GMP

Stem Cell Agency Expands Industry Alliance Program to  Accelerate Therapies

/ Kevin McCormack / Leave a comment

An ever-growing array of academic and industry resources are required to rapidly translate scientific discoveries and emerging technologies toward safe and effective regenerative medicine therapies for patients. To help, the California Institute for Regenerative Medicine (CIRM) is creating a network of Industry Resource Partners (IRP) that will make its unique resources available to help accelerate the progression of CIRM-funded Discovery, Translational and Clinical stage research projects toward transformative regenerative medicine therapies for rare and prevalent diseases.

The Industry Resource Partners will offer their services, technologies and expertise to CIRM-funded projects in a cost-effective, stage-appropriate and consistent manner.

For example, Novo Nordisk is making research-grade vials of its Good Manufacturing Practice (GMP)-grade human embryonic stem cell line available for CIRM Discovery Quest stage research projects at no cost. Having access to clinically compatible pluripotent stem cell lines such as this one will help CIRM researchers accelerate the translation of their therapeutic discoveries toward clinical use. Researchers will also have future access to Novo Nordisk’s GMP seed stock as well as opportunities for partnering with Novo Nordisk.

“CIRM is a lender of first resort, supporting projects in the very early stages, long before they are able to attract outside investment,” says Shyam Patel, PhD, the Director of Business Development at CIRM. “With the launch of this program we hope to create a force-multiplier effect by bringing in industry partners who have the resources, experience and expertise to help further accelerate CIRM-funded regenerative medicine research projects.”

This new network builds on work CIRM started in 2018 with the Industry Alliance Program (IAP). The goal of the IAP was to partner researchers and industry to help accelerate the most promising stem cell, gene and regenerative medicine therapy programs to commercialization. Four of the members of the IAP are also founding members or the IRP.

In addition to Novo Nordisk, the IRP includes:

ElevateBio is providing access to high quality, well-characterized induced pluripotent stem cell (iPSC) lines to CIRM Discovery Quest stage research projects for product development in regenerative medicine. CIRM awardees will also have access to ElevateBio’s viral vector technologies, process development, analytical development, and GMP manufacturing services.

Bayer is offering to support the cell therapy process development and GMP manufacturing needs of CIRM Translational and Clinical awardees at its newly built Berkeley facilities. The partnered projects will have access to Bayer’s cell therapy manufacturing facilities, equipment, resources and expertise. Bayer is also open to partnering from fee-based-services to full business development and licensing opportunities. 

Resilience is providing access to its GMP manufacturing services for CIRM Translational and Clinical Stage projects. In addition to providing access to its cell therapy manufacturing services and partnering opportunities, Resilience will provide project consultation that could aid CIRM applicants in drafting manufacturing plans and budgets for CIRM applications.

“These partnerships are an important step forward in helping advance not only individual projects but also the field as a whole,” says Dr. Maria T. Millan, President and CEO of CIRM. “One of the biggest challenges facing regenerative medicine right now involves manufacturing. Providing researchers with access to high quality starting materials and advanced manufacturing capabilities is going to be essential in helping these projects maintain high quality standards and comply with the regulatory frameworks needed to bring these therapies to patients.”

While the IRP Network will offer its services to CIRM grantees there is no obligation or requirement that any CIRM awardee take advantage of these services.

Overcoming obstacles and advancing treatments to patients

/ Kevin McCormack / Leave a comment

THIS BLOG IS ALSO AVAILABLE AS AN AUDIO CAST

UC Davis GMP Manufacturing facility: Photo courtesy UC Davis

When you are trying to do something that has never been done before, there are bound to be challenges to meet and obstacles to overcome. At the California Institute for Regenerative Medicine (CIRM) we are used to coming up with great ideas and hearing people ask “Well, how are you going to do that?”

Our new 5-year Strategic Plan is how. It’s the roadmap that will help guide us as we work to overcome critical bottlenecks in bringing regenerative medicine therapies to people in need.

Providing more than money

People often think of CIRM as a funding agency, providing the money needed to do research. That’s true, but it’s only part of the story. With every project we fund, we also offer a lot of support. That’s particularly true at the clinical stage, where therapies are being tested in people. Projects we fund in clinical trials don’t just get money, they also have access to:

  • Alpha Stem Cells Clinic Network – This is a group of specialized medical centers that have the experience and expertise to deliver new stem cell and gene therapies.
  • The CIRM Cell and Gene Therapy Center – This helps with developing projects, overcoming manufacturing problems, and offers guidance on working with the US Food and Drug Administration (FDA) to get permission to run clinical trials.
  • CIRM Clinical Advisory Panels (CAPs) – These are teams put together to help advise researchers on a clinical trial and to overcome problems. A crucial element of a CAP is a patient advocate who can help design a trial around the needs of the patients, to help with patient recruitment and retention.

Partnering with key stakeholders

Now, we want to build on this funding model to create new ways to support researchers in bringing their work to patients. This includes earlier engagement with regulators like the FDA to ensure that projects match their requirements. It includes meetings with insurers and other healthcare stakeholders, to make sure that if a treatment is approved, that people can get access to it and afford it.

In the past, some in the regenerative medicine field thought of the FDA as an obstacle to approval of their work. But as David Martin, a CIRM Board member and industry veteran says, the FDA is really a key ally.

“Turning a promising drug candidate into an approved therapy requires overcoming many bottlenecks… CIRM’s most effective and committed partner in accelerating this is the FDA.”

Removing barriers to manufacturing

Another key area highlighted in our Strategic Plan is overcoming manufacturing obstacles. Because these therapies are “living medicines” they are complex and costly to produce. There is often a shortage of skilled technicians to do the jobs that are needed, and the existing facilities may not be able to meet the demand for mass production once the FDA gives permission to start a clinical trial. 

To address all these issues CIRM wants to create a California Manufacturing Network that combines academic innovation and industry expertise to address critical manufacturing bottlenecks. It will also coordinate training programs to help build a diverse and expertly trained manufacturing workforce.

CIRM will work with academic institutions that already have their own manufacturing facilities (such as UC Davis) to help develop improved ways of producing therapies in sufficient quantities for research and clinical trials. The Manufacturing Network will also involve industry partners who can develop facilities capable of the large-scale production of therapies that will be needed when products are approved by the FDA for wider use.

CIRM, in collaboration with this network, will also help develop education and hands-on training programs for cell and gene therapy manufacturing at California community colleges and universities. By providing internships and certification programs we will help create a talented, diverse workforce that is equipped to meet the growing demands of the industry.

You can read more about these goals in our 2022-27 Strategic Plan.

Month of CIRM: Making sure stem cell therapies don’t get lost in Translation

/ Kevin McCormack / Leave a comment

All this month we are using our blog and social media to highlight a new chapter in CIRM’s life, thanks to the voters approving Proposition 14. We are looking back at what we have done since we were created in 2004, and also looking forward to the future. Today we feature a blog written by two of our fabulous Discovery and Translation team Science Officers, Dr. Kent Fitzgerald and Dr. Ross Okamura.

Dr. Ross Okamura

If you believe that you can know a person by their deeds, the partnership opportunities offered by CIRM illustrate what we, as an agency, believe is the most effective way to deliver on our mission statement, accelerating regenerative medicine treatments to patients with unmet medical needs.

Dr. Kent Fitzgerald

 In our past, we have offered awards covering basic biology projects which in turn provided the foundation to produce promising therapies  to ease human suffering.  But those are only the first steps in an elaborate process.

In order to bring these potential therapies to the clinic, selected drug candidates must next go through a set of activities designed to prepare them for review by the Food and Drug Administration (FDA). For cell therapies, the first formal review is often the Pre- Investigational New Drug Application Consultation or pre-IND.  This stage of drug development is commonly referred to as Translational, bridging the gap between our Discovery or early stage research and Clinical Trial programs.

One of our goals at CIRM is to prepare Translational projects we fund for that  pre-IND meeting with the FDA, to help them gather data that support the hope this approach will be both safe and effective in patients.  Holding this meeting with the FDA is the first step in the often lengthy process of conducting FDA regulated clinical trials and hopefully bringing an approved therapy to patients.

What type of work is required for a promising candidate to move from the Discovery stage into FDA regulated development?  To address the needs of Translational science, CIRM offers the Translational Research Project funding opportunity.  Activities that CIRM supports at the Translational stage include:

  • Process Development to allow manufacturing of the candidate therapy under Good Manufacturing Practices (GMP). This is to show that they can manufacture  at a large enough scale to treat patients.
  • Assay development and qualification of measurements to determine whether the drug is being manufactured safely while retaining its curative properties.
  • Studies to determine the optimal dose and the best way to deliver that dose.
  • Pilot safety studies looking how the patient might respond after treatment with the drug.
  • The development of a clinical plan indicating under what rules and conditions the drug might be prescribed to a patient. 

These, and other activities supported under our Translational funding program, all help to inform the FDA when they consider what pivotal studies they will require prior to approving an Investigational New Drug (IND) application, the next step in the regulatory approval process.

Since CIRM first offered programs specifically aimed at addressing the Translational stage of therapeutic candidates we have made 41 awards totaling approximately $150 million in funding.  To date, 13 have successfully completed and achieved their program goals, while 19 others are still actively working towards meeting their objective.  Additionally, three (treating Spina Bifida, Osteonecrosis, and Sickle Cell Disease) of the 13 programs have gone on to receive further CIRM support through our Clinical Stage programs.

During our time administering these awards, CIRM has actively partnered with our grantees to navigate what is required to bring a therapy from the bench to the bedside.  CIRM operationalizes this by setting milestones that provide clear definitions of success, specific goals the researchers have to meet to advance the project and also by providing resources for a dedicated project manager to help ensure the project can keep the big picture in mind while executing on their scientific progress. 

Throughout all this we partner with the researchers to support them in every possible way. For example, CIRM provides the project teams with Translational Advisory Panels (TAPs, modeled after the CIRM’s Clinical Advisory Panels) which bring in outside subject matter experts as well as patient advocates to help provide additional scientific, regulatory and clinical expertise to guide the development of the program at no additional cost to the grantees.  One of the enduring benefits that we hope to provide to researchers and organizations is a practical mastery of translational drug development so that they may continue to advance new and exciting therapies to all patients.

Through CIRM’s strong and continued support of this difficult stage of development, CIRM has developed an internal practical expertise in advancing projects through Translation.  We employ our experience to guide our awardees so they can avoid common pitfalls in the development of cell and gene therapies. The end goal is simple, helping to accelerate their path to the clinic and fulfilling the mission of CIRM that has been twice given to us by the voters of California, bringing treatments to patients suffering from unmet medical needs.

Overcoming one of the biggest challenges in stem cell research

/ Kevin McCormack / 1 Comment

Imagine you have just designed and built a new car. Everyone loves it. It’s sleek, fast, elegant, has plenty of cup holders. People want to buy it. The only problem is you haven’t built an assembly line to make enough of them to meet demand. Frustrating eh.

Overcoming problems in manufacturing is not an issue that just affects the auto industry (which won’t make Elon Musk and Tesla feel any better) it’s something that affects many other areas too – including the field of regenerative medicine. After all, what good is it developing a treatment for a deadly disease if you can’t make enough of the therapy to help the people who need it the most, the patients.

As the number of stem cell therapies entering clinical trials increases, so too does the demand for large numbers of high quality, rigorously tested stem cells. And because each of those therapies is unique, that places a lot of pressure on existing manufacturing facilities to meet the demand.

IABS panel

Representatives from the US FDA, Health Canada, EMA, FDA China, World Health Organization discuss creating a manufacturing roadmap for stem cell therapies: Photo Geoff Lomax

So, with that in mind CIRM teamed up with the International Alliance for Biological Standardization (IABS) to hold the 4th Cell Therapy Conference: Manufacturing and Testing of Pluripotent Stem Cells to try and identify the key problems and chart out solutions.

The conference brought together everyone who had a stake in this issue, including leading experts in cell manufacturing, commercial sponsors developing stem cell treatments, academic researchers, the World Health Organization, the US Food and Drug Administration (FDA), international regulatory bodies as well as patient and patient advocates too (after all, who has a greater stake in this).

Commercial sponsors and academic researchers presented case studies of how they worked through the development of manufacturing process for their stem cell treatments.

Some key points quickly emerged:

  • Scale up and quality control of stem cell manufacturing is vital to the development of stem cell treatments.
  • California is a world leader in stem cell manufacturing.
  • There have been numerous innovations in cell manufacturing that serve to support quality, quantity, performance and cost control.
  • The collective experience of the field is leading to standardization of definitions (so we all use the same language), standardization of processes to release quality cells, manufacturing and standardization of testing (so we all meet the same safety requirements).
  • Building consensus among stakeholders is important for accelerating stem cell treatments to patients.

Regulatory experts emphasized the importance of thinking about manufacturing early on in the research and product development phase, so that you can avoid problems in later stages.

There were no easy answers to many of the questions posed, but there was agreement on the importance of developing a stem cell glossary, a common set of terms and definitions that we can all use. There was also agreement on the key topics that need to continue to be highlighted such as safety testing, compatibility, early locking-in of quality processes when feasible, and scaling up.

In the past our big concern was developing the therapies. Now we have to worry about being able to manufacture enough of the cells to meet demand. That’s progress.

A technical summary is being developed and we will announce when it is available.

 

 

Cell mate: the man who makes stem cells for clinical trials

/ Kevin McCormack / Leave a comment

When we announced that one of the researchers we fund – Dr. Henry Klassen at the University of California, Irvine – has begun his clinical trial to treat the vision-destroying disease retinitis pigmentosa, we celebrated the excitement felt by the researchers and the hope from people with the disease.

But we missed out one group. The people who make the cells that are being used in the treatment. That’s like praising a champion racecar driver for their skill and expertise, and forgetting to mention the people who built the car they drive.

Prof. Gerhard Bauer

Prof. Gerhard Bauer

In this case the “car” was built by the Good Manufacturing Practice (GMP) team, led by Prof. Gerhard Bauer, at the University of California Davis (UC Davis).

Turns out that Gerhard and his team have been involved in more than just one clinical trial and that the work they do is helping shape stem cell research around the U.S. So we decided to get the story behind this work straight from the horse’s mouth (and if you want to know why that’s a particularly appropriate phrase to use here read this previous blog about the origins of GMP)

When did the GMP facility start, what made you decide this was needed at UC Davis?

Gerhard: In 2006 the leadership of the UC Davis School of Medicine decided that it would be important for UC Davis to have a large enough manufacturing facility for cellular and gene therapy products, as this would be the only larger academic GMP facility in Northern CA, creating an important resource for academia and also industry. So, we started planning the UC Davis Institute for Regenerative Cures and large GMP facility with a team of facility planners, architects and scientists, and by 2007 we had our designs ready and applied for the CIRM major facilities grant, one of the first big grants CIRM offered. We were awarded the grant and started construction in 2008. We opened the Institute and GMP facility in April of 2010.

How does it work? Do you have a number of different cell lines you can manufacture or do people come to you with cell lines they want in large numbers?

Gerhard: We perform client driven manufacturing, which means the clients tell us what they need manufactured. We will, in conjunction with the client, obtain the starting product, for instance cells that need to undergo a manufacturing process to become the final product. These cells can be primary cells or also cell lines. Cell lines may perhaps be available commercially, but often it is necessary to derive the primary cell product here in the GMP facility; this can, for instance, be done from whole donor bone marrow, from apheresis peripheral blood cells, from skin cells, etc.

How many cells would a typical – if there is such a thing – order request?

Gerhard: This depends on the application and can range from 1 million cells to several billions of cells. For instance, for an eye clinical trial using autologous (from the patient themselves) hematopoietic stem and progenitor cells, a small number, such as a million cells may be sufficient. For allogeneic (from an unrelated donor) cell banks that are required to treat many patients in a clinical trial, several billion cells would be needed. We therefore need to be able to immediately and adequately adjust to the required manufacturing scale.

Why can’t researchers just make their own cells in their own lab or company?

Gerhard: For clinical trial products, there are different, higher, standards than apply for just research laboratory products. There are federal regulations that guide the manufacturing of products used in clinical trials, in this special case, cellular products. In order to produce such products, Good Manufacturing Practice (GMP) rules and regulations, and guidelines laid down by both the Food and Drug Administration (FDA) and the United States Pharmacopeia need to be followed.

The goal is to manufacture a safe, potent and non-contaminated product that can be safely used in people. If researchers would like to use the cells or cell lines they developed in a clinical trial they have to go to a GMP manufacturer so these products can actually be used clinically. If, however, they have their own GMP facility they can make those products in house, provided of course they adhere to the rules and regulations for product manufacturing under GMP conditions.

Besides the UC Irvine retinitis pigmentosa trial now underway what other kinds of clinical trials have you supplied cells for?

Gerhard: A UC Davis sponsored clinical trial in collaboration with our Eye Center for the treatment of blindness (NCT01736059), which showed remarkable vision recovery in two out of the six patients who have been treated to date (Park et al., PMID:25491299, ), and also an industry sponsored clinical gene therapy trial for severe kidney disease. Besides cellular therapy products, we also manufacture clinical grade gene therapy vectors and specialty drug formulations.

For several years we have been supplying clinicians with a UC Davis GMP facility developed formulation of the neuroactive steroid “allopregnanolone” that was shown to act on resident neuronal stem cells. We saved several lives of patients with intractable seizures, and the formulation is also applied in clinical trials for the treatment of traumatic brain injury, Fragile X syndrome and Alzheimer’s disease.

What kinds of differences are you seeing in the industry, in the kinds of requests you get now compared to when you started?

Gerhard: In addition, gene therapy vector manufacturing and formulation work is really needed by several clients. One of the UC Davis specialties is “next generation” gene-modified mesenchymal stem cells, and we are contacted often to develop those products.

Where will we be in five years?

Gerhard: Most likely, some of the Phase I/II clinical trials (these are early stage clinical trials with, usually, relatively small numbers of patients involved) will have produced encouraging results, and product manufacturing will need to be scaled up to provide enough cellular products for Phase III clinical trials (much larger trials with many more people) and later for a product that can be licensed and marketed.

We are already working with companies that anticipate such scale up work and transitioning into manufacturing for marketing; we are planning this upcoming process with them. We also believe that certain cellular products will replace currently available standard medical treatments as they may turn out to produce superior results.

What does the public not know about the work you do that you think they should know?

Gerhard: The public should know that UC Davis has the largest academic Good Manufacturing Practice Facility in Northern California, that its design was well received by the FDA, that we are manufacturing a wide variety of products – currently about 16 – that we are capable of manufacturing several products at one time without interfering with each other, and that we are happy to work with clients from both academia and private industry through both collaborative and Fee-for-Service arrangements.

We are also very proud to have, during the last 5 years, contributed to saving several lives with some of the novel products we manufactured. And, of course, we are extremely grateful to CIRM for building this state-of-the-art facility.

You can see a video about the building of the GMP facility at UC Davis here.