GMP regulations in Advanced Therapy Medicinal Products

What are ATMPs?

Advanced therapy medicinal products (ATMP) are gene therapy, somatic cell therapy or tissue-engineered products regulated under (EC) No. 1394/2007 to guarantee the highest level of health protection for patients.

ATMPs are often developed in an academic or hospital environmental setting under quality systems different to those typically required for the manufacture of conventional medicinal products. There has been a surge in development of Advanced Therapy Medicinal Products (ATMPs) in the EU and the USA. Many start-ups have entered into manufacturing of ATMPs.

Which GMP regulations apply?

The basic rules for Good Manufacturing Practices (GMPs) and quality of traditional pharmaceutical manufacturing are well established, however, for ATMPs these are still new and under development. The current guide for ATMPs, EU GMP guide Part IV ‘GMP for ATMPs’, will be discussed in detail in this course.

The manufacturing of ATMP presents challenges in ensuring product quality, such as the safety and the variability of the starting materials, the quality of the raw materials, contamination during the entire manufacturing cycle, the limitations of the analytical methods available to characterize therapy products.

The environment of the ATMP-Manufacturing needs to be well understood, controlled and adapted by common sense GMP and quality principles. The available EMA/FDA regulatory authority guidance documents for ATMPs will be thoroughly presented and discussed in the course.

The GMP regulations support the biotechnological and medical development in the field of ATMPs (i.e. gene therapies, somatic cell therapies and tissue engineered products) though guidelines such as manufacturing of autologous products, automated production, outsourced reconstitution, and gene editing such as CRISPR and immunomodulators. Currently, these biotechnologies must comply with the general GMP guidelines set out by the FDA and EMA.

Evaluation of risks in ATMP manufacturing

Both European and US-American guidelines follow a risk-based approach which encourages manufacturers to design organizational, technical and structural measures appropriate to the specific risks of the product and the used manufacturing processes. The evaluation of risks and effectiveness of the manufacturing processes, including the controls and mitigation measures, should be based on current scientific knowledge and the manufacturer’s accumulated experience.

They define a number of precautions and checks to improve the safety of the finished product. The specified guidelines should simplify the detection of nonconformity that affects product safety and efficacy. For example, the manufacturers should establish specifications for the starting materials which should be agreed with the safety data determined scientifically. These specifications should cover aspects of the production, testing and control, storage, and other aspects of handling and distribution as appropriate.

ATMP manufacturing should comply with the basic GMP principles such as having an adequate number of personnel with appropriate qualifications and adequate practical experience relevant to the intended operations. The guidelines require ATMP manufacturers to ensure that premises are designed to minimize the opportunity for cross-contamination, the risk of errors and adverse effects on the product quality. Furthermore, equipment must be fit for the intended purpose and documentation systems must be designed to control, monitor and record all activities which may affect the quality of the ATMPs.