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Guidance for GMP manufacture of emerging therapies has evolved to accommodate innovation and the broader spectrum of products in development, but greater harmonization is still needed.
Novel and emerging biotherapeutics are commanding a larger portion of the development pipeline at an inflated rate. As drug companies focus greater efforts on these complex therapies, regulatory authorities have been working on various guidelines to ensure these drugs are manufactured to a high level of quality with minimum risks. Focusing on good manufacturing practices (GMPs) for emerging therapies across the United States and the European Union (EU) in particular, Pharmaceutical Technology Europe® spoke with Elena Meurer, principal consultant at Biopharma Excellence, to learn more about current regulatory expectations, the evolution of guidelines, and potential regional variances.
PTE: Could you provide an overview of current GMP expectations for emerging therapies?
Meurer (Biopharma Excellence): Both FDA and the European Medicines Agency (EMA) have published regulatory guidelines related to the implementation of GMP across the different clinical phases (1,2). Many emerging therapies fall under the definition of advanced therapeutic medicinal products (ATMPs) in the EU or cell and gene therapies in the US. Only EMA has published specific GMP guidance that is applicable to the manufacture of ATMPs.
When assessing the required application of GMP in clinical phases, there are many similarities between the EU and US GMP requirements in that they both focus on the identification and assessment of the risks to the quality of an investigational phase medicinal product. The main difference between the EMA and FDA approaches is the recognition by EMA that ATMPs require explicit GMP guidelines that take the specifics of this product class into consideration, and places a heavy emphasis on a risk-based approach for the broad application of GMP across the product lifecycle (2). It is important to note that not all emerging therapies are classified as ATMPs. Nevertheless, as with ATMPs, such novel therapeutics may also require specific manufacturing solutions that should be addressed case by case in a risked-based manner.
The vast majority of emerging therapies are developed as sterile drugs and, due to the heat sensitivity of many of these therapies, final sterilization is not feasible. Therapeutics in this class are usually sterile filtered (unless they are cell-based therapies and this is not possible) and are manufactured through aseptic processing using modern barrier technology including single-use fluid pathways and isolators, for instance.
Early clinical research is likely to be more relevant for the discussion about emerging therapies. While quite a few cell and gene therapies have moved into later clinical phases and beyond, there are new examples of emerging therapeutics such as extracellular vesicles, peptide-based vaccines, complex molecules produced by chemical synthesis, or approaches using combinations of different technologies in the development/research phases.
For early clinical phases, patient safety is a primary focus. For many emerging therapies that are sterile, fully validated aseptic manufacturing processes are required to support clinical supply, even for Phase I. There is more flexibility in areas that do not have a direct impact on patient safety such as QC [quality control] method validation, where verification may be sufficient but, at the outset, a phase-appropriate GMP assessment is required—to determine the areas where full GMP is required to ensure patient safety, and balance these areas with others that may require less rigor for the clinical program. This approach is valid for both regulatory regions—EU and the US—but in practice expectations can differ depending on the inspector and their knowledge of the product. This can be one benefit of the expedited pathways available from FDA and EMA which include built-in scientific meetings for exchanges of information between inspectors and clinical researchers—long before an MA/IND [marketing authorization/investigational new drug application] is granted and an inspection is scheduled.
PTE: How has the guidance for GMPs for emerging therapies evolved over recent years?
Meurer (Biopharma Excellence): Over recent years, the landscape for the regulation of GMP has changed in response to innovation and the broader range of therapy types being developed. Due to the huge variety of platforms and technologies, a ‘one size fits all’ approach is no longer practical nor feasible. With this change, the emphasis is being placed on the identification, assessment and control of risk. This has been a major focus in the revision of key guidance documents such as the EudraLex Volume 4 Annex 1 ‘Manufacture of Sterile Products’ and the recent revision of ICH [International Council for Harmonisation] Q9 on quality risk management (QRM) (3,4). Each revised guidance document includes a much more focused emphasis on managing the risk to product quality to safeguard patients.
The introduction of the European guidelines on GMP specific to ATMPs demonstrates a recognition of the difficulty in legislating for ATMPs, and of the important role QRM plays in the future regulation of all emerging therapies (2).
PTE: Are any major changes to GMP guidance for emerging therapies expected in the near future?
Meurer (Biopharma Excellence): The GMP for ATMP guidance published for the EU was a good start, in recognizing that GMP manufacturing of innovative drugs requires more flexible guidance to account for all different modalities. However, not all emerging therapies are covered by the ATMP guideline. One good example is personalized cancer vaccines consisting of peptide-based neoepitopes. Such therapies do not fall under the ATMP definition, yet share many common features—such as manufacturing and testing challenges imposed by their small batch sizes. Most importantly, the composition of each batch of such a personalized therapeutic differs, which requires a special approach (e.g., to their validation and stability studies).
Another important development is the increased use of prediction programs using artificial intelligence in designing personalized therapeutics. These emerging applications should drive adaptations of existing GMP regulations to further develop approaches for algorithm validation in a GMP environment, for example.
There are also more subtle changes that are already occurring such as the widening of the scope of Annex 1 in terms of applicable territories and manufacturing platforms. This further highlights the acceptance, particularly between the US and EU, that a more common approach is needed for the regulation of GMP for all product types, not just emerging therapies.
It is also evident, based on the focus on QRM in the industry, that this will be the driver for future GMP regulation—rather than relying on unilateral instructions for an industry that is now highly diverse.
PTE: Are there specific differences between the GMP guidance for emerging therapies in the US versus Europe and other parts of the world?
Meurer (Biopharma Excellence): There are no specific GMP regulations for emerging therapies in the US; this is a gap currently. The GMP applied to US emerging therapies is interpreted from existing regulations, and the US is now placing more focus on the application of QRM for emerging therapies that have unique or unusual characteristics that impact GMP. In the EU, there is an existing document (2), which although set apart from the existing GMP regulations contained in EU GMP Volume 4, is largely an amalgamation of existing documents, in addition to references relating to application of QRM where black and white guidance is impossible or unavailable.
The situation in other territories is very similar, where there is a recognition that emerging therapies can be unique in terms of the practical application of GMP. The US and EU are leading the way in recognizing the unique challenges posed by emerging therapies, and the standards that need to be applied during their manufacture.
However, it should be noted that The Pharmaceutical Inspection Convention Scheme (PIC/S) has adopted the relevant EU guidance documents including the guidance entitled ‘Manufacture of advanced therapy medicinal products for human use’ which is denoted as Annex 2A and is equivalent to the standalone EudraLex guidance (5). This adoption brings these regulatory expectations to a large cohort of global regulatory authorities. With the availability of this guidance across a large part of the global pharmaceutical industry, the main difference will be in the local application and interpretation of these industry standards.
PTE: Will there be greater harmonization between regions on GMP guidance for emerging therapies in the future in your opinion?
Meurer (Biopharma Excellence): The vast majority of emerging therapies address very specific patient groups that require global recruitment (e.g., rare diseases) or unmet medical need which is of high interest for all regulatory regions. Thus, harmonization in the GMP guidance is of the utmost importance and should be driven by the therapeutic needs, as it would significantly simplify clinical manufacturing and supply in addition to safeguarding patients and ensuring a global standard of care for equivalent patients in different countries. The agencies of major regulatory regions are in regular contact, and must be aware of these emerging needs.
Several actions are needed to progress the regulation for emerging therapies, such as the need for scope expansion for mutual recognition agreements between the EU and several other countries globally to include ATMPs and blood products. The adoption of Annex 1 by FDA and PIC/S shows the direction of travel in terms of harmonization, and is a positive step in ensuring that future regulation is likely to be global rather than local. This promises to benefit patients in all countries, while reducing the regulatory burden of trying to satisfy a myriad of differing expectations when trying to get an emerging therapy to patients.
1. FDA. Current Good Manufacturing Practice for Phase 1 Investigational Drugs. Guidance for Industry, July 2008.
2. EC. Guidelines on Good Manufacturing Practice Specific to Advanced Therapy Medicinal Products. EudraLex Volume 4, November 2017.
3. EC. Annex 1 Manufacture of Sterile Medicinal Products. EudraLex Volume 4, August 2022.
4. ICH. Q9(R1) Quality Risk Management. Final Version, January 2023.
5. PIC/S. Annex 2A Manufacture of Advanced Therapy Medicinal Products for Human Use. Version 15, May 2021.
Felicity Thomas is the European/senior editor for Pharm Tech Group.
Pharmaceutical Technology Europe
Vol. 35, No. 5
When referring to this article, please cite it as Thomas, F. Optimizing the Manufacture of Emerging Therapies. Pharmaceutical Technology Europe, 2023, 35 (5) 24–27.