Evidence of GMP compliance for prescription medicines

Guidance for sponsors

18 November 2015

This guidance is for sponsors and applicants preparing applications and requests involving steps in the manufacture of medicines regulated as prescription medicines.

GMP compliance

GMP compliance is required for all steps in the manufacture (production, quality control and release for supply) of medicines regulated as prescription medicines, unless there is an exemption. For Australian manufacturers, exemptions from the operation of Part 3-3 of the Therapeutic Goods Act 1989 are in Schedule 7 of the Therapeutic Goods Regulations 1990. (Part 3.3 relates to licensing and GMP compliance as a condition of holding a licence.)

The relevant exemptions for prescription medicines are:

  • item no. 2: ingredients, except water, that do not have a therapeutic action, however:
    • relevant monographs in the default standards include additional requirements for excipients derived from human or animal origin, bacteria, viruses and biotechnology products; these additional requirements sometimes include manufacture under GMP
    • the TGA approach to minimising the risk of exposure to transmissible spongiform encephalopathies is relevant for excipients of human or animal origin
  • item no. 17: bulk liquified medical gases
  • item no. 20: medicinal oxygen cylinders that have been decant filled, transfilled or cascade filled by a hospital or an ambulance, fire or rescue service.

We apply the same exemptions to overseas manufacturers as are legislated for Australian manufacturers.

Evidence of GMP compliance

For Australian-based manufacturers, evidence of GMP compliance is a reference to the relevant TGA licence to manufacture.

For overseas manufacturers, evidence of GMP compliance consists of current TGA GMP clearance, except for overseas blood collection centres, for which EU certification is accepted.

Submission of evidence of GMP compliance

If the manufacturing step is recorded on the ARTG, you need to provide us with evidence of GMP compliance upon entry on the ARTG and you are required to keep this evidence current while the medicine is registered on the ARTG.

If the step is not recorded on the ARTG, you do not need to submit evidence of GMP to us. It is the responsibility of the manufacturer of the first step that is recorded on the ARTG to verify ongoing GMP compliance of its suppliers. This verification is part of the supplier evaluation program described in the PIC/S Guide to GMP:

  • for active pharmaceutical ingredient manufacturers: Part II chapter 7 Materials management
  • for finished product manufacturers: Part I chapter 5 Production.

Recording manufacturers on the ARTG

If we require evidence of GMP for a manufacturing step, then that manufacturer needs to be recorded in the ARTG. You need to:

Active pharmaceutical ingredient - chemical medicines

The manufacture of chemical medicines typically consists of separate processes for the manufacture of active pharmaceutical ingredient (also known as drug substance) and finished dosage forms.

For chemical active pharmaceutical ingredient manufacture:

  • the principal manufacturing site is recorded on the ARTG
  • manufacturers of starting materials or intermediates are not recorded on the ARTG.

The principal manufacturing site is usually the site performing the last step in chemical synthesis that changes the structure of the molecule, including any subsequent recrystallisation and purification steps.

Use the table below to determine the steps for which you need to send us evidence of GMP compliance; these are the steps that need to be recorded on the ARTG.

Active pharmaceutical ingredient - chemical entities
Manufacturing step GMP compliance required Recorded on ARTG and GMP evidence required
Principal manufacture or synthesis of active pharmaceutical ingredient*^ Yes Yes
Purification* Yes Yes
Milling or micronisation (of active ingredients or other key ingredients) Yes No
Quality control (physical, chemical, biological, microbiological testing) Yes No
Review of batch production and laboratory control records (described in section 6.7, Part II of the Guide to GMP) Yes No
Packaging Yes No
Stability testing Yes No
Storage No No
Distribution No No

*: Exceptions are some common inorganic salts and simple organic compounds. For more information see 11.2 What substances require a drug master file in TGA guidance on drug master files (active substance master files).

^: For chemical entities derived from fermentation or of human origin, you may also need to provide us with GMP evidence for certain steps prior to the principal manufacturing site; these steps will be recorded on the ARTG.

Active pharmaceutical ingredient - biological medicines

For biological medicines, almost all steps in the manufacture of the active pharmaceutical ingredient are recorded on the ARTG. This is because the manufacturing processes for the active pharmaceutical ingredient and finished dosage form tend to be integrated. This integration might be because manufacture is one uninterrupted process or because quality control testing (such as potency) is done on the active pharmaceutical ingredient and cannot be repeated on the finished dosage form.

Evidence of GMP compliance is required for all crucial quality and safety tests performed on the active pharmaceutical ingredient of biological medicines that are not repeated on the finished dosage form (potency, content and purity).

Use the table below to determine the steps for which you need to send us evidence of GMP compliance; these are the steps that need to be recorded on the ARTG.

Active pharmaceutical ingredient - biological medicines
Manufacturing step GMP compliance required Recorded on ARTG and GMP evidence required
Cell culture, harvest and purification of substance Yes Yes
Master cell bank manufacture, storage and maintenance Yes Yes#
Working cell bank manufacture, storage and maintenance Yes Yes
Manufacture of intermediates from higher risk starting material (e.g. sourced from animals, bacteria, viruses, recombinant material) Yes Yes
Principal manufacture or synthesis of drug substance Yes Yes
Purification Yes Yes
Quality control (physical, chemical, biological, microbiological testing) that is later used for finished product release for supply Yes Yes
Other quality control testing, including outsourced in-process control testing Yes No
Review of batch production and laboratory control records (described in section 6.7, Part II of the PIC/S Guide to GMP) Yes No
Packaging Yes No
Stability testing Yes No
Storage No No
Distribution No No

#: Your evidence should cover the time period when the master cell bank was actually manufactured, which can be a substantial time before the medicine manufacture commences.

Plasma master files

Plasma master files (PMFs) record the quality aspects of human plasma as a raw material for the manufacture of therapeutic goods.

  • For overseas blood collection centres, EU certification is accepted without TGA GMP clearance:
    • Include a copy of such certification in the PMF.
    • These centres are not recorded on the ARTG entry.
  • For all other manufacturers:
    • Include in the PMF a copy of the current TGA licence (Australian manufacturers) or GMP clearance (overseas manufacturers).
    • Ensure that the manufacturer is recorded on the ARTG.

Submit evidence of GMP compliance for plasma master files for:

  • storage facilities
  • viral safety testing
    • individual samples
    • mini-pools
    • manufacturing pool (the manufacturer of plasma for fractionation is also considered responsible for the safety testing on the manufacturing pool)
  • transportation.

Excipients

For lower risk excipients, GMP compliance is not required for:

  • production or synthesis
  • quality control and release testing
  • packaging, storage and distribution.

Submit evidence of GMP compliance for higher risk excipients, such as those of human or animal origin for:

  • production
  • quality control and release testing.

The manufacturer of higher risk excipients is responsible for ensuring the safety of these excipients and the drug substance or drug product manufacturer first using these higher risk excipients is responsible for providing us with evidence for the safety of these excipients.

Water

For water for pharmaceutical use (e.g. water for injection, highly purified water and purified water as per the relevant pharmacopoeial monographs), submit evidence for GMP compliance of:

  • production
  • quality control
  • release for further processing.

GMP compliance of the manufacture of water for pharmaceutical use is important because the quality of the water determines the microbiological quality of the product.

Containers

The manufacture, quality control and release testing of containers do not need to be GMP compliant, except for the sterilisation of containers for sterile medicines when there is no later sterilisation of the finished products.

Please note that in 2010 the requirement for GMP compliance of various container types specified in item 5 of Schedule 7 of the Therapeutic Goods Regulations 1990 was removed.

Sterilisation

Sterilisation must always be GMP compliant.

Use the table below to determine the steps for which you need to send us evidence of GMP compliance; these are the steps that need to be recorded on the ARTG.

Sterilisation steps
Manufacturing step GMP compliance required Recorded on ARTG and GMP evidence required
Sterilisation of the active pharmaceutical ingredient when the active pharmaceutical ingredient is labelled as sterile Yes Yes
Sterilisation of active pharmaceutical ingredient, excipients and intermediates of finished product, when there is no later sterilisation of the finished products Yes Yes
Sterilisation of containers for sterile products by the finished product manufacturer (the whole container and any component that contacts the product at any stage) Yes Yes
Sterilisation of containers manufactured by a supplier when there is no later sterilisation of the finished products Yes Yes
Sterilisation of finished products Yes Yes
Sterilisation of drug substance, excipients and intermediates of finished product when there is later sterilisation of the finished products Yes No
Sterilisation of containers manufactured by a supplier when there is later sterilisation of the finished products Yes No

Finished product (all prescription medicines)

Use the table below to determine the steps for which you need to send us evidence of GMP compliance; these are the steps that need to be recorded on the ARTG.

Finished product
Manufacturing step GMP compliance required Recorded on ARTG and GMP evidence required
Assembly of kits and composite packs Yes Yes
Manufacture of intermediate Yes Yes
Dosage form manufacture Yes Yes
Diluent manufacture Yes Yes
Packaging and labelling, including secondary packaging Yes Yes
Physical, chemical, biological and microbiological testing for release for supply Yes Yes
Release for supply Yes Yes
Stability testing by finished product manufacturer* Yes No
Storage by finished product manufacturer* Yes No
Distribution by finished product manufacturer* Yes No
Stability testing - outsourced^ No No
Storage - outsourced^ No No
Distribution - outsourced^ No No

*: Evidence of GMP compliance for these steps is normally part of the evidence for the finished product manufacture

^: Compliance with other standards may apply

Version history

Version Description of change Author Effective date
V1.0 Original publication Scientific Evaluation Branch with the Regulatory Guidance Team November 2015