The cell and gene therapy space has seen a great deal of growth and progress over the last couple of years as more companies are approaching late-stage clinical development and market authorization. As a result we’ve seen a lot of progress in accomplishing consistent manufacturing on a global scale. One of the biggest challenges in achieving this is the elimination of variations, especially in starting and raw materials and manual manufacturing steps. To eliminate variations in raw materials we see an increased demand for GMP-grade raw materials and an increased need for regulatory guidance.
As a provider of GMP-grade raw materials we are actively participating in raising awareness of the need to use high quality GMP-grade raw materials and are in constant interaction with regulatory authorities worldwide. The regulatory agencies are starting to acknowledge the increasing need for guidance around the quality of raw materials but there’s still a degree of confusion. In our opinion, the current guidelines do not offer the level of guidance that is needed. With USP Chapter <1043>, the FDA only offers a recommendation for raw materials uses and not for the manufacturers of raw materials. The EMA’s new Ph. Eur. General Chapter 5.2.12 is rather unspecific and can be interpreted in different ways. A more clearly specified guideline would simplify the harmonization of quality and safety requirements. The challenge is, however, to write one guideline for all raw materials since there is a large diversity between the raw materials being used in ATMP manufacturing. In addition, there’s currently no global harmonization although we do see a strong push form the market to change this. To help improve regulatory guidance we are actively involved in many of the regulatory initiatives and discussions. Together with the USP we have written the first version of USP <92> and were actively involved in the discussions for the setup of Ph. Eur. General Chapter 5.2.12. At the moment we are actively contributing to the ISO technical committee TC276. This committee is the only global initiative that is working on a best practice guide for raw materials for suppliers and for users. The guide is aimed to be the global ISO technical standard.
Scale up is one of the key challenges faced by companies in the cell and gene therapy space. Scaling up from clinical trials phase 1 to large-scale commercial manufacturing the number of patients (i.e. doses to be produced) might go up by several magnitudes. As a consequence the supply of high quality GMP-grade raw materials is getting more critical. If high quality GMP-grade raw materials are not available in time this could lead to delays in ATMP production. This does not only increase costs but also puts precious patient samples in jeopardy. A raw material supplier must, therefore, be able to provide materials in strongly increasing quantities in a consistent high quality. Their manufacturing process must be appropriately designed in order to allow for a scale up as needed.
The safest way to eliminate possible problems with the supply of GMP-grade raw materials is having a supply agreement in place well before large-scale manufacturing is planned to start. Giving the supplier a clear and reliable forecast of doses to be produced and consequently the amounts of raw material needed will allow the supplier to have enough products available on demand. As the supplier, this for instance allows us to produce large size batches that are reserved for one customer.
In case unique bio-processing models are used for ATMP manufacturing, customized GMP-grade raw materials might be desired. For customized products the supply chain gets even more complex. The initial setup and full validation process of a custom product under GMP requires a good amount of time. If full stability of the final product has to be demonstrated, more than a year might be needed from initial design to delivery of the first batch. We therefore recommend getting a clear understanding on time needed from design to delivery of these customized products well in advance.
To continue this discussion join CellGenix at the roundtable session “Raw materials for ATMP manufacturing: regulatory and supply issues” on September 20 at 10:30-11:15 or visit us at booth #20 during the Gene and Cell Therapy Europe Meeting in Berlin.
CellGenix is a leading global supplier of high quality raw and ancillary materials for the expanding market of cell and gene therapy and regenerative medicine. We develop, manufacture and market human cytokines and growth factors in preclinical and GMP quality as well as proprietary serum-free media for further manufacturing of ATMPs.
Vice President of Development & Production
Am Flughafen 16