June 29, 2017

Good Manufacturing Practice for Cell and Cell-Based Therapies: Facilities & Quality Control

Novel cell and cell-based therapies require stringent manufacturing, testing and oversight to ensure integrity, function, and above all else, patient safety upon administration.  Tissue-derived cellular products are considered to be manufactured products and are regulated as such.  Thus, you must ensure that your cell manufacturing process is aligned to current Good Manufacturing Practice requirements.  (Note the “current”.  This means that these are evolving requirements, so you must stay up-to-date!)  In the United States, human cells, tissue and cellular- and tissue-based products (HCT/Ps) are regulated by the Center for Biologics Evaluation and Research (CBER), a division of the U.S. Food and Drug Administration (FDA).

When manufacturing cell and cell-based products, a production facility under strict Quality Control must be used.  Ideally, this facility includes the cell manufacturing suites, the storage space for raw and finished product and any laboratory/testing areas.  Thus, (1) facility design, access and maintenance, (2) equipment purchase, installation and operational qualification (I/OQ), use and maintenance and (3) raw material specifications, purchase, use and storage must all be carefully controlled.  For cell and cell-based therapies, terminal sterilization of the final product is often not possible.  As such, quality by design (QbD) is highly important in cell therapy, with stringent testing conducted on the tissue Donor (our next blog post in this series will cover this topic) to preclude risk of contamination at the source.  In addition, facility and equipment standards and monitoring must be instituted to ensure aseptic processing of cell and cell-based products.  To this end, closed systems and single-use disposables should be used whenever possible to minimize risk of contamination.  Therefore, a cGMP manufacturing facility must include clean rooms which control for temperature, humidity, pressure and air particulates, preventing any contamination of manufactured product due to the environment, materials, human handlers and cross-contamination from other products manufactured in the same facility.  As such, there should be uni-directional flow of materials and people through these areas and personnel must follow proper gowning procedures.  Facilities and equipment requirements are defined under US FDA 21CFR§211 and 21CFR§1271.

As mentioned above, stringent Quality Control systems must be in place to qualify all reagents and processes and to institute Standard Operating Procedures (SOPs) to ensure quality and consistency in manufacturing processes and the end product. 

Facility and Quality Control considerations for cGMP cell manufacturing.

June 23, 2017

Demystifying Clinical Translation of Stem Cell-Based Therapies

As our company matures and we continue to execute to our mission of accelerating Regenerative Medicine, we find ourselves increasingly involved in conversations around scalable cGMP cell manufacturing, qualification of cell and cell-based therapies, and regulations around clinical translation of hMSCs and hMSC-based therapeutics.  While the US FDA and other global regulatory agencies provide guidances on the regulations surrounding clinical translation of cellular products, it is evident that there is still great uncertainty around rules, regulations, processes, timelines and costs associated with clinical translation.
How do you move from pre-clinical to clinical studies?
How must you manufacture your cells?
What data do you need to present to the FDA to move to clinical trials?
What sort of characterization assays are needed? 
What is the process for engaging the FDA and moving to clinical trials?
When do I need to do all of this?!

These are just a few of the questions that we commonly hear from our customers.  In an effort to facilitate our customers’ path to the clinic, we will be publishing here a series of blog posts on clinical translation of hMSCs.  These posts are meant to point you to the relevant guidances and points to consider surrounding clinical translation of hMSCs and are not meant to be the definitive authority on these matters.  We recommend that you engage your Quality and Regulatory teams (and/or consultants) early on in your Process Development efforts to ensure that you are considering all regulations and guidelines in developing a scalable, clinically- and commercially-relevant process and product.

What other questions do you have around clinical translation of hMSCs and hMSC-based therapies?

Check back in next week for our first blog post in this series.

June 15, 2017

Opportunities for BioManufacturing Sciences to Accelerate Upscaled Mesenchymal Stem Cell Manufacturing Technologies

Contributed by: Timothy R. Olsen, PhD - Sr. Scientist, Process and Product Development at RoosterBio Inc.

After the National Institute for Standards and Technology (NIST) identified upcoming challenges in the U.S. biopharmaceutical manufacturing landscape (see document here), the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL) was formed to help solve these challenges through the formation of a public-private partnership between industry, government, academia, and non-profits. The goal of NIIMBL is to accelerate Biopharmaceutical manufacturing innovation, support the development of standards that enable more efficient and rapid manufacturing capabilities, and educate and train a world-leading Biopharmaceutical manufacturing workforce to maintain the United States’ global lead and competitiveness in this industry. NIIMBL will be leveraging a $70 million investment from NIST, with at least $129 million more in funds from private partners. One of the great aspects of this institute is that they are encouraging partnership between large companies and smaller or medium size companies (called Small to Medium Enterprises “SME”), which will be sure to bolster innovation and streamline commercialization and implementation of new technologies. Kelvin Lee, the NIIMBL Institute Director, did a fabulous job taking the lead on organizing the Consortium's first National Meeting, where members from the United States Congress, Directors from the Food and Drug Administration, and many executive level industry representatives were invited to speak about the importance of manufacturing sciences and the current challenges we are facing as an industry. I had the opportunity to represent RoosterBio as an SME at this inaugural NIIMBL National Meeting, and I gave a talk in the “Rapid Fire” SME Innovation Showcase, as well as presented some of our work on how we are radically shortening the development timelines of Biopharmaceuticals that include a stem cell-derived component.
Confluent hMSCs on Solohill microcarriers.
Image from RoosterBio Inc
Among the many relevant talks given throughout the day, one specifically caught my attention. In his talk titled “Key Process & Assay Challenges in Cell Therapy Development,” Greg Russotti (Vice President, Technical Operations at Celgene Cellular Therapeutics) laid out challenges in the upscaled manufacturing of human mesenchymal stem cells (hMSCs). To meet the pressing need for economical manufacturing of hMSCs at clinically- and commercially- relevant scales, researchers have turned to single-use bioreactor systems that have successfully been used to manufacture other biomolecules, such as monocolonal antibodies which make up the lion’s share of blockbuster pharmaceuticals. However, unlike small molecule or large molecule production, cell therapy products are living, breathing cells, which presents unique bioprocessing constraints and challenges. Greg noted that there are technologies based on monoclonal production that can expand hMSCs in large quantities, like using 3D microcarrier-based bioreactor systems, but there are still many manufacturing innovations required before these manufacturing platforms can support a commercial cell therapy product.  
The technology gaps that he specifically mentioned for upscaled hMSC manufacturing were downstream processing technologies, specifically the unit operations related to: