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Feature Articles : Jan 15, 2009 (Vol. 29, No. 2)

Identifying Best Practices for Advanced Therapies

U.K. Knowledge Transfer Network Initiates Dialogue on New Product R&D
  • Susan Aldridge, Ph.D.

It is not too soon to consider the challenges of manufacturing advanced therapies, including cell- and tissue-based products, according to bioProcessUK. 

The Knowledge Transfer Network, which was set up by the government to build the bioprocessing sector in the U.K., has made advanced therapies the focus of one of its special interest groups (SIG)—Advanced Therapies Group. Late last year, bioProcessUK held the inaugural workshop of its new SIG, “Bioprocessing for Advanced Therapies” in Edinburgh. The meeting was organized in collaboration with the Scottish Stem Cell Network (SSCN).

While the initial focus at bioProcessUK was on recombinant proteins, there is a growing interest in vaccines and regenerative medicine, according to Malcolm Rhodes, Ph.D., technical director. It is also becoming clear that cell-based therapies will play a major part in the U.K.’s biotech pipeline in the future. “There is huge potential to reduce the cost and improve the availability of cell therapies through better product design and more efficient supply chains,” he said.

The Advanced Therapies Group covers cell therapy, tissue engineering, and, perhaps in the future, gene therapy, and has links to other existing networks such as SSCN, the Institute of Chemical Engineers, and Remedi (an engineering and physics science research council regenerative medicine program in the U.K.).

The group aims to promote a broad vision of the sector through the exchange of knowledge between academia, regenerative medicine companies, biotech companies, suppliers, and regulators.

Aesthetics and Utility

Intercytex, a U.K.-based cell therapy company, has a number of products in development based upon allogeneic fibroblasts and autologous dermal papilla cells. The company and its products are governed by the rules of the European Human Tissue Directive and licensed by the Human Tissue Authority. It is through this route that the company has been able to progress Vavelta® to the marketplace in the U.K.  

Vavelta is a skin repair and regeneration therapy developed specifically to treat skin damaged by scarring (e.g., acne scars) or the aging process. “With Vavelta, we are creating a working model for our cell-based products for the future,” said John Lovelady, Ph.D., vp, operations. Intercytex has also completed Phase III trials with Cyzact® for venous leg ulcers. Icx-Skna, a skin-replacement product, is also being evaluated.

These products are temperature sensitive, with a shelf life of 2–21 days, which creates challenges for both packaging and transportation. “Their efficacy depends upon being a living product,” Dr. Lovelady added.

Vavelta is currently distributed to a select number of highly qualified clinics in the U.K. “It must arrive in the best possible condition, and the clinic must understand and comply with the storage requirements on receipt. We are using packaging befitting the high-quality status of the product, which is independent of the clinic destination and the courier.”

Intercytex is currently using NanoCool™ packaging, which can generate and maintain a cold temperature, is self-contained, and independent of external temperature and transport method, as well as being easy to use. The cells are also stored in a hypothermic solution.

“We are committed to ensuring that all elements of the development program, including shipping, are such that we can deliver the product to the clinic in perfect condition—an expensive undertaking,” pointed out Dr. Lovelady. Aesthetics and utility go hand-in-hand to create a high-quality brand that supports this new technology.

A further challenge for cell-based products is loss of cell viability during transportation, caused by a build-up of toxic components as a result of natural processes of the living cells, e.g., apoptosis or metabolic activity. This is linked to storage conditions as cycling of temperature is particularly detrimental to cell viability.

Dr. Lovelady also believes that there should be a clear definition of when a cell-based product is no longer usable. “In the early stages of cell therapy, there is likely to be a lot of waste. However, this will get better with time and experience. In recent months with Vavelta, we have been able to provide a reasonable shelf life, facilitating easier treatment planning in the clinic,” he commented.

As the business expands, Intercytex is considering how it will go global. Once the product is formulated, the clock is ticking. “To facilitate worldwide distribution,” explained Dr. Lovelady, “we may consider manufacturing in the country of use to shorten the supply chain.”

Distributors would need to be able to guarantee delivery and demonstrate full traceability just as the parent organization does. This is indeed a challenge, but a positive step to take as cell therapies could become mainstream in the future.

Packaging of a cell-therapy product must also be able to cope with the range of production—from small scale to bulk orders—and take into account that even something as simple as orientation of the product within the packaging could be crucial.

Finally, cryoprotectants and cryopreservation issues may also be important for the future; how the product would be resuscitated, and the biocompatibility of the solutions are challenges yet to be solved.

Importance of Regulatory Oversight

Companies developing and manufacturing an advanced therapy also need to deal with an emerging regulatory regime. Duncan Mackay, director of regulatory affairs at Genzyme, explained that “the absence of a regulatory framework hinders the development of the cell-therapy sector.” He added that it should always be remembered that “the priority of the regulators is to protect the patient,” so the level of regulation should be proportional to risk. Companies, therefore, need to have a risk-management plan in place. 

Mackay went on to summarize recent developments in the regulatory area. The EU introduced the Advanced Therapies Directive in December 2007, which means that the European Medicines Agency (EMEA) has control of cell-therapy products and that they are treated mainly as medicines (rather than devices). 

In the U.K., the government has named the Human Tissue Agency as the competent authority for the Human Tissue Act, and firms now need licenses to develop cell and tissue therapies. It means dealing with a network of different agencies, all of which have different interpretations of what is required.

Although the U.K. remains a liberal environment for Phase I, once licensed, some products move quickly from the limited clinical environment of 500 patients, for example, to a situation where half a million could be receiving a product. Regulators, therefore, have to be conservative.

Product Characterization

“One question the regulators are interested in, especially the FDA, is how you characterize your product. In other words,  do you know what you are putting into patients?” Mackay said. There is also concern over what effect transportation systems have on cells, and whether dead cells should be treated as contaminants and the impact of cell lysates. (Put simply, should patients be loaded with dead cells?).  

“It is fundamental to characterize your product, and at an early stage,” Mackay added.

Genzyme takes the VIP (viability, identification, potency) approach to characterization with a raft of technologies for each aspect. Viability, measured by proteases, must be more than 85%; for identification, the company looks at gene expression; and for potency, rtPCR provides the necessary data. This combination, to characterize what you are actually putting into the patient, is what the regulators expect.

Furthermore, to commercialize a product it is essential to have complete traceability of everything that comes into contact with the cell.

Genzyme is tough on its products—it will dispose of any units that are in any way suspect. It also performs studies on the impact of any disturbances on the supply chain and carries out a challenge (fire drill) on its distribution cycle once a year to ensure that recovery and recall are possible in the event of a disaster. “Your product can change,” Mackay warned. “Therefore, these studies are critically important.”

Preserving Hepatocytes

There are now recommendations in the EU that traceability records should be kept for 30 years for advanced therapies (compared to five years for conventional pharma products). One question that arises is—what happens to this kind of data when a company folds?

Encouraged by bioProcessUK, companies are now reviewing cell-therapy questions, although, in reality, many of these products will not come on the market for some time. However, there are other uses for cells coming up in the near term—particularly in the area of drug testing.

Nathan Griffiths, Ph.D., CSO of Abcellute, described his company’s approach to the preservation of hepatocytes—a cell type vital in drug discovery and development. “Researchers want to know what the drug is doing to you, and what you are doing to the drug,” he said.

Screens of drugs on liver cells or preparations are a good way of testing this and there are a range of options from primary hepatocytes to S9 and microsomes. But the simpler or less physiological the testing material, the less relevance it has to the in vivo situation in man. Primary hepatocytes give the most information in drug testing, but they are hard to obtain and work with. The key enzymes in hepatocytes for screening belong to the CYP group.

Dr. Griffiths noted that CYP enzymes start to “crash” in culture, rendering data from hepatocytes unreliable. “Of course, cryopreservation has been tried, but it has its limitations.” 

The Abcellute approach is an alternative method for preserving hepatocytes. The company’s goal is to maximize the use of hepatocytes with its plate-based technology that preserves the viability and function of the cells with a proprietary gel.
“The cells can be reactivated after seven days, and they still have CYP activity and the ability to attach,” Dr. Griffiths explained. The cells have recently been evaluated successfully by third parties against freshly isolated cells, with measurement of CYP activities, he added.

Abcellute hepatocytes also allow for a decrease in the number of animals used in testing, Dr. Griffiths noted. The technology allows hepatocytes, including valuable fresh human ones, to be distributed to a wide number of users, spread across a number of geographical separate sites.

Abcellute has been able to show that the technology can also be applied to tissues, and it is working with Biopta on preservation of human artery tissue. Technologies such as these may be applied to the extension of shelf life of cell therapies in the future and, if successful, will help to improve the economics of these treatments.

bioProcessUK intends to continue to foster dialogue regarding best practices in advanced therapies. Future topics to focus on could include scale-up versus scale-out in manufacturing, discussions with regulators, and the development of an attractive business model for these products to make them attractive to investors.