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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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Biological medicinal substances and products for human use (Annex 2)

Implications of changes in Annex 2

Annex 2 of PE009-13 contains greater guidance for the management of biological medicinal substances and products. The main changes are:

  • Application of GMP principles to all critical stages in the production of biological medicines, following a risk-based approach and in alignment with international regulations
  • Greater emphasis has been placed on the control of initial components used, e.g. management of animals, materials sourced from animal or plant sources, establishment and maintenance of master cell banks and/or seed lots. Specific guidance has been included that emphasises the importance of managing risks associated with the starting materials used
  • Clarification of existing requirements and the application of quality risk management
  • Re-write of the annex to provide clarity on the GMP requirements for novel technologies used in biotechnology, including transgenic animal and plant products

Most of the changes in Annex 2 relate to a clarification of existing requirements, and as such it is anticipated that most manufacturers involved with the manufacture of biotechnology products should already be compliant with the updated requirements.

The main emphasis of the changes relate to the management and oversight of manufacturers in the supply chain undertaking critical early steps in the manufacturing process. These entities include, but are not limited to, those involved in:

  • collection of organs, tissues or fluids
  • establishment and maintenance of master and working cell banks or seed lots

It is expected that manufacturers using these suppliers undertake appropriate evaluation and oversight of these critical suppliers to ensure appropriate GMP principles are met.

For more information, see guidance on the GMP evidence requirements for these manufacturing activities.

Annex 2 applies to APIs for biological medicines

The manufacture of APIs for biological medicines is usually performed in immediate conjunction with the manufacture of the biological medicinal product itself. For that reason, Annex 2 is written to cover both the API and the finished product manufacturing steps of biological medicines. Additionally, Part II of PE009-13 is applicable to the manufacture of APIs for biological medicinal products.

Guidance relating to the application of Annex 2 and Part II of the GMP guide to the manufacture of biological APIs may be found in the tables published in the respective documents.

Human blood, blood components, tissues and cellular therapies are not covered by Annex 2

Annex 2 has not been adopted by the TGA for the regulation of human blood, blood components, human tissues and human cellular therapies. These products will continue to be inspected in accordance with the Australian Code of Good Manufacturing Practice for human blood and blood components, human tissues and human cellular therapy products.

Biological substances covered by Annex 2

As a general guide, the following are considered biological medicinal products under the requirements of Annex 2:

  • animal derived fractionation products
  • antibiotics produced by fermentation
  • antigens
  • antitoxins, antivenenes, enzymes and venoms
  • products used for allergy testing
  • biological medicinal products
  • cytokines
  • hormones
  • human derived fractionation products
  • immunosera
  • monoclonal antibodies
  • somatic cellular products
  • therapeutic recombinant products
  • toxoids/toxins

Raw materials intended for listed medicines are not covered by Annex 2

Also, as a general guide, although certain starting materials listed in the Catalogue of permitted ingredients for use in listed medicines could be considered biological medicinal products, the additional requirements of Annex 2 will not be applied to raw materials included in the catalogue intended for use in the manufacture of listed medicines, e.g.:

  • beta-carotene
  • shark cartilage
  • bee propolis
  • green lipped mussel
  • deer antler
  • royal jelly

Biological medicinal products with a short shelf-life

Biological medicinal products with a short shelf-life can be released for supply before all quality control results are finalised, provided an adequate control strategy is in place. The requirements for this control strategy are provided in clause 71 of Annex 2, and should reflect any conditions of the marketing authorisation (where relevant).

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