GMP for ATMP Investigational Medicinal Products

The development and clinical testing of ATMPs are particularly challenging

GMP adaption allowed by risk-based approach

For the clinical development of advanced therapy medicinal products (ATMPs), only few uniform standards are currently established. This makes it possible to do justice to the particular scientific advances, the complexity and the technical characteristics of advanced therapies, even at the individual stages of development.

In principle, the requirements for quality, safety and traceability must be met. However, adjustments in the application of good manufacturing practice (GMP) requirements are possible, especially in the early phases of clinical development, if a risked based approach is justified.

For example, risk-based adjustments are acceptable for:

• Premises, equipment and maintenance
• Qualifications and validations
• Starting materials and special consumables
• Documentation (formalities and content details) with the exception of traceability requirements

Different regulatory guidance for development stages

In addition to the general GMP requirements from Part IV of the EU GMP Guideline, the requirements of Annex 13 for investigational medicinal products also are applicable here, as well as an extensive set of guidelines that reflect product-specific requirements for the individual stages of development.

Starting materials in ATMP manufacture

The guidelines as well as reflection papers from the European Medicines Agency (EMA) outline in particular the requirements for starting materials and the manufacturing process in order to minimize risks. For cell- and tissue-based medicinal products, safety and efficacy are addressed first and foremost. In addition to ensuring process stability, particular attention is paid here to excipients and to the biotechnological manipulation of raw materials. In order to standardize the test methods, a whole series of monographs of the EU Pharmacopoeia have been adapted.

Gene therapeutics – Vector in the spotlight

For gene therapeutics, the focus is also on the genetic origin of the vector, the vector design, the starting material used, and the purification and control steps. In non-clinical studies, risks to which the patient could be exposed, such as insertional mutagenesis or unintended germline transmission of the gene transfer vectors, must be considered in advance. Furthermore, environmental compatibility tests are necessary.

Inherent variability of the donor material

All ATMPs have a number of additional requirements that differ from those of conventional medicinal products. The variability of the donor material results in a generally lower stability, so storage and transport have a special role to play. The novelty implies that only a small collective is treated, therefore a guideline on clinical trials in small populations is necessary as well as a clear requirement on biostatistics.

ATMP development is a matter of time

The challenge of GMP for ATMPs in the development phase is therefore to present the risks accordingly and to adapt the risk-minimizing and controlling measures to the respective state of knowledge. To ensure the success of clinical development, the subsequent development steps must be considered in a timely manner so that processes, materials and equipment do not have to be fundamentally changed, if possible, and continuous improvements can be made.

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