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PE009-13, the PIC/S guide to GMP for medicinal products

TGA interpretation and expectations for demonstrating compliance

2 January 2018

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Radiopharmaceuticals (Annex 3)

Implications of changes to Annex 3

Annex 3 of PE009-13 contains some minor changes from PE009-8. The main additions are:

  • clarification of the application of the Annex to steps in the production of radiopharmaceuticals and radiochemical (APIs)
  • a new explicit requirement to have separate gowning facilities at the entry to the production areas
  • a greater emphasis on radiation monitoring as a contamination control measure
  • changes to the environmental requirements for the location of closed systems used for sterile products


Irradiation of targets in a reactor or cyclotron

Annex 3 now clarifies that activities relating to the irradiation of targets in a reactor or cyclotron are outside the scope of GMP. This means that the reactor and cyclotron equipment are not generally subject to inspection for compliance to PE009-13. However, GMP requirements apply to the supply and preparation of target materials prior to irradiation, as well as any subsequent post-irradiation processing of the irradiated targets. GMP requirements also apply to the target and transfer system from cyclotron to synthesis equipment.

Hospitals supplying radiopharmaceuticals to other hospitals

Hospitals supplying radiopharmaceuticals to other hospitals require a TGA licence, with one exemption. Public hospitals supplying radiopharmaceuticals to other hospitals or public institutions in the same state or territory do not require a TGA licence. In that case, the biomedical engineers, radiochemists and pharmacists employed by those public hospitals are exempt from the requirement to obtain a TGA licence to manufacture radiopharmaceuticals. Further information may be found in Schedule 8 of the Therapeutic Goods Regulations 1990.

Room classification for sterile radiopharmaceuticals

Manufacturing environments for sterile products must follow the general principles outlined within Annex 1 of the PIC/S GMP Guide, and equipment and processes should be located within environments conforming to the required grade, (A, B, C or D). The new version of Annex 3 (clause 27) permits fully closed and automated systems used in the manufacture of sterile goods to be located in a Grade C environment. ‘Fully closed and automated systems’ are interpreted to be those where the product sterile fluid pathway is at no point open to the external environment, and where manual intervention for operation is not required, e.g. a closed sterile holding vessel.

Minimum background grade for hot-cells used for sterile products

Hot-cells should be located in a suitable background environment in accordance with Annex 1 requirements. Fully closed hot cells used for sterile products, should be located in an environment that meets at least Grade D requirements. Higher background grade environments may be required for open processes performed in hot-cells.

A closed process is not opened to the environment at any point after sterilisation, and is normally verified by pressure testing. For this reason, operations involving the piercing of stoppers or septa with needles are not closed systems.

Record retention requirements

Documents used to record the manufacture of radiopharmaceuticals should be stored for a minimum of 3 years.

Retention samples for radiopharmaceuticals

The retention period for radiopharmaceuticals is at least 6 months following product expiry unless justified by sound risk assessment.

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