GMP Compliance for Cell and Gene Therapies

In general, the product life cycle of an ATMP is considered in a risk-based approach. This gives the cell and gene therapy manufacturer flexibility, but also the obligation to identify and assess the existing risks of the manufacturing process, product quality, safety, and efficacy and to implement appropriate measures. The application of the risk-based approach can facilitate compliance with regulatory requirements but does not relieve the manufacturer of its obligation to fulfill them. The application of the risk-based approach should be closely related to the provisions of the clinical trial authorization. This results in a high level of documentation work, which we will gladly support you with.

Risk-based adjustments are justifiable for: 

• Premises, equipment, and maintenance
• Qualification and validation
• Starting materials and special consumables
• Documentation with the exception of traceability requirements

Cell and gene therapeutics require individual handling, additional stability tests, and quality controls due to their often low stability and sometimes short service life. The differences in quality of the starting material often result in high demands on incoming controls. The manufacturing process is usually carried out manually in complex processes. A particular challenge is the often limited and heterogeneous starting and final material. The batch sizes are small, or it is a personalized individual therapy.

However, vigilance is also a challenge, as cell and gene therapies may pose an increased risk of contamination, subsequent immunological reactions, or as yet unknown risks for patients compared to conventional medicinal products.

Automation of cell and gene therapy production will only be possible in subsequent further development or can be ruled out altogether due to the small batch sizes.

Nevertheless, the identity, purity, and functionality of the products must be fully guaranteed and a GMP-compliant manufacturing process ensured.

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Would you like to shape the future with cell and gene therpeutics? We will be happy to support you from bench to bedside. Get in touch with us now. Together we will take your therapy to the patients.

To date, there are no mandatory requirements for compliance with Good Laboratory Practice (GLP). However, this may change soon.

Hence it generally makes sense to introduce controlled documents at an early stage, which outline the responsibilities and show the development of the processes by means of versioning. Process validations prove the stability of the processes; development reports document whether the product is state-of-the-art in terms of science and technology and whether the required specifications have been achieved. In parallel, test methods must be valid. These are essential requirements to apply for a manufacturing authorization.

Qualified cleanrooms are a prerequisite for obtaining a manufacturing authorization. A sterile environment is required for the manufacture of cell and gene therapies. The rooms must be regulated in accordance with DIN EN ISO 14644 and must have appropriate High Efficiency Particulate Air (HEPA) filters, a specified temperature and humidity regulation, as well as pressure cascades depending on the cleanroom class, and must be qualified regularly. The GMP environment also requires equipment whose suitability has been proven in a comprehensive qualification.

If a process is transferred to a GMP-compliant cleanroom, manufacturers must address the requirements of the ATMP GMP Guideline and perform appropriate technical runs and the validation of aseptic procedures. In addition, they must present validation of the sterile process control (Media Fills). Once all measures, including GMP-compliant documentation, are completed, an application for a manufacturing authorization can be submitted to the responsible regional council.

The first major challenge in development is obtaining a manufacturing authorization in accordance with § 13 AMG (for Germany). This manufacturing authorization is the basic prerequisite for the manufacture of iATMPs. It must already be available for iATMPs as phase I investigational medicinal products, i.e. for the first application in humans. The corresponding GMP certificate must be renewed every three years by the authority carrying out a re-inspection.

Valicare will gladly support you in applying for such a manufacturing authorization at the responsible regional council and in meeting the requirements.

Would you like to shape the future with cell and gene therapeutics? We will be happy to support you in applying for a manufacturing authorization. Get in touch with us now. Together we will take your therapy to the patients.

According to article 28 of Regulation (EC) No. 1394/2007, individual EU member states can approve their ATMPs on a national basis as part of a derogation. Within the scope of the 15th AMG amendment, a corresponding regulation was also implemented in the German AMG. All requirements for an ATMP specified in § 4b (3) AMG must be fulfilled. Amongst others, the cell and gene therapy must correspond to the state of scientific knowledge, fulfill the intended function, and have a balanced benefit-risk ratio. 

Quality, efficacy, and safety are assessed in an approval process which requires a manufacturing authorization. Furthermore, there is an obligation to document and report to the PEI in regular intervals. Reports must be submitted on the scope of manufacture and the knowledge gained about the medicinal product and its pharmacovigilance. Art 15. of Regulation (EC) No. 1394/2007, § 13c of the Transplantation Act (Transplantationsgesetz, TPG), and the Tissue Ordinance (TPG-GewV) apply with regard to the traceability of medicinal products derived from human tissue or cells. 

Would you like to shape the future with cell and gene therapeutics? We will be happy to support you in complying with and implementing the specific requirements of the national exemption. Get in touch with us now. Together we will take your therapy to the patients.

Once pharmaceutical development is finished and market supply is secured, the central registration with the EMA takes place. The minimum requirements for approval are:

• Description of the manufacturing environment including naming of the premises and responsibilities, the validation master plan (VMP), documents on the qualification and validation status, and specifications on hygiene and monitoring
• Presentation of the GMP system (pharmaceutical risk management, GMP documentation, procedural instructions for GMP-relevant processes, change and deviation management, CAPA system, personnel qualifications, and training)
• Reports on the development of manufacturing and quality control methods
• Specifications of starting materials including supplier qualification

• Dossier of the investigational medicinal product (IMPD)
• Preclinical and clinical trials
• Measures to secure market supply
• Documents on contract manufacturing procedures, if applicable

Would you like to shape the future with your cell and gene therapeutics? We will be happy to support you in preparing and submitting the necessary documents. Get in touch with us now. Together we will take your therapy to the patients.