma
This guidance provides information for sponsors and manufacturers about the regulatory requirements for therapeutic goods that contain, or are produced from, human blood or plasma (except biologicals, as defined in the Therapeutic Goods Act 1989 [the Act]).
Examples of the therapeutic goods covered by this guidance are coagulation factors, immunoglobulins of human origin and albumin and in vitro fertilisation (IVF) media.
On this page: Background to the regulation of therapeutic goods containing human blood or plasma | Standards and guidelines for human blood or plasma | Plasma master files for human blood or plasma | Plasma master files for human blood or plasma products in the ARTG (Type I) | Plasma master files for plasma processed in the same facility as Australian plasma (Type II) | Variations to plasma master files
9.1 Background to the regulation of therapeutic goods containing human blood or plasma
Australia is signatory to a World Health Organization (WHO) policy that states that each country should aim to be self-sufficient with regard to the supply of goods derived from human blood.
The aim under this policy is for therapeutic goods containing human blood or plasma for supply in Australia to be manufactured from blood or plasma from Australian donors.
The National Blood Authority (NBA) manages the supply of these products.
The TGA uses international standards and guidelines to evaluate data on therapeutic goods that are derived from human blood or plasma to minimise the risk of transmitting infectious diseases through their use.
Sponsors are required to:
- submit a PMF to support an application to enter the therapeutic goods on the Australian Register of Therapeutic Goods (ARTG)
- update the PMF every year to ensure continued safety and quality of the therapeutic goods.
9.2 Standards and guidelines for human blood or plasma
The TGA has adopted the European Medicines Agency (EMA) guideline:
- outlines the quality and control measures expected of a medicinal product that is manufactured from human plasma
- is used as guide to assess these products.
Related information and guidance
9.2.1 Medicines derived from human plasma
The plasma used as a raw material in the manufacture of medicines derived from human plasma must comply with either:
- the European Pharmacopoeia (Ph. Eur.)
- the British Pharmacopoeia (BP) monograph 'Human plasma for fractionation' (0853) which is a Standard under subs. 3(1) of the Act.
220.127.116.11 Plasma used for fractionation
In addition to the requirements of the standard monograph, the plasma used for fractionation must comply with Therapeutic Goods Order No. 102 - Blood and blood components (TGO 102) and TGO 108 Standard for Human Cell and Tissue Products - Donor Screening Requirements with regard to donor exclusion and screening requirements, particularly exclusion criteria for variant Creutzfeldt-Jakob disease (vCJD).
Sponsors include in Module 3 (in the PMF):
- a statement identifying the countries of origin of the plasma
- an assurance that the individual donors had not resided in the United Kingdom for a cumulative period of six months or more between 1980 and 1996, or received a blood transfusion in the United Kingdom from 1980 onwards
- an assurance that donations had been screened using nucleic acid amplification technology for human immunodeficiency virus (HIV) and hepatitis C virus (HCV).
The United States Pharmacopeia-National Formulary (USP-NF) monograph 'Plasma protein fraction'
The United States Pharmacopeia-National Formulary (USP-NF) monograph 'Plasma protein fraction' is not a Standard because it is exempted under the Therapeutic Goods (Exempt Monographs) Amendment Determination 2022, thereby excluding the USP-NF as a Standard for these products.
For this reason the Monographs of the USP-NF cannot be used for the following medicines derived from human plasma:
- Antithrombin III Human
- Factor IX Complex
- Plasma Protein Fraction
Standard for human albumin
The standard for human albumin accepted by the TGA is defined by Therapeutic Goods (Standard for Human Albumin) (TGO 111) Order 2022 , which states that that the requirements for human albumin are the requirements specified in an individual or general monograph in the BP or the Ph. Eur. that is applicable to human albumin, as interpreted in accordance with the General Notices section of the relevant Pharmacopoeia.
9.3 Plasma Master Files for human blood or plasma
The PMF is a stand-alone document that records the quality aspects of human plasma used as a raw material for the manufacture of therapeutic derivatives, including clotting factors, immunoglobulins and albumin. The PMF includes information on:
- the source of the plasma
- the location(s) where the plasma was collected
- the screening process for donors
- the tests used to screen donated blood and plasma
- the results of these testing procedures (epidemiology data).
9.3.1 When is a plasma master file required?
18.104.22.168 Applications for plasma derivative or a product containing a plasma derivative
Include a PMF as part of the product quality data in Module 3 of the Common Technical Document (CTD) format.
The PMF will be evaluated in conjunction with the other product quality data, such as virus removal/inactivation steps.
22.214.171.124 Requests to make a variation to an existing ARTG entry
The PMF is also required in some requests to make a variation to an existing ARTG entry. For example:
- If a manufacturer of a therapeutic good that includes human albumin changes the supplier of the albumin to a different manufacturer, the variation request would need to include the PMF (or a letter of access to the PMF) of the new manufacturer of the albumin as part of the Module 3 data for that application.
- If a manufacturer of a plasma-derived medicine applies to use a fractionation intermediate from an alternative manufacturer, the Module 3 data for such a variation request would need to include the PMF from the alternative manufacturer.
126.96.36.199 Data and format of the Plasma Master File
The data and format of the PMF should conform to 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 Annexes)
- Guideline on epidemiological data on blood transmissible infections (EMEA/CHMP/BWP/125/04).
All activities from donor recruitment and selection through to manufacturing of the first homogeneous plasma pool should be stated in the PMF and are subject to evaluation.
9.3.2 Administrative categories of plasma master files
For the purposes of administration, the TGA has grouped PMFs into two categories:
- Type I PMFs provide the information to support products registered for supply to the Australian market.
- Type II PMFs are those that are required to be submitted to the TGA under Therapeutic Goods (Manufacturing Principles) Determination 2020.
9.4 Plasma master files for human blood or plasma products in the ARTG (Type I)
PMFs for applications for new entries in the ARTG or requests for variations to existing ARTG entries (e.g. where a new plasma fractionator or supplier of albumin is requested) should use the CTD format. The PMF remains a stand alone document distinct from the registration/variation dossier. These should be submitted to Prescription Medicines Authorisation Branch via electronic submission.
Annual updates to Plasma master files
Once a plasma derivative is included in the ARTG, or the variation to the product is approved, a condition of registration is usually applied requiring the PMF to be submitted to the TGA every year.
A PMF update must include updated epidemiology data, and information about changes in plasma collection and screening that have occurred since the last update.
The TGA reviews the PMF update to ensure the continuing quality and safety of the plasma being used in the production of the plasma derivative(s).
Provide a covering letter with the annual update stating:
- the sponsor's name
- the plasma source(s) covered by the PMF that are relevant to the Australian product
- the product(s) covered by the PMF, including the ARTG number(s)
- the period covered by the PMF.
Submit the annual updates to Biological Sciences Section via electronic submission.
There is no statutory timeframe for the evaluation of PMF updates; however, the TGA tries to review them within 60 working days of receipt.
Sponsors will be advised in writing of the outcome of the review and the expected date of the next update.
In lieu of submitting a PMF update for an excipient, the TGA may agree for sponsors to obtain a letter from the fractionator responsible for the PMF to allow the TGA to access the latest version of the PMF on the sponsor's behalf.
9.5 Plasma master files for plasma processed in the same facility as Australian plasma (Type II)
Sponsors are required to submit a PMF for plasma that is sourced outside Australia but processed in the same facility as Australian plasma. This is prescribed by the Therapeutic Goods (Manufacturing Principles) Determination 2020.
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, for that source:
- a PMF, prepared in accordance with the requirements of the European Agency for the Evaluation of Medicinal Products document entitled Guideline on the scientific data requirements for a plasma master file (PMF) Revision 1 (EMEA/CHMP/BWP/3794/03 Rev 1) has been submitted to the Secretary by the licensee of the relevant blood processing plant.
- the Secretary has advised the licensee of the plant, based upon the PMF, and having taken into account the plant's processes, that the plasma from the source outside Australia is unlikely to present a risk of contamination to the Australian product with any known blood borne pathogens.
9.5.1 Manufacturers who fractionate Australian and overseas sourced plasma
Manufacturers that fractionate both Australian plasma and plasma sourced from overseas in the same facility must submit a separate PMF for plasma from each different overseas source.
Only overseas-sourced plasma with a TGA-approved PMF can be fractionated in the same facility as Australian plasma.
These requirements, together with good manufacturing practice (GMP), ensure that products that are manufactured from plasma from Australian donors do not have their safety and quality compromised if the same facility also processes plasma from donors outside Australia.
Submit PMFs to:
Manufacturing Quality Branch
Therapeutic Goods Administration
PO Box 100
WODEN ACT 2606
Approval of PMFs for plasma that is processed in the same facility as Australian plasma is usually granted for one year.
9.5.2 Annual updates
Annual updates to PMFs for plasma that is processed in the same facility as Australian plasma (Type II PMFs) are required under the Therapeutic Goods (Manufacturing Principles) Determination.
A PMF update must include updated epidemiology data, and information about changes in plasma collection and screening that have occurred since the last update. The TGA reviews the PMF update to ensure the continuing quality and safety of the plasma being used in the production of the plasma derivative(s).
Type II PMF updates should be submitted at least three months before the approval of that PMF expires, to allow time for evaluation and resolution of any issues. Sponsors will be advised in writing of the outcome of the evaluation and whether any issues need to be addressed.
Fees apply for the submission of Type II PMFs.
9.6 Variations to plasma master files
Once a PMF has been accepted by the TGA, any changes in plasma collection and testing represent changes to the quality information that may affect product quality and safety.
Major changes to plasma collection and testing require prior approval from the TGA and should not be introduced for the first time in a PMF annual update.
Related information and guidance
9.6.1 Variations that require data to be submitted to the TGA
The point at which individual plasma units are pooled into a manufacturing pool is the first homogeneous pool is a critical point in the manufacture of plasma derivatives.
- Submit any change made to the manufacture of the first homogeneous pool as a Category 3 application.
- Include approved changes in the next PMF update with reference to the TGA approval date and submission number.
The types of changes that should be reported as a Category 3 application are described in the TGA guidance: Variations to prescription medicines - excluding variations requiring evaluation of clinical or bioequivalence data, Appendix 2: Variation types - biological medicines.
9.6.2 Variations that can be reported in an annual plasma master file update
Minor changes do not generally require prior approval or notification to the TGA but should be reported in the PMF annual update.
The types of changes that could be introduced for the first time in a PMF annual update include, but are not limited to:
- addition or removal of collection centres for a currently approved collection organisation
- change of sites for testing individual donations
- change of tests for testing individual donations provided the type and principle of the test remain unchanged.
|Version||Description of change||Author||Effective date|
|V1.0||Original publication||Office of Medicines Authorisation||09/08/2013|
|V1.1||Changed references to TGO 81 to TGO 102||Scientific Evaluation Branch||05/04/2019|
Minor edits to update references to historic legislation including from:
|Scientific Evaluation Branch||March 2022|
|V1.3||Changed references from TGO 88 to TGO 108 and updated electronic submission details||Scientific Evaluation Branch||13/12/2022|