Risk-based approach as per EU Good Manufacturing Practice specific to Advanced Therapy Medicinal Products
ATMPs are complex products and risks may differ according to the type of product,nature/characteristics of the starting materials and level of complexity of the manufacturing process. It is also acknowledged that the finished product may entail some degree of variability due to the use of biological materials and/or complex manipulation
steps (e.g. cultivation of cells, manipulations that alter the function of the cells, etc.). In addition, the manufacture and testing of autologous ATMPs (and allogeneic products in a donor-matched scenario) poses specific challenges and the strategies implemented to ensure a high level of quality must be tailored to the constraints of the manufacturing process, limited batch sizes and the inherent variability of the starting material.
ATMPs are at the forefront of scientific innovation and the field is experiencing rapid technological change that also impacts on the manufacturing processes. For instance,new manufacturing models are emerging to address the specific challenges of ATMPs (e.g. decentralised manufacturing for autologous products). Additionally, ATMPs are
also often developed in an academic or hospital setting operating under quality systems different to those typically required for the manufacture of conventional medicinal products.
It follows that, in laying down the GMP requirements applicable to ATMPs, it is necessary to recognise a certain level of flexibility so that the ATMP manufacturer can implement the measures that are most appropriate having regard to specific characteristics of the manufacturing process and of the product. This is particularly important in the case of investigational ATMPs, especially in early phases of clinical trials (phase I and phase I/II), due to the often incomplete knowledge about the product (e.g. potency) as well as the evolving nature of the routines (in order to adjust the manufacturing process to the increased knowledge of the product).
Application of the risk-based approach by ATMP manufacturers
The risk-based approach (“RBA”) is applicable to all type of ATMPS. It applies in an equal fashion to all type of settings. The quality, safety and efficacy attributes of the ATMPs and compliance with GMP should be ensured for all ATMPs, regardless of whether they are developed in a hospital, academic or industrial setting.
Manufacturers are responsible for the quality of the ATMPs they produce. The riskbased approach permits the manufacturer to design the organisational, technical and structural measures that are put in place to comply with GMP -and thus to ensure qualityaccording to the specific risks of the product and the manufacturing process. While the risk-based approach brings flexibility, it also implies that the manufacturer is responsible to put in place the control/mitigation measures that are necessary to address the specific risks of the product and of the manufacturing process.
The quality risks associated with an ATMP are highly dependent on the biological characteristics and origin of the cells/tissues, the biological characteristics of the vectors (e.g. replication competence or reverse transcription) and transgenes, the level and characteristics of the expressed protein (for gene therapy products), the properties of
other non-cellular components (raw materials, matrixes), and the manufacturing process.
When identifying the control/mitigation measures that are most appropriate in each case,the ATMP manufacturer should consider all the potential risks related to the product or the manufacturing process on the basis of all information available, including an assessment of the potential implications for the quality, safety and efficacy profile of the product, as well as other related risks to human health or to the environment. When new
information emerges which may affect the risks, an assessment should be made whether the control strategy (i.e. the totality of the control and mitigation measures applied) continues to be adequate.
The evaluation of the risks and the effectiveness of the control/mitigation measures should be based on current scientific knowledge and the accumulated experience. Ultimately, this evaluation is linked to the protection of patients.
The level of effort and documentation should be commensurate with the level of risk. It is neither always appropriate nor always necessary to use a formal risk management process (using recognized tools and/ or internal procedures e.g., standard operating procedures). The use of informal risk management processes (using empirical tools
and/or internal procedures) can also be considered acceptable.
The application of a risk-based approach can facilitate compliance but does not obviate the manufacturer’s obligation to comply with relevant regulatory requirements and to demonstrate that it is able to adequately manage the risks of the product/manufacturing process. It likewise does not replace appropriate communications with the authorities.
The application of GMP to investigational ATMPs is intended to protect the clinical trial subjects and it is also important for the reliability of the results of the clinical trial, in particular by ensuring consistency of the product, that the results of the clinical trial are not affected by unsatisfactory manufacturing used and that changes of the product throughout the development are adequately documented.
It is important to ensure that data obtained from the early phases of a clinical trial can be used in subsequent phases of development. Therefore, a functional quality system should be in place for the manufacturing of investigational ATMPs.
The quality and safety of the product needs to be ensured from the first stages of development. Nevertheless, it is acknowledged that there is a gradual increase in the knowledge of the product and that the level of effort in the design and implementation of the strategy to ensure quality will step up gradually. It follows that the manufacturing
procedures and control methods are expected to become more detailed and refined during the more advanced phases of the clinical trial.
For aspects that are not specifically covered by the clinical trial authorisation, it is incumbent upon the manufacturer to document the reasons for the approach implemented and to justify that the totality of the measures applied are adequate to ensure the quality of the product. In this regard, it is recalled that alternative approaches to the
requirements explained in these Guidelines are only acceptable if they are capable of meeting the same objective.
For authorised ATMPs, the application of the risk-based approach should be consistent with the terms of the marketing authorisation. When providing the description of the manufacturing process and process controls in the marketing authorisation application (or, as appropriate, in the context of the submission of a variation), account can be taken of the specific characteristics of the product/manufacturing process to justify adaptation/deviation from standard expectations. Thus, the strategy to address specific limitations that may exist in connection with the manufacturing process, including controls of raw materials and starting materials, the manufacturing facilities and
equipment, tests and acceptance criteria, process validation, release specifications, or stability data should be agreed as part of the marketing authorisation.
For aspects that are not specifically covered by the marketing authorisation, it is incumbent upon the manufacturer to document the reasons for the approach implemented when the risk-based approach is applied, and to justify that the totality of the measures applied are adequate to ensure the quality of the product. In this regard, it is recalled that
alternative approaches to the requirements explained in these Guidelines are only acceptable if they are capable of meeting the same objective.
Examples of the application of the risk-based approach
This Section contains a non-exhaustive list of examples to illustrate some of the possibilities and limitations of the risk-based approach.
RBA in connection with raw materials
The application of the risk-based approach when determining the strategy to ensure the quality of the raw materials is explained
The application of the risk-based approach requires that the manufacturer has a goodunderstanding of the role of the raw material in the manufacturing process and, in particular, of the properties of the raw materials that are key to the manufacturing process and final quality of the product.
Additionally, it is important to take into account the level of risk of the raw material due to the intrinsic properties thereof (e.g. growth factors v. basic media, culture media containing cytokines v. basal media without cytokines, raw material from animal origin v. autologous plasma, etc.), or the use thereof in the manufacturing process (higher risk if the raw material comes into contact with the starting materials).
Finally, it needs to be assessed if the control strategy (e.g. qualification of suppliers,performance of suitable functional testing, etc.) is sufficient to eliminate the risks or to mitigate them to an acceptable level.
RBA in connection with the testing strategy
It is acknowledged that in some cases it may not be possible to perform the release tests on the active substance or the finished product, for example due to technical reasons (e.g. it may not be possible to perform the release tests on the combined components of certain combined products, time restrictions (i.e. the product needs to be administered
immediately after completion of manufacturing), or when the amount of available product is limited to the clinical dose.
In these cases, an adequate control strategy should be designed. For example,consideration can be given to the following options:
• Testing of key intermediates (instead of the finished product) or in-process controls (instead of batch release testing) if the relevance of the results from these tests to the critical quality attributes of the finished product can be demonstrated.
• Real time testing in case of short shelf-life materials/products.
• Increased reliance on process validation. When the scarcity of materials or the very short shelf-life limits the possibilities for release controls, the limitations should be compensated by a reinforced process validation (e.g. additional assays, such as potency testing or proliferation assays may be performed after batch release as
supporting data for process validation). This may also be relevant for investigational ATMPs: while process validation is not expected for investigational medicinal products , it may be important when routine in-process or release testing is limited or not possible.
It is stressed that the release testing strategy should be performed in accordance with the marketing/clinical trial authorisation.
The following examples may also be considered:
• The application of the sterility test to the finished product in accordance with the European Pharmacopoeia (Ph. Eur. 2.6.1) may not always be possible due to the scarcity of materials available, or it may not be possible to wait for the final result of the test before the product is released due to short shelf-life or medical need. In these cases, the strategy regarding sterility assurance has to be adapted. For example, the use of alternative methods for preliminary results, combined with sterility testing of media or intermediate product at subsequent (relevant) time points could be considered.
The use of validated alternative rapid microbiological methods may also be considered. For example, sole reliance on alternative microbiological methods according to Ph. Eur. 2.6.27 may be acceptable when this is justified having regard to the specific characteristics of the product and the related risks, and provided that the suitability of the method for the specific product has been demonstrated.
If the results of the sterility test of the product are not available at release,appropriate mitigation measures should be implemented, including informing the treating physician.
• As cells in suspension are not clear solutions, it is acceptable to replace the particulate matter test by an appearance test (e.g. colour), provided that alternative measures are put in place, such as controls of particles from materials (e.g.filtration of raw material solutions) and equipment used during manufacturing, or the verification of the ability of the manufacturing process to produce low particle products with simulated samples (without cells).
• It may be justified to waive the on-going stability program for products with shorter shelf-life.
Additional considerations relevant for ATMPs that are not subject to substantial manipulation
Manufacturing processes of ATMPs not involving substantial manipulation of the cells/tissues are typically associated with lower risks than the manufacturing of ATMPs involving complex substantial manipulations. However, it cannot be inferred that processes that are not qualified as “substantial manipulation” are risk-free, notably if the processing of the cells entails long exposure of the cells/tissues to the environment.
Accordingly, an analysis of the risks of the specific manufacturing process should be performed in order to identify the measures that are necessary to ensure the quality of the product.
With a view to reduce administrative burden, in the application of the GMP requirements to ATMPs the manufacturing process of which does not involve substantial manipulation, account may be taken of equivalent standards that are applied by ATMP manufacturers in compliance with other legislative frameworks. For instance, the premises and equipment that have been duly validated to process cells/tissues for transplantation purposes in accordance with standards that can be deemed comparable to those laid down in these Guidelines need not being validated again (for the same type of manufacturing operation).
However, there are certain elements of GMP that are intended to ensure the quality,safety and efficacy of the ATMPs which are not specifically addressed under other legislative frameworks and which, therefore, should follow the requirements in these Guidelines, also when the manufacturing process does not involve substantial manipulation. In particular, the requirements on product characterisation (through the setting of adequate specifications), process validation (the expectations for investigational ATMPs are described in Section 10.3), quality controls (in accordance
with the terms of the marketing/clinical trial authorisation), and QP certification should be complied with.
ATMPs manufactured and applied during the same surgical procedure are not exempted from the ATMP Regulation (including therefore GMP compliance).
Additional considerations relevant for investigational ATMPs
While additional adaptations in the application of GMP may be justified in the case of investigational ATMPs, it is stressed that the quality, safety and traceability of the product should be ensured also in a clinical trial setting.
The following are examples of additional possible adaptations that may be acceptable in the case of investigational ATMPs:
• While investigational ATMPs should be manufactured in a facility with air quality requirements in accordance with the requirements set out in Sections 4.3.2 and 9.5,in case of investigational ATMPs in very early phase/proof of concept trials, it may be exceptionally possible to manufacture the product in an open system in a critical clean area of grade A with a background clean area of grade C if the following (cumulative) conditions are met:
(i) A risk-assessment has been performed and demonstrated that the implemented control measures are adequate to ensure manufacture of the
product of appropriate quality. In addition, the control strategy should be described in the investigational medicinal product dossier.
(ii) The product is intended to treat a life threatening condition where no therapeutic alternatives exist.
(iii) The relevant competent authorities agree (agreement of both the assessors of the clinical trial and the inspectors of the site).
• In early phases of clinical research (clinical trial phases I and I/II) when the manufacturing activity is very low, calibration, maintenance activities, inspection or checking of facilities and equipment should be performed at appropriate intervals, which may be based on a risk-analysis. The suitability for use of all equipment should be verified before it is used.
• The level of formality and detail for the documentation can be adapted to the stage of development. The traceability requirements should however be implemented in full.
• During early phases of clinical development (clinical trial phases I and I/II) specifications can be based on wider acceptance criteria taking due account of the current knowledge of the risks and as approved by the competent authority that authorises the clinical trial.
• Possible adaptations regarding qualification of premises and equipment, cleaning validation, process validation, and validation of analytical methods are described in Section 10
References:EudraLex ,The Rules Governing Medicinal Products in the European Union,Volume 4,Good Manufacturing Practice