Annex 2A – Manufacture of ATMPs under GMP PE009-015

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Annex 2A – Manufacture of ATMPs 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 separates Annex 2 into advanced therapy medicinal products (ATMP) and biological medicines, as follows:

  • 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 and 2B (read Annex 2B blog post) are structured and what the changes are.

Annex 2A: Manufacture of Advanced Therapy Medicinal Products for Human Use

ATMPs are modern personalised medicines which hope to provide cures to diseases by eliminating or repairing disease-causing cells. Put simply, there are three main types of ATMPs:

  • gene therapy medicines: these contain genes that lead to a therapeutic, prophylactic or diagnostic effect. They work by inserting ‘recombinant’ genes into the body, usually to treat a variety of diseases, including genetic disorders, cancer or long-term diseases. A recombinant gene is a stretch of DNA that is created in the laboratory, bringing together DNA from different sources
  • somatic-cell therapy medicines: these contain cells or tissues that have been manipulated to change their biological characteristics or cells or tissues not intended to be used for the same essential functions in the body. They can be used to cure, diagnose or prevent diseases
  • tissue-engineered medicines: these contain cells or tissues that have been modified so they can be used to repair, regenerate or replace human tissue

Source: European Medicines Agency

ATMP manufacturing is a fast-growing sector with many products in development that require compliance with the standards of Good Manufacturing Practice.

PE009-14 guide did not provide an in-depth industry guideline to support ATPMs’ rapid transition from research and development to marketing authorisation and major updates to Annex 2 were necessary to begin aligning the new sector to expected GMP industry standards.

The new Annex 2A was based on the structure of Annex 2, drawing out clauses specifically relevant to ATMPs and then including further GMP principles and components from traditional industry understanding and practices.


PharmOut has expert consultants ready to help if you need assistance implementing/adapting Annex 2A ATMPs’ Good Manufacturing Practices. Please contact us if you want more information, or to discuss your requirements.


The information below explores some of the specifics for Annex 2A Manufacture of Advanced Therapy Medicinal Products for Human Use (ATMP):

Chapter: Scope

The quick-changing nature of the ATMPs sector is recognised and the intentions to accept amendments to assimilate technological changes, clarify uncertainty or consider alternatives if amendments are required, are clearly defined.

Following the previous Annex 2’s principles, this annex was divided as well into two main parts, as follows:

  • Part A: contains supplementary guidance and alternative provisions on the manufacture of the ATMPs (beginning with starting materials control through to final activities and testing).
  • Part B: contains further guidance on selected types of ATMPs and their substances.

The scope clearly defines the applicability of the annex:

  • Investigational ATPMs
  • Market-authorised ATMPs
  • ATMP manufacturing in hospital settings and for compassionate use programs, following national laws.

Chapter: Application of the Annex

  • Part I: Basic requirements for Medicinal Products and Part II: Basic Requirements for active pharmaceutical ingredients of the PIC/S GMP guidelines are still applicable, however extra specific guidance is provided in this annex.

Compliance with this annex is expected and takes precedence over other sections of the PIC/S GMP Guide, however Quality Risk Management (QRM) principles should be used to justify reasons for not doing so.

Other national laws may be applicable as well, for example:

  • To the starting materials for ATMPs, e.g.:
    • Tissues and cells: This legislation covers donation, procurement, testing, processing, preservation, storage, and distribution.
    • Blood and blood components: National legislation may provide the technical requirements for the selection of donors and the collection and testing of blood and blood components.
  • To the manufacturing process (product specific):
    • The appropriate application of GMP should be in accordance with the national law and should be described and justified in the Clinical Trial Application (CTA) or Marketing Authorisation (MA).
  • To the facilities:
    • Appropriate containment should be established and maintained in facilities where any genetically modified organism is handled. An appropriate Biological Safety Level should be established and maintained according to national law alongside with the required level of GMP requirements.

Chapter: Principle

This section aligns with the previous Annex 2, but additions include:

  • Manufacturing processes need to be well designed and controlled so as not to add further variability to the product.
  • To consult any other available guidance documents on the validation of specific manufacturing methods (e.g. virus removal or inactivation).
  • Natural variability of cell-based products needed for ATMPs manufacture should be controlled. These controls, correlated to a well-defined characterisation of the ATPMs, form an important part of the QC.

Chapter: Part A – Supplementary Provisions to PIC/S GMP Guide Part I

This section was fundamentally redesigned. Building on the structure of GMP Part 1, it provides a well-structured section in which the information is well classified and detailed.

Chapter 1: Pharmaceutical Quality System

  • The traditional batch certification by the Authorised Person (AP) following CTA, MA and other relevant regulations is applicable.
  • Two-step release process, or release of products which do not meet release specifications for cases when no alternative treatments are available, are applicable as well.

From the QRM perspective, GMP applies to all lifecycle stages and ATMPs have no exceptions. QRM should be applied across all stages of ATMP development, technology transfer, manufacturing, and product discontinuation.

Chapter 2: Personnel

A few new principles were added to this section, for example:

  • OH&S legislation to be considered for personnel involved with hazardous substances.
  • Clean protective garments appropriate to the operations to be performed should be worn by personnel entering the manufacturing areas.
  • Contamination Control Strategy (CCS) based on the QRM principles should be applied if movement from areas of exposure, for example, to live micro-organisms or genetically modified organisms, to areas where other products, for example, inactivated products or other organisms, are handled cannot be avoided.

Chapter 3: Premises and Equipment

Everything we know about production areas and equipment is reiterated here, for example:

  • Production areas: Detailed requirements regarding the design and operation of manufacturing facilities to prevent cross-contamination, to mention a few:
    • The use of segregated or same (for concurrent production of batches) production areas is justified under QRM principles.
    • Manufacturing activities involving infection viral vectors (e.g. oncolytic viruses, etc.) should be segregated based on documented CCS and QRM principles.
    • For aseptic processes, in line with Annex 1, the environmental monitoring program should include testing and monitoring of non-viable and viable contamination and air pressure differentials. Monitoring locations should be selected based on the QRM principles.
    • Areas’ classifications are based on the QRM principle, considering closed vs open systems, following Annex 1.
    • If small stocks of materials required during the production process are kept in the production area, this should be done for a specific duration and based on defined criteria.
    • A manufacturing step can be performed on premises that are not under the direct control of the manufacturer or MAH (for example hospital wards) only if approved by the Competent Authority and following CTA, MA, or other national requirements.
  • Production equipment should:
    • Not present any hazard to product quality (to not be reactive, additive, or absorptive).
    • If single-use systems are used, the impact on the product from extractable, leachable, insoluble particulate and insoluble matter derived from these systems should be assessed.
    • Like personnel movement, movement of equipment should be restricted, however, if unavoidable, QRM principles should be applied to ensure an effective CCS.
    • Electronic systems used to support manufacturing must be qualified following Annex 11 Computerised Systems and Annex 15 Validation.

Chapter 4: Documentation

Elements added are mainly linked to traceability, for example:

  • The supplier of starting materials of human origin and the anatomical environment from which these materials originate should be identified and described.
  • Records should be kept as auditable documents and linked to the relevant batch documentation. The storage system should ensure that data is easily accessible.
  • Human cells must comply with the principles defined in national law regarding traceability.

Chapter 5: Production

A few general requirements:

  • The use of antimicrobials does not replace the requirement for aseptic manufacturing. Antimicrobials should not interfere with any product microbial contamination testing or sterility testing and should not be present in the finished product unless justified in the CTA or MA.
  • Labels applied to containers, equipment or premises should be clear, well defined and in the agreed format. Care should be taken for the preparation, printing, storage, and application of labels.
  • Primary and secondary packaging operations should be performed in such a way to minimise the risk of cross-contamination, mix-ups or substitutions.
  • Cryopreservation technics – the type of storage chamber, placement and retrieval process should minimise the risks of cross-contamination, maintain the quality of products and facilitate their accurate retrieval.

More requirements regarding the prevention of cross-contamination in production were included, for example:

  • The methods used for sterilisation, disinfection, virus removal or inactivation should be validated.
  • Accidental release of viable organisms should be dealt with following an emergency plan.
  • Decontamination measures should be available and in line with the QRM principles.
  • When the risk of cross-contamination is assessed, the characteristics of the product and the manufacturing process should be scrutinised.
  • Control measures to prevent cross-contamination should be appropriate to the risks identified.

Validation studies should be conducted following defined procedures, and results and conclusions recorded.

  • Phase I and I/II clinical trials are expected to be validated proportionally with the knowledge and risk associated with their phase.
  • For aseptic processes, Annex 1 is applicable.
  • During process validation, if there is a shortage of the starting materials the use of surrogate materials may be acceptable. Where possible, samples from the actual starting materials for critical parts of the manufacturing process should be taken.

Materials control (including ATMP Active Substances) should consider:

  • The approval and maintenance of suppliers of materials.
  • Regular qualification of vendors to confirm their compliance with relevant GMP requirements.
  • QRM principles should be applied to the total supply chain. Quality by Design (QbD) principles could be applied.
  • The Quality Target Product Profile (QTPP) should be established, and the Critical Quality Attributes (CQA) and Critical Process Parameters (CPP) defined to determine the Product Risk Profiles (PRP).

The donation, procurement and testing of human blood, tissues and cells used as starting materials should be following the applicable national law.

Documentation should be available to support traceability for all pre-master bank stages.

Chapter 6: Quality Control

Standard Quality Control principles are listed under this chapter, including:

  • The sampling plan should be based on a risk management approach.
  • Annex 19 is applicable for reference and retention samples.
  • For products with short shelf life, the retention of the sample under conditions that prolong the shelf life (e.g. cryopreservation) could be considered, if indicative of the intended purpose.
  • Stability studies on the reconstituted and thawed product are performed during product development and are not required to be monitored on an ongoing basis.

Batches of ATMPs should be released for sale or supplied to the market after certification by an AP.

If a finished product does not meet release specifications should not be administered to a patient unless justified. The administration of these types of products could be performed only under exceptional circumstances and only by the treating physician.

Chapter 7: Outsourced Activities

Collection of starting materials and highly specialised testing in the jurisdictions that are subject to licensing can be outsourced to a non-GMP licensed third party, as accepted by national law, if:

  • The rationale and justification are captured by the quality system.
  • The contract giver takes responsibility that the contract acceptor demonstrates an appropriate level of GMP commensurate to the risk to the product and the activities performed according to Annex 20.
  • The proportionate qualifications/validations are performed following Annex 15 and Annex 20.

Chapter 8: Complaints and Product Recall

Some of the requirements included are:

  • A “look-back” procedure should be in place for cases when additional donor information, which affects product quality, becomes available after procurement. This involves risk analysis and corrective and preventive actions.
  • In addition to recalls, other risk-reducing actions may be considered to manage the risks presented by quality defects.
  • In addition to the mock recall, the mock transmission of appropriate information to health care professionals should be performed. The frequency should be yearly unless otherwise justified.

Part B – Specific Guidance on Selected Product Types

B1. Animal-sourced Products

Whilst some clauses have been updated and rephrased, the requirements remain for the most part unchanged. Additions include further detail about the quality systems required for abattoirs supplying materials, eg., QMS requirements, training, and material traceability.

B2. Gene Therapy Medicinal Products (GTMPs)

This section (previously B9) has been generally restructured and rewritten, giving more emphasis to a customised risk-based approach to safety than before.

Guidance regards viral vectors and plasmids have been separated and asks that:

  • Annex 2A and elements of Part II of the PIC/S Guide should be considered for the manufacturing of viral vectors and plasmids where appropriate.
  • The ATMP manufacturer is responsible for the appropriate quality of the viral vectors and plasmids used as starting materials.
  • Outsourced manufacture of vectors should be conducted by a suitably qualified vendor.

B3. Somatic Human and Xenogeneic Cell Therapy Products and Tissue Engineered Products and Combined ATMPs

This section (previously B10) has also been rewritten and includes:

  • In the manufacture of products involving human or animal origin cells special attention should be given to traceability requirements.
  • If combined with medical devices, an appropriate Qualify Agreement should be in place between manufacturer and device suppliers to assure consistent qualification of the device during the lifecycle of the product.
  • The applicability of B2 section should also be considered.

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


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

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