What are the GMP Requirements for ATMPs?

What are ATMPs and how can they be classified?

Advanced Therapy Medicinal Products (ATMPs) are medicinal products for novel therapies that differ fundamentally from traditional chemically synthesised medicinal products. They are based on genetic, cellular or tissue material and intervene deeply in biological processes. The legal definition of ATMPs can be found in Article 2 of Regulation (EC) No 1394/2007 in conjunction with Part IV of Annex I to Directive 2001/83/EC. According to this, three main categories are distinguished:

• Gene therapy medicinal products (GTMP)
• Somatic cell therapy medicinal products (sCTMP)
• Tissue-engineered products (TEP)

Gene therapy medicinal products contain or consist of recombinant nucleic acid (DNA or RNA) that is introduced into the human body to regulate, replace, add or delete a genetic sequence. The therapeutic effect is based directly on the nucleic acid or its expression product. Somatic cell therapeutics contain or consist of cells or tissues that have been manipulated or are used non-homologously and whose effect is transmitted pharmacologically, immunologically or metabolically. Tissue-engineered products, on the other hand, are used for the regeneration, repair or replacement of tissue; here, the focus is on structural or functional restoration. The criteria of "substantial manipulation" and "non-homologous use" are essential for the distinction.

Scientific classification is carried out by the EMA, at the request of the sponsor of a clinical trial, with the involvement of the Committee for Advanced Therapies (CAT) in accordance with Article 17 of Regulation (EC) No 1394/2007. National authorities such as the Paul Ehrlich Institute (PEI) provide advice and oversight within the national context. The decision-making logic established by the PEI makes it clear that the first step is to assess whether a biological medicinal product is involved, and whether it contains recombinant nucleic acid or whether cells have been substantially manipulated or used in a non-homologous manner. This structured assessment is essential in practice, as both the authorisation procedure and the applicable GMP requirements depend on the classification. An incorrect classification can have significant regulatory consequences. While this primarily has regulatory and supervisory consequences in the EU context, comparable misclassifications have led to FDA warning letters in the US. There is no global harmonisation of classification.

Legal background, critical manufacturing and release

The legal basis for ATMPs includes Regulation (EC) No 1394/2007, which has been in force since 2007 and has been applicable since 30 December 2008. It supplements Directive 2001/83/EC and establishes a harmonised set of rules, directly applicable throughout the EU, for authorisation, supervision, pharmacovigilance and market surveillance. Directive 2009/120/EC was adopted to govern the technical structure of the marketing authorisation dossier (Modules 3–5). In terms of GMP legislation, EudraLex, Volume 4, Part IV is particularly relevant – the standalone EU GMP guideline specifically for ATMPs.

Part IV does not constitute an isolated parallel regime, but is an integral part of the EU GMP guidelines. This specialisation takes account of the fact that ATMPs are often manufactured outside an industrial setting, on a patient-specific basis, in very small batches and under time-critical conditions. The GMP approach therefore follows the risk-based approach of EU Directive 2009/120/EC. The principle of "proportionality" plays a central role: validation, qualification and documentation must be proportionate to the risk to quality and patient safety. Risk analyses are carried out in accordance with the Quality Risk Management (QRM) of ICH Q9.

In practice, the manufacture of medicinal products using human cells, tissues or blood components requires an integrated quality system that takes into account both the requirements of the EU GMP regulations and the specific legal provisions of tissue and blood legislation. In addition to batch-related traceability in accordance with GMP, donor- and recipient-related traceability systems must be implemented in accordance with Directives 2006/86/EC and 2005/61/EC respectively. The Single European Code (SEC) must be applied to tissue and cell preparations, subject to specific exceptions. With the entry into force of the SoHO Regulation (EU) 2024/1938, this regulatory framework will be harmonised and expanded in future. The transition phase will require significant organisational adjustments, particularly in the areas of traceability and quality systems.

Another key focus of GMP is on starting materials, particularly viral vectors. These are essential for many gene therapies and CAR-T products. Although they are of biological origin, the practical implementation of GMP requirements in upstream manufacturing steps is not fully harmonised and is assessed on a risk-based basis. However, their manufacture is generally subject to the GMP requirements set out in Part II and Part IV of the EU GMP Guidelines. ATMP manufacturers are responsible for ensuring an appropriate level of GMP standards is met by their suppliers. This is typically achieved through risk-based audits, supplier qualification and scientifically sound release strategies. This is a particular focus during inspections of ATMP manufacturers.

The manufacturing process itself is often aseptic, as terminal sterilisation is not possible with living cells, nor with viral or non-viral vectors. Although the relevant requirements are contained in Part IV,  certain requirements of Annex 1 apply in addition. At the same time, the ATMP Guide permits more flexible validation approaches, such as conducting concurrent validation or validating related products where there is a shortage of materials. Cleaning validation may also deviate from traditional "health-based exposure limits" and be conducted in a more risk-based manner.

Batch release is of particular practical relevance. Due to short shelf lives and patient-specific applications, release may be permissible in certain cases before all QC results are fully available, provided that robust risk management is in place. Similarly, the use of out-of-specification (OOS) batches is conceivable under strictly defined conditions, for example in autologous therapies where there is no therapeutic alternative. Prerequisites include SOP-regulated procedures, a documented risk analysis, and medical justification and supervision.

Finally, it should be noted that ATMPs may also be manufactured under the so-called "hospital exemption". Although these products are not subject to centralised EMA authorisation, they must be manufactured under GMP conditions of equivalent quality. This presents a particular challenge for university institutions, which must reconcile industrial GMP standards with clinical flexibility. The quality requirements for these products are set out in the European Pharmacopoeia.

In summary, the GMP requirements for ATMPs are characterised by two key elements:

• a separate, specifically adapted GMP framework (Part IV in combination with Part I and the Annexes)
• a consistently risk-based and proportionate approach to ensuring patient safety
  

For manufacturers, this means a high degree of regulatory complexity; however, the risk-based approach also offers "scope for flexibility" – provided that Quality Risk Management is scientifically sound, transparently documented and consistently focused on patient protection.