Jump to questions:
- Please introduce yourself and Miltenyi Biotec
- What are the challenges when moving from a research environment to a GMP environment?
- What can researchers do to ensure they are fully prepared for this transition?
- How could a closed system enable and support GMP manufacturing?
- What should researchers consider when moving to a closed system method of manufacturing?
- Are Miltenyi Biotec media compatible with a closed system?
- What support/resources are available for researchers looking to transition to GMP manufacturing?
Please introduce yourself and Miltenyi Biotec
I am a Senior Product Manager at Miltenyi Biotec’s headquarters in Germany. After completing my PhD in Molecular Biology and a postdoc in neurodegenerative research, I joined Miltenyi Biotec’s marketing team in 2010. Currently, my team manages the portfolio for stem cells and neuroscience research, with special focus on media for cell culture and differentiation.
In the research community, Miltenyi Biotec is valued as the company pioneering MACS® Magnetic cell separation technology. Today, the company’s portfolio spans a broad spectrum of products and tools ranging from tissue dissociation, through cell separation, flow cytometry and recombinant antibodies, to cell culture media and cytokines. Our goal is to provide our customers with products and tools that enable seamless transition from ground-breaking basic research to clinical applications in cellular therapy.
What are the challenges when moving from a research environment to a GMP environment?
The main challenge is the increasing level of regulation when moving from basic research to pre-clinical and clinical studies. This entails higher demands for documentation of the manufacturing process and of each of the reagents used within the process. The reagents must be risk assessed and qualified for safety and compliance with regulatory criteria. Consequently, changing reagents during the clinical trial phases provokes a lot of re-evaluation and documentation work. It is therefore advisable to take the decision for certain reagents early on and to ensure constant supply with the vendor throughout the clinical phases.
What can researchers do to ensure they are fully prepared for this transition?
My first and foremost recommendation is: start planning early; don’t wait until the last minute. This applies, on one hand, to the layout of your manufacturing process. I see many researchers moving forward with bench protocols developed in basic research settings and the aim to perform that exact same process in a GMP environment. This may work in selected cases, but if you are planning with a tedious culture process in conventional flasks, sooner or later costs will become an issue and scalability may as well. Considering upscale and automation as soon as possible is important to end up in a commercially viable process. Things that work manually on your bench may not necessarily work in a GMP environment.
“The main challenge is the increasing level of regulation when moving from basic research to pre-clinical and clinical studies”
Early planning is also crucial when it comes to reagent choice. All materials that come in contact with your cell product will require appropriate risk assessment and qualification. Right from the beginning, cell manufacturers need to ensure they understand what their supplier can and can’t support: what type of quality management system is in place, which documents are available for risk assessment, does the general product design, e.g. serum-containing vs. chemically defined, meet the regulatory requirements? In general, it is helpful to work with a supplier that has a track record in cellular therapy and GMP-compliant cell processing.
How could a closed system enable and support GMP manufacturing?
Handling your cell product in a closed system helps to reduce the risk of contamination and ensures consistent product quality. In the discussion with your regulatory authorities, this may be helpful, for example, to agree on using a lower clean room class. Clean room costs are one of the major cost drivers for cell products, especially when dealing with open cell culture processes that must be performed in a class A in B environment. Being able to perform parts of such processes outside of an A/B environment may reduce costs significantly.
Learn more about Miltenyi Biotec’s cell culture solutions:
Another point is the possibility of processing multiple lots in the same room. Open processes bear the risk of mix-up and cross contamination, and are therefore typically restricted to processing of only one lot per room. If each cell product is contained in its own closed system, however, regulatory authorities might permit parallel handling of closed system processes in the same room.
What should researchers consider when moving to a closed system method of manufacturing?
Closed systems are particularly powerful when combined with automation. In addition to reducing the risk for contamination and mix-up, such integrated systems can eliminate manual handling steps, reduce operator-to-operator differences and automatically log individual processing steps. This will reduce the costs for trained personnel along with documentation work. The CliniMACS Prodigy® is such a platform that combines automation with processing in a single-use, closed-system tubing set. It supports automation of predefined processes, for instance T cell transduction, but also provides the flexibility to run customized applications.
Are Miltenyi Biotec media compatible with a closed system?
Miltenyi Biotec’s MACS® GMP Media are compatible with closed-system processing. They come in bags and can be easily connected to various automation platforms, using either standard luer locks or sterile welding. For example, the TexMACS™ GMP Medium, which is designed for human T cell expansion and transduction, can be easily connected to automation systems such as the CliniMACS Prodigy® during the manufacture of CAR T cell products.
“Handling your cell product in a closed system helps to reduce the risk of contamination and ensures consistent product quality”
Other MACS GMP Media include the iPS-Brew and MSC-Brew GMP Medium for the expansion of pluripotent and mesenchymal stem cells respectively, the HSC-Brew GMP Medium for expansion and transduction of hematopoietic cells, or – a new addition that will be released this fall – the GMP-compliant MACS NK cell medium for NK cell expansion.
What support/resources are available for researchers looking to transition to GMP manufacturing?
MACS® GMP Products are designed following the recommendations of USP <1043> on ancillary materials, manufactured and tested under an ISO13485-certified quality management system and in compliance with relevant GMP guidelines. That means that every processing step from development to production and quality control is extensively documented.
For MACS GMP Products, we provide our customers with lot-specific Certificates of Analysis and Certificates of Origin. On request, we support them in their risk assessment with product-specific information files that describe in more detail the specifications and parameters used for functional quality testing, as well as the raw materials and clean room levels used during the production process. Finally, there is also the possibility to audit our production facility in Teterow, Germany, where all MACS GMP products are manufactured.