Industry Update: ARM Submits Comments on FDA Cell Therapy “Minimal Manipulation” Guidlines

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At the tail end of December, the FDA released draft guidelines on Cell and Tissue-Based Products, titled “Minimal Manipulation of Human Cells, Tissues, and Cellular and Tissue-Based Products.” The guidelines came on the heels of another set of guidances,  “Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception,” which the FDA had released a month prior.

The December guidelines define a Human Cell or Tissue Therapy Product (HCT/P) under section 361 of the PHS Act and 21 CFR Part 1271 if the following apply (taken from

  • The HCT/P is minimally manipulated;
  • The HCT/P is intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer’s objective intent;
  • The manufacture of the HCT/P does not involve the combination of the cells or tissues with another article, except for water, crystalloids, or a sterilizing, preserving, or storage agent, provided that the addition of water, crystalloids, or the sterilizing, preserving, or storage agent does not raise new clinical safety concerns with respect to the HCT/P; and either:
    1. The HCT/P does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function; or
    2. The HCT/P has a systemic effect or is dependent upon the metabolic activity of living cells for its primary function, and:
    a.Is for autologous use;
    b.Is for allogeneic use in a first-degree or second-degree blood relative; or
    c.Is for reproductive use.

This week, the Alliance for Regenerative Medicine (ARM), a large advocacy organization supporting the cell therapy industry, released a set of comments on the FDA guidelines, asking for the FDA to provide clarification on a number of concepts, one of them being “main function.”

From the release:

“ARM requests more information on the concept, origin and application of the draft guidance’s inclusion of the new and yet-undefined term “main function” of the human cells, tissues, cellular and tissue-based products (HCT/Ps) when assessing minimal manipulation, as these products may have more than one function and it is not clear which of these functions would be considered primary.”

ARM calls on the FDA to “hold a public hearing to engage with stakeholders in a full airing of the topic.”

Similar comments and requests for clarification followed the release of the FDA’s previous guideline. Nonetheless, the industry appears to agree on the consensus that the FDA’ efforts in standardizing the development of cell therapy products are commendable

Toward Better 3D Tissue: Vascular Tissue Created by Microimprinting and Electrospinning

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Because of a shortage of autologous vascular tissue for transplant procedures, in recent years, researchers and surgeons have turned to to synthetic options to achieve biocompatible vascular graft suitable for therapy. Achieving optimal physicochemical behavior of tissue engineered-scaffolds has been a significant challenge, however, as new technologies have had to adapt to the sophisticated needs of three-dimensional tissue.

Now, an interesting new development in scaffold-based tissue engineering appeared: Authors led by Quingxi Hu at Shanghai University described the creation of composite multi-layer vascular channels formed by both micro-imprinting and electrospinning.

The term “multi-layer” here refers to the generation of two electrospun layers of chitosan and polyvinyl alcohol which surround a middle later of micro-imprinted poly-p-dioxanone.

The “sheet” was rolled into a tube to create a vessel-like 3D structure.

Image of the finished 3D stucture.


The use of both electrospinning and micro-imprinting generated a rigid structure with a higher tensile and radial strength.

The authors demonstrated that the new scafffold promoted cell proliferation of rat fibrloblasts seeded on the scaffold over 21 days of culture, and the hydrophilic surface yielded good biocompatibility.

As more complex applications call for more sophisticated tissue engineering products, composite approaches like the one described in this paper appear as innovative solutions to these problems. There is still a ways to go before this scaffold reaches the clinic, but we are excited to see new applications of novel electrospinning-based fabrication approaches.

Akron has been a pioneer of electrospinning – our capabilities of creating custom shapes of electrospun tissue in a variety of polymers are the result of extensive research and development efforts that are now being expanded into more process-intensive and sophisticated applications. If you have any questions about any of these processes, contact us.



Cryopreservation of Stem Cells: Evaluating Approaches for Clinical Potential

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Despite a growing number of publications discussing various aspects of stem cell cryopreservation, a clear understanding of an optimal set of guidelines, including protocols and, most importantly, cryopreservation solutions that are clinically-suitable is still lacking. The unpredictable behavior and differing biophysical characteristics of different cell types has made making such generalizations less straightforward, as an understanding of individualized cell behavior is becoming of increasing importance.

A recent study by the University of Leuven in Belgium sought to bring some more clarity to these issues. The authors compared seven different freezing and thawing protocols using human amniotic fluid-derived stem cells.

These were:

  • (1) 10% dimethyl sulfoxide (DMSO)
  • (2) 2.5% DMSO, caspase inhibitor, and catalase
  • (3) 5% glycerol, caspase inhibitor, and catalase
  • (4) sperm freezing medium
  • (5) slow-freezing solution
  • (6) ethylene glycol, sucrose, and Ficoll 70
  • (7) vitrification solution

Medium 4, sperm freezing medium, was Irvine Scientific’s TYB Freezing Medium, solution 6 was Vitrolife’s FreezeKit medium, while the vitrification solution (7) was Vitrolife’s RapidVit vitrification kit.

While protocols 1, 2, 5 and 6 resulted in successful recovery of hAFSCs based on live/dead assay, a lower CD marker expression profile was much weaker for protocol 2.

Expression levels of GAPDH, Oct-4, SOX17, vimentin, KSP and NCAM showed increased SOX17 gene expression for protocols 1, 2 and 6 compared to the unfrozen control samples.

Taking all of the results into account, the authors identified approaches 1, 5 and 6 as being superior in terms of recovery of cells by yielding a significant amount of cells with strong surface marker expression.

Screen Shot 2015-02-15 at 6.18.18 PM


Out of these, the slow-freezing solution (5) was identified by the authors as being the most robust in terms of cell recovery and desirable properties after thawing, and recommendations were made as to its clinical use.

While these are preliminary results that apply to stem cells derived from amniotic fluids, the paper raises important points about the development of freezing solutions by highlighting the important fact that cell-specific behavior does not necessarily show consistency across a range of assays when analyzing treatment response and that multiple analyses need to be considered as a whole.

At Akron, we have been investigating a range of new solutions for cell cryopreservation that are both DMSO-based as well as DMSO-free and have developed a strong know-how of products and solutions for various cell types, particularly those that are free from DMSO. If you have any questions or need help understanding your options for cell cryopreservation (without or with DMSO), feel free to get in touch with us via email at

Cell Therapies: Toward Cost-Effective (Personalized?) Medicine

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As we remarked in our previous blog, cell therapies are slowly coming of age, fueled by strong research and a number of therapies bravely advancing through the clinic. While confidence is increasing, there are significant hurdles before many of the therapies currently showing early clinical promise advance to mainstream status. A term that has long been thrown around to almost deafening level – “personalized medicine” – is becoming increasingly important as medicine turns to meet the needs of individual patients.

Just over one year ago, Novartis announced it had moved into the personalized T cell therapy space with CTL019 CAR therapy. Since then, the field has promptly followed suit.

Achieving a standardised, clinical and commercial-grade cell therapy product that is specific to each patient’s medical needs requires an interdisciplinary approach with innovation at every step.

Long-thought to be the main contributor to cost, raw materials are now being superseded by complex technologies, analytical systems and production requirements in the development of new personalized cell therapies.

In manufacturing, companies are turning to more inventive approaches for cost reduction.

For instance, Argos Therapeutics recently announced a partnership with Saint Goban’s Performance Plastics Division to use disposables in their manufacturing process for the production of their carcinoma immunotherapy. By doing so, Argos claims it will significantly reduce costs to off-the-shelf product levels, while allowing them to increase throughput by minimizing equipment intervention during the development of their closed-system, patient-specific immunotherapies.

While it is the belief of many that the only way for cell therapies to become competitive and self-sustaining as well as commercially viable is to develop off-the-shelf products that provide solutions specific for each human, complex needs will need increasingly smarter solutions.

Prior to manufacturing, at the development stage, new technologies have revolutionized the scientific process, from DNA sequencing to next-generation proteomics. However, the increasingly more elaborate technologies have also introduced the burden of an ever-increasing amount of data and the necessity for the interperetation, storage and analysis of this growing data pool.

Moreover, efforts are underway to establish uniform analytical protocols, which will ultimately translate to compliant manufacturing processes.

Consistent standards will be key as personalized medicine moves from research and development to data analysis.

However, the drive to develop personalized medicines has identified GMP compliance as an ever-increasing contributor to cost. Speaking to recently, immatics Biotechnologies CSO Harpeet Singh stated, “GMP production is cost-intensive because of the regulatory requirements, particularly related to various in-process and post-process controls and extensive documentation.”

Once all the steps are in place and compliant processes have been established, the cost is already extremely high, even before the manufacturing stage has reached.

At that point the scientific burden is reduced, but another one altogether follows: how to keep costs of production down. Outsourcing vs. in-house production, raw materials, efficient processes (disposable vs. reusable), are considerations that are going to grow are cell therapies reach maturation.

Akron Biotech has been at the forefront of new initiatives by participating in Whitepapers regarding ancillary materials with ISCT and other regulatory standardization activities through the Alliance of Regenerative Medicine. The objective of such initiatives is to achieve compliant quality standards and cost effective options in ancillary materials used in advanced cell therapies.

If you want to learn more about options and key products email us at



Akron at Phacilitate 2015: Raw Materials Control for Bioassay Consistency

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From 26-28 January, Akron attended the 11th Annual Phacilitate’s Cell and Gene Therapy Forum, which brings together bioleaders from the regenerative medicine and cell therapy fields to discuss issues relating to manufacturing, product characterization, logistics, R&D and regulatory challenges and outline paths forward for the industry.

Akron’s Dr. Claudia Zylberberg participated in the Manufacturing and Product development panel sponsored and chaired by Dr. Jiwen Zhang from GE Healthcare alongside Margarida Menezes Ferreira, Member of the Committee for Advanced Therapies (CAT), and of the Biologics Working Party at the European Medicines Agency (EMA) and Robert Preti, PhD., President of Progenitor Cell Therapy (PCT) and CEO of Neostem.

Questions discussed included process compatibility when moving from 2D to 3D cell culture, considerations and insights into serum-free processing options, new developments in 3D bioprinting for the production of personalized tissues or organs for transplantation.

One important topic that the panel also discussed is raw material control and compliance from a regulatory and manufacturing  point of view. Quality standards needed for raw materials used in a process vary for different regulatory agencies. For instance, the EMA does not have drug master files like FDA does in the US.

Akron Biotech has long championed the critical importance of raw material qualification, and at Phacilitate, we discussed at length the implications that such control – or the lack thereof – has.

Raw materials for cell therapy are in itself a complex concept and it is recommended that a minimum Quality Managment System be in place to control and allow traceability. The requirements that will allow compliance and assist with the claims of the final cellular product should be agreed between the manufacturer and the user. The main issue with biological raw materials is consistency and performance, which makes qualification of batches critical.

Akron’s stance on raw material control and its implications on bioassay also stresses some important points:

Because cell therapy products are often linked to the biological performance of a living entity often characterized in terms of a biological assays (such as for cytokines and growth factors), the implications of bioassay consistency is important.

When developing cytokine bioassays, while raw material control is important, it is not the only determining factor for cytokine activity.

Bioactivity of cytokines depends on two main factors:

  • Consistency of raw materials
  • Cell behavior in culture and assay

Users should, firstly, ensure that raw materials and the corresponding suppliers are qualified across multiple batches and that, at the time of use, there is consistency in age and nature of the raw material.

Having said this, while consistency in raw materials helps ensure consistent cell processing, raw material consistency does not in and of itself guarantee consistent cell behavior.

Cells respond to multiple factors – raw materials being one – when in culture. These are protocol-related (such as manual processing), age of the cells, freeze/thaw conditions, environmental conditions and many more.

Finally, the bioassay conditions, which involves both cells and cytokines as well as assay materials, must be qualified in the same way – this includes everything from assay reagents qualification, instrument calibration, to data analysis, to reaction conditions control and finally analytical equipment maintenance.

In short, users should ensure raw material consistency by strictly qualifying all materials, but also be aware that the same level of control must be maintained across the entire process.Contact us to learn more :

Across the World, MSC Therapy Ready to Pick Up

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In an interview with Morrie Ruffin and Michael Werner of the Alliance of Regenerative Medicine published just recently in The Life Science Report, the ARM executives discuss their outlook for the regenerative medicine field and their predictions for the years ahead. It is an interesting read that touches on issues such as commercialization, regulatory compliance as well as commercial viability of current cell therapy companies. When asked about the main hurdles to the clinical acceptance, Michael Warner put it clearly:

“One of the challenges in this space is the issue of commercialization, which concerns manufacturing, scale-up and all the things required to make these new products available and successful.”

For the entire article, click here.

On the heels of the interview are two interesting papers on MSC therapy that have just appeared. The first is from the University of Miami Miller School of Medicine, published in Journal of the American College of Cardiology, titled “Effect of Aging on Human Mesenchymal Stem Cell Therapy in Ischemic Cardiomyopathy Patients.” The paper investigated whether the therapeutic effect of culture-expanded mesenchymal stem cells persisted at 1 year in patients younger than 60 years and older than 60 years. Data was obtained by measuring absolute scar size at baseline and 1 year post-transendocardial stem cell injection (TESI), while functional capacity was measured. While the study is limited by the nature of the analytical methods used, as well as a conservative functional approach employed, the authors showed a difference in scar size at the end and beginning that did, however, not differ by age.

The main finding was that, no – age does not impart response to MSC therapy.

Elsewhere across the world, the Chinese Academy of Sciences this week announced the start of an important human MSC trial to damage injured spinal cord. The trial, for which 6 patients have been recruited, is testing an implant made of mesenchymal stem cells and a collagen collagen scaffold fibers that contains collagen binding brain-derived neurotrophic factor (BDNF).

While the first transplant was just performed, these are the very earliest days of the study, which is expected to recruit up to 30 patients in the upcoming stages, and the results of which will be closely monitored.

This is by no means the first MSC trial currently ongoing, but it is a landmark development both from a medical perspective as well as a reminder that across the world, MSC therapies are coming of age.


iPSCs: A Few Steps Closer to the Clinic

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New reprogramming and gene correction techniques are expected to drive iPSCs to new clinical therapies in the coming year at a pace that may significantly outweigh the achievements in the field over the last few years. 2015 is poised to be a significant year for iPSCs, with efforts to speed up their clinical feasibility picking up steam.

One step toward clinical use of iPSCs came last week, when the UK Cell Therapy Catapult signed a licencing agreement with iPS Academia Japan. Under the agreement, the Cell Therapy Catapult will licence, manufacture and commercialise GMP-grade iPS cell lines for use in early-stage research and clinical trials. The Cell Bank was first established in 2013. The establishment of such a GMP cell bank is expected to be pivotal to the translation of iPSC therapies from the bench to the clinic, in the UK and beyond.

The current state of iPSC research was described in an interesting overview on iPSC assays published this week in Genetic Engineering and Biotechnology News, available here.

The industry has also been responsive to the growing need for iPSCs for clinical use. Pre-clinical successes that companies such as ViaCyte have been reporting are sending positive waves through the industry. Cellular Dynamics International, who has been developing large-scale reprogramming technologies for iPSCs, last week announced it had entered into an agreement with Cord Blood Registry to reprogram umbilical cord blood cells into iPSCs, which is hoped will translate into new therapies.