When the process changes, keep it equivalent: Comparability in manufacturing discussed by regulators and industry
Process changes during manufacturing of regenerative medicine products occur often. They can be caused by a process-based change, such as changes in the manufacturing process (eg. new formulation, new purification column, new equipment) or they can be material-related, caused by such reasons as donor or raw material changes (eg. new resin, new Master Cell Bank, etc.).
In such cases, the FDA – as well as international regulatory agencies – dictate that cell therapy and regenerative medicine manufacturers must demonstrate that any manufacturing changes do not affect safety, identity, purity, or potency.
In their own words, the FDA specifies:
The demonstration of comparability does not necessarily mean that the quality attributes of the pre-change and postchange product are identical, but that they are highly similar and that the existing knowledge is sufficiently predictive to ensure that any differences in quality attributes have no adverse impact on safety or efficacy of the drug product.
When it comes to biologics, the FDA has been active this year. Earlier in 2016, the FDA updated its guidance for Comparability Protocols for the first time in 13 years. The new guidance, officially titled Comparability Protocols for Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Information, places, for the first time, a particular emphasis on QbD (Quality by Design), PAT, and Process Validation principles, which are now more significantly emphasized.
Such guidances were also reflected internationally, particularly in Europe.
In response to a recent publication by members of the Committee for Advanced Therapies at the EMA, which emphasized that demonstrating comparability in cell therapy manufacturing following process changes may be “difficult for cell-based medicinal products,” a UK-based panel published a response following a workshop held last year. The panel, it should be emphasized, focused on pluripotent stem cell-based products.
The workshop was held September 15-16, 2015 at Cambridge Unversity in Cambridge, United Kingdom, while the resulting opinion paper came out earlier this month.
Titled “Comparability: manufacturing, characterization and controls, report of a UK Regenerative Medicine Platform Pluripotent Stem Cell Platform Workshop” and authored by a contingent of scientists, researchers and industry professionals, the paper highlights considerations that arise when “comparability” is to be maintained in the cell therapy manufacturing process.
Issues of “automation vs. mechanization” and “interchangeable manufacturing” are addressed, with the manuscript mentioning that “there is still a need for the manufacturing community to convince other stakeholders of the value of the application of automation and mechanization approaches to control variation.”
These ongoing conversations are important as the regenerative medicine industry advances to wider commercialization of products and technologies while addressing challenges that are unique to bringing these products to market.
Most studied focused on the transplantation of stem cells in the central nervous system have demonstrated a cell survival of 2%–8%. Because of such poor viability, biomaterial and scaffold-based approaches have become attractive in recent years.
However, the selection of biomaterial is critical for successful cell transplantation. We have previously discussed the importance of selection of biomaterial for scaffold development, and a new study takes these concepts further by testing biomaterial-specific transplantation of cells into multiple tissues of injured mice.
Authored by the lab of Dr. Molly Shoichet at the Department of Chemical Engineering and Applied Chemistry at the University of Toronto, a new study describes an injectable hydrogel based on hyaluronan (HA) and methylcellulose (MC), which is known to be minimally swelling, bioresorbable, and fast gelling for improved stem cell transplantation. Two types of cells – neural stem cells and progenitor cells – were used for that purpose, and they were injected in stroke injured brains and retinas of target mice, respectively.
The paper, titled A Hyaluronan-Based Injectable Hydrogel Improves the Survival and Integration of Stem Cell Progeny following Transplantation, was published in Stem Cell Reports last week.
The authors used a previously developed hyaluronan (HA) and methylcellulose (MC) (HAMC) hydrogel, which they injected, alongside target cells as a blend, into the brain or sub-retinal space of adult CD10 mice.
Immunocytochemical analysis of euthanized mice was carried out to evaluate differentiation of transplanted cells. Evaluation of the number of animals with surviving cells was carried out via anti-GFP to identify the transplanted cells. They observed improved cell distribution and NSC differentiation toward GFAP-positive cells, which they postulate was at least partially caused by the positive transplantation environment.
They further reported that the HAMC-based transplantation approach resulted in the greatest absolute number of adult stem cell-derived rods integrated into neural retina to date.
The authors did not postulate about any of the mechanisms underprinning differentiation of their transplanted cells, leaving it as something to be followed up on alongside additional work related to further development of this biomaterial-based delivery system.
This remains, nonetheless, a valuable study that elucidated a significant advance in the difficult area of CNS cell transplantation.
Steering Committee to Evaluate Proposed Florida Institute of Regenerative Medicine First Meeting + More Cell and Gene Therapy Developments
British Scientists Warn On Disruption In Cell and Gene Therapy Innovations
Alongside the European Commission’s recently closed Call for Comments on their upcoming Draft Guidelines for Good Manufacturing Practice for Advanced Therapies (which ended last week), a group of British researchers – Andrew Baker from the University of Edinburgh, Robin Ali from the UCL Institute of Ophthalmology, London, and Adrian Thrasher from University College London – published a paper calling for clarity in the cell therapy field in the wake of the British public’s June 23rd, 2016 vote to leave the European Union. The authors call the current uncertainty in the field as “potentially harmful.” The article, titled Impact of BREXIT on UK Gene and Cell Therapy: The Need for Continued Pan-European Collaboration, was published in the journal Human Gene Therapy. The authors express the desire, and hope, that pan-European and international scientific collaboration will continue regardless of the outcome of the political situation involving the United Kingdom.
Akron leads Florida institute for Regenerative Medicine Initiative
At this year’s annual BioFlorida conference, a special session dedicated to exploring the initiative of setting up a “Florida Institute of Regenerative Medicine” will take place. Led by Akron Biotech’s Claudia Zylberberg, the session will explore feasibility of such an institute to support and foster fast-growing regenerative medicine development and manufacturing efforts in the State of Florida.
Details with an agenda will be forwarded prior to the meeting.
The Florida Institute for Regenerative Medicine Steering Committee session will take place on Monday, October 10, 2016 from 3:15 PM – 4:30 PM at the Hyatt Regency Jacksonville Riverfront at 225 E. Coastline Dr. (Room: Conference Center B) in Jacksonville, FL 32202.
The meeting is open to registration to interested parties. To learn more and register, go here.
This week: Akron attends Stem and Gene Meeting on the Mesa
This week, Akron will attend this year’s Cell & Gene Meeting on the Mesa, and will participate in the associated Partnering Forum. The Partnering Forum takes place October 5 – 6, 2016, while the Scientific Symposium takes place on Friday, October 7, 2016. Please see the Cell & Gene Meeting on the Mesa website for more details and to set up an individual meeting please contact us directly.
Upcoming: Akron to speak at Wharton Undergraduate Healthcare Conference
Akron will participate in the Third Annual Wharton Undergraduate Healthcare Conference, set to take place on November 12, 2016 at University of Pennsylvania’s Wharton Business School in Philadelphia, PA. Dr. Claudia Zylberberg will speak during the panel “A Drug’s Life: From Basic Science to Pharmaceuticals” alongside a number of other industry and academic panelists. To register for the event, follow this link.
That the cost of development of any new drug is extremely high has been a known fact that the biotech and pharmaceutical industry has grappled with for a long time. This issues have recently become more publicized as high profile clinical trials have shed light on the dichotomy between keeping the development, testing and manufacturing processes in line with regulatory constraints and the business-dependent issues of development costs, profits and selling price.
This week, a United Nations panel issued a report that addresses the rising costs of commercial drugs, patent issues as well as associated development-related matters.
One of the most urgent points involved the allegedly disproportionate cost of drugs relative to what the UN believes, or recommends, they should cost. The report, specifically, calls on governments to negotiate a binding treaty “de-linking” R&D costs from the final price of drugs in areas where market incentives have been insufficient, such as for new antibiotics or for tropical diseases.
The report on the United Nation’s Secretary General High Level Panel on Access to Medicines is publicly available and can be read here.
That the cost of developing a new drug is high is not news. A recent manuscript, published earlier this year, titled Innovation in the pharmaceutical industry: New estimates of R&D costs, estimated that the cost to bring a new drug to market is approximately $2.56 billion.
The pharmaceutical industry has largely criticized the report, with the Biotechnology Innovation Organization saying:
“Sadly the United Nations High Level Panel ignored the real issues that impact or delay delivery of innovative treatments and cures throughout the developing world, while focusing on policy recommendations in the one area – intellectual property – that would actually undermine ongoing research and development by hundreds of companies, universities and researchers.”
While much of the UN’s report is focused on developing countries, there are parallels and potential impacts of such actions that would affect the pharma and biotech industries globally.
There is no doubt that the cost of drugs has lately become a significant topic with high international interest, and it will be interesting to see how things play out now that the report has seen light.
New study mobilizes T cells to become therapeutic + State of the Science in Regenerative Medicine Workshop Coming Up
New study describes mobilization of adult T cells to become therapeutic
We wanted to highlight an interesting new paper that came out this week with potentially significant applications for adoptive T cell therapy. In this type of therapy, tumor-specific T cells are isolated and expanded ex vivo prior to being administered. T cells in adult bodies are typically maintained by the differentiation of a small population of adult stem cells.
A new study study, published in the Journal of Clinical Investigation, described the identification of genes involved in the mobilization of a quiescent subset of tissue-resident memory (Trm) cells. The genes are ABC transporters and the NR4A family of transcription factors, and they influence the function and differentiation of Trm cells.
in doing so, the authors effectively were able to “boost” and create Trm cells from otherwise quiescent T cells, which would have a significant impact in adoptive T cell therapy, which relies on sufficient numbers of T cells for efficacy.
The study came out of the lab of Dr. Madhav V. Dhodapkar at the Department of Medicine at Yale University and can be read here in full.
Akron to attend Cell & Gene Meeting on the Mesa Partnering Forum
As previous years, Akron will this year attend the upcoming Cell & Gene Meeting on the Mesa, and will participate in the preceding Partnering Forum. The Partnering Forum takes place October 5 – 6, 2016 and brings together over 500 participants from every facet of the academic, research, cell and gene therapy and pharmaceutical as well as business fields. If you want to meet us please check partnering session opportunities at the Cell & Gene Meeting on the Mesa website or contact us directly.
State of the Science in the Field of Regenerative Medicine: Challenges of and Opportunities for Cellular Therapies – A Workshop
We are also excited to share some information about a workshop by the Forum on Regenerative Medicine at the National Academies of Science, Engineering and Medicine, set to take place on October 13.
The purpose of the workshop is to highlight, and discuss, challenges associated with developing cell-based therapies for regenerative medicine. The planning committee has developed a great agenda for the day (link below) and the public registration is now open. We encourage you all to share the information with colleagues who may be interested in attending. The workshop takes place on October 13th at the National Academy of Sciences Building (125) • 2101 Constitution Avenue, NW, Washington, DC with an 8:30 AM start time.
The coming week is heavy on CAR-T and cell therapy developments. Not only is the FDA holding a public hearing on cell therapies (which you can read about here), but the CAR-T Summit is taking place in Boston (more on that below) alongside satellite meetings such as Cell & Gene Therapy (which takes place September 12 and 13, 2016).
Additionally, the Blue Ribbon Panel of the Cancer Moonshot initiative presented its report to the National Cancer Advisory Board earlier this week on September 7, 2016.
The report, which can be downloaded here, describes “10 transformative research recommendations for achieving the Cancer Moonshot’s goal.”
President Barack Obama has requested about $1 billion over two years for the project — however, the funding has yet to be approved.
On the subject of immunotherapies, the report recommends the generation of a “cancer immunotherapy clinical trial network.” More specifically, the purpose of the network would be to:
“[…] provide a national infrastructure to take advantage of a standardized baseline protocol (including drug treatments and prevention strategies for high-risk individuals, tissue acquisition, and biomarker interrogation) embedded in the broader community (both academic and industry) to test novel immunotherapies efficiently and with a deep understanding of fundamental obstacles to success.”
The Blue Ribbon Panel’s report is part of a larger initiative, and another important milestone in the current government’s plan to advance much-needed funded for the development and commercialization of therapies for serious diseases that currently have no cure.
Akron to present at CAR-TCR Summit 2016
Akron Biotech will be attending the CAR-TCR Summit which this year takes place in Boston from September 13 – 16, 2016. Alongside having a booth set up at the meeting which will feature our latest innovations in product and process development, Akron will also be featured as a speaker at the conference.
Dr. Claudia Zylberberg, Akron’s CEO, will speak during the Manufacturing, Supply Chain & Commercialization session which is scheduled for Wednesday, September 14th, 2016. The talk, titled “Innovating CAR-T Manufacturing: Challenges and Considerations for CMOs” will take place at 12:40 pm and will address issues relevant to the manufacturing of CAR-T therapies and focus on current challenges and bottlenecks in the manufacturing as well as new concepts and strategies that can bring opportunities to in-process improvements of CAR-T therapies.
For more information or to schedule private meetings, contact us directly.
Earlier this year, the FDA announced it would hold a hearing on cell therapy, originally scheduled for April 13, 2016. However, due to overwhelming public interest, the FDA decided to postpone the meeting. Now, finally, that time for the meeting has come.
Taking place over two days later this month (September 12 and September 13, 2016) at the NIH campus in Bethesda, MD, the meeting is officially dubbed a “Public Hearing.” The impetus behind this hearing is to provide comments to the FDA about the draft guidances issued recently. In the FDA’s own words, the purpose of the hearing is:
“[…] to obtain comments on the four draft guidance documents relating to the regulation of human cells, tissues, and cellular and tissue-based products (HCT/Ps). […] FDA would like comments on the scope of the four draft guidances, including the particular topics covered, the particular questions posed, whether there are additional issues for which guidance would be helpful.”
Open to the public as well as researchers involved in stem cell-based work, it is unofficially said the FDA is also curious about receiving feedback so that it can better assess the state of the industry in order to provide greater oversight of stem cell clinics operating in the country.
The meeting comes on the heels of the latest guidances, issued in late 2015, on the
Regulation of Human Cells, Tissues, or Cellular or Tissue-Based Products.
Registration was closed on July 1st, 2016 – and while the previous hearing, that took place in October 2015, featured over 50 speakers which were given either 3 or 6 minutes of “talk time,” this meeting is expected to far surpass the previous one in attendance due to it taking place over two days.
The FDA will make the meeting available via Webcast from their website, so for those of you who haven’t managed to register, here is your chance.
For more information on the hearing, go here.
We will be following the meeting, and – as we continuously closely follow regulatory developments in the cell therapy field – will report on any industry-wide relevant updates.