HOW TO SECURE YOUR SUPPLY OF GMP-GRADE RAW MATERIALS FOR ATMP MANUFACTURING
24 April, 2020
The below article has kindly been provided by Frank Hecht of CellGenix. Join CellGenix at the roundtable at Cell & Gene Therapy Europe this week.
The strong expansion of the cell and gene therapy space brings many challenges to the manufacturers of advanced therapy medicinal products (ATMPs). With the first therapies receiving market authorization and the expectation of successful market entry of the first CAR-T cell therapies in early 2017, not only GMP production facilities are at a premium. Also the supply of high-quality, GMP-grade raw materials for the manufacturing process is getting more critical. From clinical trials in phase I to large-scale commercial manufacturing the number of patients (i.e. doses to be produced) might go up by several magnitudes.
Ideally, the same raw material/supplier is used for preclinical development, the different clinical trials and commercial production. Whereas the safety and quality of raw materials has a lower priority in the initial preclinical phase, it is crucial in Phase III and commercial production. At these stages the safety and quality of raw materials is critically evaluated by regulatory authorities. Changing raw materials for Phase III in order to meet these regulatory requirements makes a full change control necessary which is very time consuming and costly. Switching to the required GMP-grade raw materials at an early stage in development will however prevent these high costs and thereby gives a significant economic benefit. The CellGenix approach allows for this seamless transition by providing a specific raw material in different quality grades (preclinical grade/GMP grade), with more comprehensive QC testing and documentation in the GMP version.
As successful production of an ATMP relies on the timely availability of GMP-grade media and cytokines, planning and managing this demand requires some considerations:
If standard off-the-shelf products (growth factors, media) are used during manufacturing, they can in most cases be ordered right from stock. This does not guarantee though that enough product is available at a given point in time. In the worst case this could lead to delays in ATMP production, not only increasing costs but also putting precious patient samples in jeopardy.
GMP requires incoming QC inspections of all production materials, even though batch to batch consistency is very high with premium products. These tests are time and cost intensive and increase the duration from ordering the raw material to actually being able to use it in the production of ATMPs. Larger batches reduce the inspections required per year and the associated costs. They also reduce the occurrence of any batch to batch variability. So, for most raw materials it is beneficial to have as much product as possible from one batch.
The supply chain gets more complex if customized products are involved. In many production settings it is advantageous to have for example medium in a special bag or cytokines in different forms (e.g. larger fill sizes, bulk material, mixture of cytokines). Although this can be easily fulfilled by a premium raw material supplier, the initial setup and full validation process under GMP of a custom product requires a good amount of time. If full stability of the final product has to be demonstrated, one or two years might be needed from initial design to delivery of the first batch. Even in the following routine ordering process the times to delivery might be longer than for standard products. Special production runs might have to be scheduled under GMP conditions. If the supplier’s quality control for release involves functionality assays this step might take weeks to months, depending on assay and cell culture time.
Considerations for raw material supplies:
- Is raw material available in different quality levels (e.g. preclinical grade and GMP grade) and different sizes (e.g. cytokines in 1 mg size, bulk) from the supplier of choice to stay with the same product through the whole process?
- Can standard products be used in the manufacturing process, allowing for easy ordering from stock with short delivery times?
- Are large batch sizes available to reduce cost and time for incoming QC inspection?
- Can the supplier of choice provide customized products to make the ATMP manufacturing process more efficient?
- Is there a clear understanding on time needed from design to delivery of these customized products?
- Is the supplier able to distribute one batch to several sites in case of decentralized production?
The safest way to eliminate possible problems with the supply of 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 him to have enough product available on demand.