Annex 2B – Manufacture of Biologicals under GMP PE009-015

Annex-2B-Biologicals

Annex 2B – Manufacture of Biologicals under GMP PE009-015

PE00-015 Guide to Good Manufacturing Practice for Medicinal Products has recently been adopted by the TGA in Australia. Notably, this update splits Annex 2 into Annex 2A: Advanced Therapy Medicinal Products and Annex 2B: Biological Medicines separately:

Annex 2A: Manufacture of Advanced Therapy Medicinal Products for Human Use (ATMP) harmonises with the EudraLex Volume 4 Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products.

Annex 2B: Manufacture of Biological Medicinal Substances and Products for Human Use continues to harmonise with the EudraLex Volume 4 Annex 2 Manufacture of Biological active substances and Medicinal Products for Human Use.

This blog series explores how the new Annexes 2A (read Annex 2A blog post) and 2B are structured and what the changes are.


PharmOut has expert consultants ready to help if you need assistance implementing/adapting Annex 2B Manufacture of Biological Medicinal Substances and Products for Human Use Good Manufacturing Practices. Please contact us if you want more information, or to discuss your requirements.


Annex 2B: Manufacture of Biological Medicinal Substances and Products for Human Use

It was surprising to see that this annex has been left open to some interpretation and that it does not so closely follow the structure of GMP Part 1, as for Annex 2A.

Requirements for the PQS and QRM seem hidden rather than manifestly stated as critical GMP principles. Additionally, electronic systems and Annex 11 are not mentioned, even though computerised systems are part of our day-to-day professional lives.

The intention to achieve harmonisation with the formatting structure of the EU GMP Guide is explicit, some clauses have been left intentionally blank, for example:

  • Clause 44: “Seed lot and Cell Bank System” section, regarding the cell-based medicines generated from a cell stock obtained from a limited number of passages or
  • Clause 68: “Quality Control” section, regarding the ongoing stability programme for intermediates stored for an extended period.

Let’s see what the additions are:

Chapter: Scope

  • If tissues and cells provide the active substances for biological medicinal products within the scope of this annex, GMP and other medicinal product legislation requirements apply.

Chapter: Principle

  • Manufacturing should be consistent with other specifications and not only with specifications related to products, for example, the number of generations between the seed lot or cell bank. These specifications should be set out in the CTA or MA.
  • Biological medicinal products, which incorporate human tissues or cells, must comply with national requirements for the coding, processing, preservation, storage and distribution of human tissues and cells.

Chapter: Part A – Supplementary Guideline

Premises and Equipment

Live organisms and spores should be prevented from entering non-related areas or equipment by:

  • considering all potential routes of cross-contamination
  • utilising single-use components
  • engineering measures (e.g., closed systems)

Starting and Raw Materials

  • The donation, procurement and testing of human tissues and cells used as starting materials for biological medicinal products should be following national law.

Operating Principles

  • For autologous products, the unique patient identifier, and the statement “for autologous use only” should be indicated on the outer packaging or, where there is no outer packaging on the immediate packaging.

Chapter Part B – Specific Guidance on Selected Product Types

Clauses for specific guidance on selected biological product types remain unchanged from that of PE009-14:

  • B1 Animal-sourced products
  • B2 Allergen products
  • B3 Animal Immunosera Products
  • B4 Vaccines
  • B5 Recombinant Products
  • B6 Monoclonal Antibody Products
  • B7 Transgenic Animal Products
  • B8 Transgenic Plant Products

The lack of detail in Annex 2B compared with that of Annex 2A is noteworthy – why such a robust adoption of modern GMP principles for the latter compared with the former? But the answer is signposted in the guidance document itself:

This annex is not a stand-alone document and should be applied in conjunction with PIC/S GMP guidelines and annexes. It has however been written in a manner that it could enable the development of a standalone guide if integrated with PIC/S GMP Part I, Part II and related annexes.

Indeed, ATPMs are a dynamic area which requires a sound and adaptive compliance framework that can accommodate the inevitable changes that will arise from scientific and technological progress.

NB, It is worth noting that Australia’s TGA have chosen to implement PE009-15 whilst much of the rest of the world are already moving on with PE009-16, published in February 2022. In the context of this blog, there are no differences between Annexes 2A and 2B of these two versions, but PE009-16 does update Annex 13 for IMPs and implements Annex 16 for Authorised Persons and Batch Release, in line with Europe’s approach. The TGA will continue to follow the Release for the supply of medicines Technical guidance on the interpretation of the PIC/S Guide to GMP Version 3.0, February 2019.

Want more?

PharmOut has expert consultants ready to help, if you need assistance implementing or adapting Annex 2B contact us

To further improve your understanding of the changes implemented by the introduction of Annex 2A and 2B, PharmOut has the following eLearning modules available: Annex 2A ATMP Manufacturing