Jeffrey Lacouchie is a Regulatory Affairs Specialist at Polyplus-transfection®. After graduating from the Faculty of Pharmacy of Strasbourg with a double degree, Doctorate in Pharmacy and Master’s degree in Regulatory Affairs, he worked as a Regulatory Affairs Product Manager in a Pharmaceutical & Cosmetics company. He joined Polyplus-transfection® in June 2021.
	Lionel Montémont joined Polyplus-transfection® in 2018 after 15 years’ experience within the chemical industry (Dow®) as European Business Development Manager (including missions for the United Nations (UNIDO)) as well as in pharmaceutical industry in a laboratory certified EU-GMP Part I – EU-GMP Part II and Excipact™ as Business Manager.

What is your advice on the use of GMP raw materials for viral vector manufacturing?

JF: A primary topic in AAV vector bioprocessing is the choice of starting and raw material. During AAV manufacturing there are less opportunities to improve downstream purification, but many aspects of the upstream process can still be improved. 

For example, FDA (USP 1043) and EMA (Eudralex Volume 4 part 4) regulations recommend pharmaceutical grade/GMP grade for transfection reagent. However, both agencies accept that many raw material suppliers only supply research-grade reagents. It is ultimately the product manufacturer’s responsibility to ensure that the product meets all the necessary functional quality and recommendation requirements. 

In future, regulation should move to a fully GMP compliant supply, so starting the process with a supplier that can offer a GMP raw material from the beginning to the final product will be a real advantage. Remember that any change in raw materials will lead to regulatory verification that could increase the time to market for the product. Moreover, a good raw material supplier can provide scientific support during the scale-up process.  

LM: Clearly for viral vector manufacturers and gene therapy developers, raw material risk assessment is critical to secure sourcing of qualified raw materials and for supplier qualification, manage supply chain and ensure patient safety. Because transfection reagents are critical raw materials, they should be part of risk assessment studies. Therefore Polyplus as a supplier must meet expectations of regulatory bodies by manufacturing transfection reagents in compliance with cGMP guidelines ICH Q7 and Eudralex Vol 4 Part II, Annex 1. 

Read more on Not all cGMP transfection reagents are made equal:  Pharmaceutical versus medical device cGMP manufacturing. 

What are the key points of evolution relating to regulatory guidance and requirements for viral vector production, and what are the chief resulting considerations for manufacturers?

JF: There have been no major changes in regulation for advanced therapy medicinal products (ATMPs) in recent years. However, several guidance have been provided by the regulatory bodies over the past 4 years. 

The number of cell and gene therapy clinical trials has been steadily increasing for the past 20 years, creating a demand for regulatory frameworks for ATMPs. The COVID pandemic crisis has also led to regulatory advances relevant to the cell and gene space – in particular, the rapid approval of mRNA vaccines.  

Recent guidance such as “CMC information for Human Gene Therapy IND Applications – Guidance for Industry,” published by the FDA in 2020, or the revision of the “Guideline on quality of genetically modified cells,” published by the EMA in June 2021, target important aspects in drug development strategy. It is positive to see that regulatory bodies are now more open to working with industry to develop regulations for ATMPs. 

LM: To add to Jeffrey’s overview of the evolution of the regulatory guidance, I think that it is safe to say that once ATMPs become more common and routinely used, we can expect to see guidelines become more demanding. Guidelines are still relatively new and leave sufficient room for interpretation to avoid blocking innovation. To anticipate on these evolving guidelines, we can see that there are more consortiums of key actors in CGT, manufacturers, developers and suppliers that work together to improve safety and efficacy of viral vector manufacturing to ensure sustainability of gene therapy treatments. 

Are there any concerns relating to regulatory disharmony, for example between the US and Europe?

JF: Indeed, there are some discrepancies between the US and Europe, especially in the regulatory framework for ATMPs. Even the definitions of ATMPs differ – regulatory agencies agree on the legal basis, but there are some differences in sub-classification. In the EU, there are four major groups (gene therapy products, somatic-cell therapy medicinal products, tissue-engineered medicinal products, and combined products) whereas the US sub-classification covers only three groups (gene therapy products, cellular products, and combined products).  

There are more differences when applying to run a clinical trial. In the US, an Investigational New Drug (IND) application will offer unlimited access during the development program and be updated through amendments. Meanwhile, in the EU, a Clinical Trial Application (CTA) approval is only valid for one clinical trial. Moreover, the CTA must be validated by each country in the EU area and is not centralized as in the FDA process. Fortunately, requirements for dossier submissions and GMP are harmonized by the International Conference of Harmonization (ICH). ICH provides a general platform for drug development requirements, which historically harmonized regulations between Japan, the EU, and the US. There are differences in regulatory pathways but requirements regarding drug product quality are harmonized.  

LM: Viral vector manufacturers need regulatory support from suppliers in order to facilitate their IND or CTA submission to the different regulatory bodies. At Polyplus, we always consider that our customer may want to commercialise their ATMP worldwide, meaning that we are able to support them with full documentation as per requested by US and EMEA regulatory bodies. Global harmonization is indeed ongoing (ICH Q7), and to my knowledge there are not major changes that are to be expected in the coming years. Hence, I believe the discrepancies between regulatory bodies will soon become less and less of a concern. 

How can you avoid or mitigate risk in making changes to an AAV vector bioprocess?

LM: Changes in a AAV manufacturing process during pre-clinical and clinical phases involves additional regulatory, supply chain and process development workload as well as additional financial investment. Therefore, to avoid or decrease risks associated with making a change in the manufacturing process, it’s important to develop as early as possible a manufacturing process that is industrializable, cost-effective, sustainable and compliant with regulatory demands.  

JF:  It’s important to understand the interactions between the manufacturing process and the product – in other words, quality by design. It’s an approach that has been around since the early 2000s but has really gained traction amongst manufacturers and regulators in recent years.  

QbD is defined in ICH Q8(R2) and ICH Q11 as a holistic approach to pharmaceutical development, using knowledge management to enhance the quality of the product and the manufacturing process. It encompasses all the aspects of GMP, including the materials, equipment, and personnel.  

Quality by design is based on several quality tools, which are described in the ICH Q9 guideline on quality risk management and the ICH Q10 guidelines on pharmaceutical quality systems. Quality by design can be summarized in six major steps:  

• Step 1 is to identify the Quality Target Product Profile of the product – a prospective summary of the candidate drug quality characteristics required to ensure quality goals while taking into account efficacy and safety.  
• Step 2 is to define the Critical Quality Attributes – physical, chemical, biological, or microbiological characteristics with defined limits to ensure product quality goals. These include but are not limited to the drug substance, the excipients, the intermediates, and the raw materials.  
• Step 3 is to conduct a risk assessment linking material attributes and process parameters to the drug products, in order to identify which material attributes and process parameters could affect the final drug product.  
• Step 4 is to formalize the Design Space – interactions between the product and manufacturing process. The concept of Design Space covers all development phases of a product so mastering it will significantly ease the scale-up process.  
• Step 5 is the control strategy phase, which is designed to ensure that a product of required quality will be produced consistently all the way through the product lifecycle.  
• Finally, Step 6 is to ensure continuous improvement throughout the product lifecycle.  

The end goal of quality by design is that the quality parameters of the product should be within a predefined target range, rather than a specific value. This is possible because you have a detailed understanding of the Design Space and allows more flexibility to make changes during scale-up – and ultimately a faster time to market.