Regulatory Requirements for ATMPs
In general, every medicinal product for human use is subject to the requirements of;good manufacturing practice (GMP). These are regulated throughout Europe and written down in EudraLex, Volume 4 – The rules governing of medicinal products in the European Union. This guidance on the interpretation of the principles and guidelines of Good Manufacturing Practice for medicinal products for human and veterinary use serves to implement commission Directive 91/356/ECC as well as its amendments by Directive 2003/94/EC and 91/412/ECC. Moreover, a guideline on requirements for investigational ATMPs in clinical trials in preparation and is planned to be finalized in 2023.
In order to do justice to the special features of ATMPs, special GMP regulations have also been drafted for this purpose. This guidance, “Guidelines on Good Manufacturing Practice (GMP) specific to Advanced Therapy Medicinal Products”, was adopted by the European Commission on 22.11.2017 and has been mandatory since May 2018.
Part IV of the EU GMP Guideline was designed to accommodate the development of new therapies, as it is particularly applicable to the development of new ATMPs (investigational ATMPs or iATMPs). In contrast to Part I of the EU GMP Guideline, which describes standard expectations, for ATMPs under Part IV, alternative approaches can be implemented by manufacturers if it can be demonstrated that the alternative approach achieves the same objective. Any adaptation used must be consistent with the objective of ensuring quality, safety, efficacy, and traceability of the product.
This explicitly means that alternative methods must be considered on a risk-based approach. As a result, a greater amount of documentation is required in the form of risk analyses, assessments and reports. In addition, new requirements are formulated that are due to the special characteristics of ATMPs. For example, special starting materials, such as cell banks, and special manufacturing methods, especially those involving automation, are considered, as well as a requirement for reconstitution after release. In addition, an extended retention period of 30 years is required, as these are novel medicines about which not enough information is yet available.
The regulations are independent whether the medicinal product is launched on the market within the scope of an exemption according to § 4b of the German Medicines Act (Arzneimittelgesetz, AMG), individually prepared, for use in a clinical trial or as an approved market product.
If you have any questions regarding Part IV of the EU GMP Guideline, please call us. We will advise you how to bring your product to the market faster.
In general, the product life cycle of an ATMP is considered in a risk-based manner. A risk-based approach provides flexibility to the ATMP manufacturer, but also obliges him to name and assess the existing risks of the manufacturing process, product quality, safety, and efficacy and to implement appropriate measures. The use of the risk-based approach can facilitate compliance with regulatory requirements, but does not relieve the manufacturer of its obligation to meet them. However, this is reflected in a very extensive documentary effort, as well as the obligation to keep the documentation for 30 years. While the responsibility for the application of the risk-based approach lies with the manufacturer, it is recommended to seek the advice of the competent authorities (scientific advice) when implementing the risk-based approach for investigational ATMPs (iATMPs). The application of the risk-based approach should be closely related to the provisions of the clinical trial authorization.
For approved ATMPs, the application of the risk-based approach should be consistent with the provisions of the medicinal product authorization. The application for medicinal product approval may highlight the specific characteristics of the product or manufacturing process to justify the adaptations or deviations from the standard requirements. This applies to managing specific limitations that exist related to the manufacturing process, including control of raw and starting materials, manufacturing facilities, manufacturing equipment, acceptance criteria, process validation, release specifications, or stability data.
ATMPs require due to their often reduced stability and sometimes short lifetime an individual handling, additional stability tests and quality controls. The quality differences of the starting material often require high demands on incoming controls. The manufacturing process is often carried out manually in complex processes. The particular challenge is the often limited and heterogeneous starting and final material, batch sizes are small up to personalized individual therapy. However, ATMP vigilance is also a challenge, as ATMPs, due to their origin and handling, may pose an increased risk of contamination compared to conventional medicinal products, immunological secondary reactions or still unknown risks to patients. Possible risks and side effects cannot always be predicted from preclinical data and clinical studies conducted, as the therapies are too individual. Automation of the manufacturing process will only possible in subsequent further development or can be ruled out altogether due to the small batch sizes. In addition, ATMPs are sometimes prepared in such a way that they have to be reconstituted after release and before application.
However, it must be ensured that certain specifications are met. These include:
The journey of an ATMP from the laboratory bench to the bedside takes a long time, during which methods and processes of manufacturing and quality controls must be established and stabilized. A great deal of knowledge must be available or generated until the idea is ready for development. The instructions used must be laid down in standard operating procedures (SOPs) and their implementation in corresponding protocols and reports. As a rule, development reports are written about the lengthy preclinical phase of development.
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Beyond that, however, more is needed: A sterile environment is also required for the manufacturing of ATMPs. Many university hospitals have clean room facilities. As in the pharmaceutical environment, the rooms are regulated according to DIN EN ISO 14644 and have appropriate high efficiency particulate air (HEPA) filters, predetermined temperature and humidity control and pressure cascades depending on the cleanroom class. These are intended to help exclude particles and contaminants on them. In a required particle monitoring (at rest and in operation) as well as a defined air and surface germ determination, it has to be shown that the particle and germ input is below a defined threshold value. In the GMP environment, devices are required whose suitability has been demonstrated within a qualification (including the installation qualification, operational qualification and performance qualification phases).
If a process is transferred to a clean room in a GMP environment, the requirements of the ATMP GMP Guideline must be addressed and appropriate technical runs and validation of aseptic procedures must be performed. In addition, the validation of sterile process control (Media Fills) must be presented. After completion of all measures and compilation of the documentation, an application for manufacturing authorization can be submitted to the regional council.
The first major challenge for a developer is to obtain a manufacturing authorization according to § 13 AMG. However, this manufacturing authorization is the basic prerequisite for the manufacturing of iATMPs. It must already be available for the manufacturing of iATMPs as phase I test product, i.e. for the first application in humans. Valicare will gladly support you in applying for such a manufacturing authorization at the responsible regional council and in meeting the requirements. According to § 4 Abs. 14 AMG, the term “manufacturing” includes the manufacturing, preparation, processing, decanting including filling, packaging, labelling, and release of a medicinal product. The corresponding GMP certificate must be renewed every three years by means of a repeat inspection by the competent authority.
The development of a new medicinal product can basically be divided into several stages: First, the characterization and standardized manufacture of the product are performed to ensure quality, followed by the safety and efficacy demonstrations in non-clinical models. In the final phase, the product is tested in clinical trials to determine its safety and efficacy in humans. The Paul Ehrlich Institute (PEI), the responsible higher federal authority, offers a needs-oriented, step-by-step consulting concept, in which Valicare will gladly support and accompany you in the pre- and post-trial phases. Within the scope of this consultation, product-specific questions in the quality, non-clinical and clinical areas can be discussed with regard to regulatory requirements, e.g. questions about the manufacturing process, microbiological or viral safety as well as pharmacokinetics, toxicology, biodistribution, inclusion, and exclusion criteria or the study population. Many ATMPs offer therapeutic concepts for the treatment of rare diseases, which often mean small patient populations and thus limitations in patient recruitment. This contingency must be considered when planning the pharmaceutical development of the ATMP. In such cases, orphan designation status may be sought from the European Medicines Agency (EMA).
The testing of clinical trials in the field of vaccines and biomedical medicinal products is also the responsibility of the PEI in Germany. Already from phase I of the clinical trial, a manufacturing authorization according to § 13 AMG is required, and these preparations may then be used on patients if the responsible ethics committee has also examined the procedure and assessed it as ethically justifiable. Valicare offers comprehensive services in investigational product management.
According to Article 28 of Regulation (EC) No. 1394/2007, individual member states of the EU may approve their ATMPs on a national basis under 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 AMG, Abs. 3 must be met so that such an approval can be obtained. The ATMP must correspond to the state of scientific knowledge, fulfill the intended function and have a balanced benefit-risk ratio. In addition, the following requirements for a classified ATMP must be met:
Quality, efficacy and safety are assessed through an approval process. In this context, the specific quality standards must correspond to the specifications at community level that apply to ATMPs requiring central authorization, for which reason a manufacturing authorization is required in accordance with § 13 AMG . Furthermore, the holder of such an authorization has a documentation and reporting obligation to the PEI at regular intervals and must report on the extent of manufacture and on the knowledge gained of the medicinal product and its pharmacovigilance. With regard to the traceability of medicinal products derived from human tissue or cells, Art 15. of Regulation (EC) No. 1394/2007,§ 13c of the Transplantation Act (Transplantationsgesetz, TPG) and the Tissue Ordinance (Transplantationsgesetz-Gewebeverordnung, TPG-GewV apply. Valicare has also been able to support customers with special requirements in this area on several occasions. Valicare guides and supports clients in complying with and implementing the specific requirements of the National Exemption.
Only after a pharmaceutical development of the preparation and the securing of a market supply, a central registration with the European Medicines Agency takes place. The documents required for a submission can be prepared by Valicare with the help of your information. The minimum documents required for approval are: