Michelle Hoffman, editorial director of Pharmaceutical Technology.

Michelle Hoffman

Close observers of the pharmaceutical industry know that after technical and safety issues, the odds of a drug making it to market depend heavily on who will pay for the drug's use. This is why "go" or "no go" decisions at pharmaceutical firms take into consideration formularies and payment schedules of third-party payers. And many physicians are reluctant to prescribe some very effective medications if they know a patient's insurer won't pay for them. 

With this in mind, we at PharmTech are keeping a close eye on federal budgetary resolutions that affect the Medicare program. One such resolution was made by Congress last month.

In mid-July, the president vetoed a bill that sought to cancel Medicare pay cuts to physicians. Instead, the bill cut payments under a program called Medicare Advantage, in which, explains Paul Krugman in his 

 column (July 11, 2008), "Medicare funds are funneled through private insurance companies, rather than directly paying for care."

Following a dramatic appearance on the Senate floor of an ailing, postoperative Senator Edward Kennedy (D-MA), the Senate overrode the president's veto by 70 to 26. The House followed suit by a vote of 383 to 41. The consequences of the veto override are that physicians will not experience a pay cut, but private insurers participating in Medicare Advantage will.

President George W. Bush, in a July 15 letter to Congress explains that, while he supports the "primary objective of this legislation, to forestall reduction in physician payments," he believes that "...taking choices away from seniors to pay physicians is wrong." The curtailed choices he enumerates include "private health plan options." Medicare's accounting office, among others, believes this not to be the case. (A thorough explanation of the consequences of reducing payments to private insurers by the Center on Budget and Policy Priorities, a private nonprofit group, can be found online at: 

A second concern of the president's is that the bill would "undermine the Medicare prescription drug program." And this confuses me. The bill in fact expands the classes of drugs covered by the Medicare program to include anti-anxiety drugs and sleep aids for patients suffering from conditions stemming from chronic mental health problems, cancer, or epilepsy.

And while I'm very happy to see any movement that treats mental illnesses more like other illnesses (The bill also reduces out-of-pocket costs for mental-health services to keep them in line with out-of-pocket payments for other illnesses), I also wonder about some of the more subtle reverberations of increasing the Medicare formulary.  Increases in the Medicare formulary might ratchet up—just a bit—a contest that may be looming between Medicare and the US Food and Drug Administration.

This is an interesting potential tug of war that I've heard discussed only briefly at the moment, but could have a tremendous impact in the future on which drugs actually make it to market. As I noted above, reimbursement issues figure mightily in go—no go decisions. As the US population ages, Medicare is increasingly becoming the 800-pound gorilla among third-party payers and will have an indirect influence on which drugs get produced in the future. For example, if the Center for Medicare and Medicaid Services (CMS), the government department that administers the Medicare system, decides that it wants new drugs to be significantly more effective than existing drugs for the same condition, then efficacy will be an important determinant of whether the new drug makes it to market, and whether or not FDA approves it.

Close observers of the pharmaceutical industry are watching this particular contest very carefully. The drugs we all use and the ones you develop and manufacture may well depend on this tug of war. 

Articles

Legislative decisions to increase Medicare's formulary may lead to a fight over drug approvals.

FDA and Medicare at Odds?

With a fresh infusion of capital, a new executive team, including a new CEO and president, and a new board, Patheon brass decided to give the company a fresh new look, a new beginning, and an opportunity to embrace a new vision. The name remains the same, says CEO Wes Wheeler, who joined the company in December 2007, to reflect the company's "heritage of quality and service." 			

However, he adds, "we put the name in lower case to project a more people-friendly, compassionate company.  We changed the logo color to green to reflect a fresh new start, and to venture into colors that none of our competitors own to convey that we are unique.  The unique 'P' in the logo ... called the 'infiniP,' signifies our commitment to continuous improvement. The new slogan 'Performance the world over' reminds our customers that we have a global footprint, and are committed to proving through metrics that we get the job done." 

Wheeler recently took some time to share his perspective on the challenges and opportunities that lay ahead for contract service providers with 

. What follows is a transcript of that talk. 

				» What is your overall assessment of the market for contract service providers? 

 We operate in two areas of that market. Twenty percent of our business is in pharmaceutical development, 80% in commercial manufacturing. So I can speak to those two markets specifically. 

Our original concept in the development market was to bring products in when manufacturing was being scaled up for Phase II and III clinical trials. This would load our pipeline for commercial manufacturing. Now, however, we treat development as a separate business and offer services for formulation and process development for Phase I trials. Then, if we are lucky, we transition these drugs to our commercial manufacturing units. 

 What in the market changed to motivate Patheon's change in approach? 

 In the old days, contract manufacturing organizations (CMOs) were awarded 'tail' products—that is, products that were further along in their life cycles, so that the clients could free up their capacity for newer products. We like those 'tail' products, but we're a bit selfish in that we also want to get products that are at an earlier stage in their life cycle.  It gives us growth in volume and better stability. 

 That implies a change in Big Pharma's approach to outsourcing. What are your thoughts in this regard? 

 Several of the large pharma companies are coming to us to help develop new products, which has been a nice change.  So we have both the large companies and the smaller 'virtual' companies which have traditionally outsourced to us. We can offer all of them full formulation development, analytical services, and scale-up. 

Why do you think pharma is bringing you earlier-stage projects? 

  Pharma companies are outsourcing up to 30% of their development, and that number is expected to grow to 40%. The trend by pharma to outsource development is motivated by a desire to reduce cost, temper the ebbs and flows, and manage risk.  

 I hear it said that pharma companies are varying their product mix. Is this accurate? 

 Yes. Traditional pharma is moving into biologicals and biotechs are moving into small molecules. The two types of Big Pharma companies are becoming one. 

 What do you think the market is for development services? 

 We estimate that market to be about $10 billion annually. We have between 2–3% of that market and have high expectations for our ability to grow.  

We operate six development centers around the world—in North America and Western Europe. We just opened a sales office in Japan and are moving headquarters to Research Triangle Park in North Carolina. 

 When you say you share the risk, what do you mean? 

  We share the risk if we put time and effort into a compound that doesn't make it to market. We don't get the benefit of the revenues from commercial production. 

 What are you seeing on the commercial side of the business? 

 On the commercial side, we see the market to be $10 billion, including Japan, but not India, Australia, or the rest of Asia. We have 7% of that market, which puts us second in the world in market share. We operate nine plants in five countries, excluding two plants we're selling (one in Canada and one in Puerto Rico). The retail value of the products we produce is more than $50 billion. We employ just under 5000 people, distribute to 85 countries, and manufacture all dosage forms. 

We don't currently own much of our own technology, but we hope to do that in the future. We will encourage scientists in all six of our development centers to file patents. We also expect to partner with academia. 

 What do you perceive to be the trends in commercial manufacturing? 

 We divide that market into five segments, each with its own dynamic: Big Pharma, specialty pharma, generics, biologics, and biotech 

Depending on the company, Big Pharma outsources anywhere between 5% and 25% of its total manufacturing. Many companies have established strategic outsourcing divisions and are becoming very sophisticated. Specialty pharma companies are growing scripts faster than Big Pharma. About 200 companies classify as specialty pharma, and Patheon will focus more energy on this segment. Generics represent a very large market. Over 60% of all US prescriptions are now written generically. It's a market segment we can't ignore. Even though we've traditionally not worked closely with generics manufacturers, we are starting to establish relationships with them. But of course, we don't want to help cannibalize business from our own customers, the innovator companies.  

As a company, we practice portfolio management. That's why generics are becoming so important to us. They produce high volumes of predictable products. It allows us to absorb our overheads and take on other, riskier projects. 

For the biologics manufacturers who have traditionally produced proteins and peptides, we serve to fill out their capacity in biologics. But we are starting to work with them to develop their small molecules as well.  

Companies in the biotech space generally don't have their own commercial manufacturing capacity, so we can help them develop their products. Also for the biotech companies, we can offer full service, from early clinical through commercialization, and we do this for many of them. 

 What's your read on the markets in India and China? 

 No question that they are large players in the active pharmaceutical ingredient market. The majority of the industry's intermediates are now manufactured in India and China.  

But the final finish step, the purification step, is still typically done in the West. For final dosage-form manufacturing, however, I see slower movement toward China and India.  China is a longer way off, given the well publicized issues with quality and intellectual property. India is closer.  

Combined, however, they don't have much more than 5% of the western (American and European) markets, and that might double to 10% in the near term. They are the lower cost alternative, but I don't see them taking over the majority of the market within the next five years. 

 Why doesn't Patheon have a finished-dose plant in Asia to service that market? 

 We are considering a joint venture for development services in India. There is a huge amount of talent, and India can offer a lower cost alternative. We want to test the waters—test the logistics of that relationship as well as the quality standards. Patheon represents a high-quality brand, and we wouldn't want to neutralize our brand, but we do want to test the waters where it makes sense.  

We are also thinking about Eastern Europe, possibly Poland, for commercial manufacture. 

Another dynamic I've noticed with regard to India is that Indian companies are now acquiring finished-dose facilities in North America and Europe. In these cases, they're competing within our own cost structure. I say: Bring it on! I can be competitive on that kind of playing field. 

Outsourcing strategies of large pharma companies are changing. The CEO of Patheon talks about his company's plan to meet customers' changing needs.

Contract Service Providers: The State of the Market

 No one can dispute that these are turbulent times all around. Not only are we in the midst of choosing a new president for the next four (at least) years, but our economy, most particularly, our banking system, is undergoing some seismic upheavals, and our stock market has officially transmogrified from bull to bear. The pharmaceutical industry has of course been in flux for several years now, but only recently do I think I see a real impact on contract service providers and manufacturers. Certainly that seems to be the theme we discern from this year's PharmSource–

Outsourcing Survey and from anecdotal evidence and discussions I've had with contract research and contract manufacturing organizations (CROs and CMOs).      

In fact, if I had to sum it up, I'd say that the line between CRO and CMO is becoming more and more blurred. Let's start at the beginning. As I understand it, CMOs originally served to provide extra capacity to pharmaceutical companies that had exhausted their internal capacity. Later, as the biotech industry grew and entered clinical and then manufacturing phases, biotech companies turned to outside contractors for manufacturing  and some development services. But large pharmaceutical companies pretty much restricted their outsourcing activities to manufacturing. 

Now, however, capacity is not an issue. In fact, as Jim Miller points out in his article in this supplement, there may be too much capacity. So contractors have to find something else to offer their clients, something that differentiates them. For many, this means moving up the value chain and into services. 

More and more CMOs seem to be offering various development services, process development, and formulation for clinical-trial-scale production, for example, as well as analytical services and scale-up to commercial-level production. Other vendors are specializing in certain specialty-type production, usually focusing on some kind of bioprocessing in which many traditional pharmaceutical companies are still not expert. Still others have developed proprietary processes for their clients. But they all seem to feel pressure to grow and specialize, or otherwise become ossified relics—fossils.  

In no small part, this transformation is due to changes on the client side. Namely, pharmaceutical companies seem to be outsourcing larger parts of projects, including much more of their development work than before. Contract vendors, are operating increasingly as partners with their customers, sharing the risks and responsibilities as well as the rewards of their businesses.  

Among the risks, of course, are the source and quality of the raw materials they work with. Even though the burden of compliance falls squarely on the shoulders of the client company, the diligence of contract provider partners will go a long way toward securing the integrity of supply chains. I do hope that while they enjoy the bounty of business, contract vendors take that responsibility very seriously. 

As pharma companies outsource new types of projects, contractors are trying to meet new needs.

Contract Vendors, They Are A Changin'

Drugmakers seeking to block the activity of a protein may have a new strategy at their disposal, according to a paper published in the June 11, 2008, issue of 

. Traditionally, drugs that block protein activities do so by binding the protein's active site, which in turn prevents the natural substrate from binding at that site, which ultimately inhibits the protein's activity. But there may be another way to skin that particular cat. The new paradigm proposes to prevent substrate binding by attaching the drug directly to the substrate instead of to the protein. In theory, this also would prevent the substrate from binding the protein's active site with the same effect of inhibiting the protein's activity. 

The notion of interfering with protein-substrate binding by tying up the substrate may have several advantages over the traditional approach. For one thing, many of the protein-blocking drugs are monoclonal antibodies, themselves large proteins that can be difficult to deliver. Substrate blocking, on the other hand, might be accomplished with smaller molecules. In addition, substrates are often found circulating in the bloodstream, which may facilitate drug delivery. 

Source: T. Kodadek, "Biochemsitry: Molecular Cloaking Devices," 

Drugmakers seeking to block the activity of a protein may have a new strategy at their disposal.

Coming Down the Pike: Protein-Substrate Binding

What's old is new again, as the economy once more becomes the focus of America's anxieties. These days, when I tune into the news, I find myself listening to reports about how formerly middle class families are struggling to meet expenses for basic needs. Suddenly it seems that the "need" for a second home is supplanted by the more pressing need to meet the mortgage on the first home. Food is now prohibitively expensive for many people that previously didn't even check price tags. And the cost of health care and drugs weighs ever more heavily on people—even those with health insurance. 

On a national level, the government has always struggled with national priorities in spending issues, but it seems to me that even the US government is now weighing the costs of meeting basic needs. Take for example, infrastructure, safe food, water, air, and drugs 

 more high-ticket items such as war, space programs, and tax cuts.  

Most of us are familiar by now with endless reports from within and outside the US Food and Drug Administration that the agency needs more funds to perform its job properly. And thankfully, Congress has responded by increasing appropriations for FDA activities. But there are other measures that will, in theory, improve the efficiency of drug manufacturing, measures that, in theory will also improve drug safety.  

I'm thinking specifically of the quality-by-design initiative in which scientists get a handle on the basic physiochemical properties of drug ingredients in order to better predict how they'll move through the manufacturing line and come up with equipment and processes that rationally move ingredients through the line with a minimum of variability. But acquiring that physiochemical knowledge requires basic research that someone has to pay for.  

Who should that someone be? If we ask drug companies to take on that expense, they may pass the costs onto consumers who already feel as though they pay too much for drugs. Should the government pay for that research? Should equipment manufacturers? I don't know the answers to these questions. But I would like to see a public discussion of them. And, without sounding like a broken record, I would like to hear our presumptive presidential candidates address these issues as they talk about the healthcare system. 

Some of you may recall my editorial in the January 2008 issue of P

, in which I had to report that—sadly—none of then contenders for the office of

US President responded to my questions about their future plans for FDA. At that time, the editors decided to try again once we knew who would be the nominees from the major parties.  

Of course, we won't know definitively who they are until later this summer, but in the interest of making our deadlines and being able to publish their answers before the general election, we have contacted the press offices of the two presumptive nominees: Senator John McCain  (R-AZ) and Senator Barak Obama (D-IL). This time, instead of asking them to answer the editors' questions, we'd like them to answer yours.  

We'll have an area set up on our website (

) at which you can send us your questions, or, if you prefer, email them directly to me: 

 and we'll forward them to the candidates. Hopefully this time, we'll hear something back. Either way, you'll learn the outcome.  

With no economic relief in sight, industry, like all of us, is grappling with high-and new-costs.

How to Pay for it All?

This story is about a technology so new, it hasn't been invented yet.

 Not quite. It's so new that "Googling" the search term "cell manufacturing" pulls up largely irrelevant entries—ones that pertain more to computer hardware configuration than to the large-scale culturing of cells. And yet it is based on traditional cell culture, one of the oldest technologies in biology and the foundation on which so many modern biological discoveries rest.

Although small-scale cell culture has been around for about a century, the notion of culturing cells on a large scale is only a decade old, invented out of the necessity to accommodate the growing commercial success of biotech-based therapeutics, mostly monoclonal antibodies and small peptide-sized molecules. 

Protein drugs can theoretically be synthesized in a laboratory, but the procedure would be painstaking, labor intensive, and expensive. It is far more efficient to follow nature's lead and produce proteins inside the cells. 

Figure 1: CompacT SelecT is a medium-throughput automated cell-culture system made by The Automation Partnership. 

The industrial route for making protein drugs inside cells is fairly well established, even at the relatively callow age of ten. In the general paradigm, a gene for a therapeutic protein is inserted into a cell—the most popular mammalian cell for industrial purposes being a line of Chinese hamster ovary (CHO) cells. Great quantities—thousands of liters—of the genetically engineered CHO cells are cultured, fed, and nurtured and encouraged to undergo successive cell divisions to make yet more  cells, which, of course, are also producing large quantities of the therapeutic protein. The therapeutic protein is secreted from the cells, or the cells  are later cracked open so the therapeutic protein can be extracted and purified from them, formulated, packaged, and then sold as a drug. 

Either way, the cells are disposable, used only to produce protein product before they're discarded. The techniques used to culture them are rather harsh, by cell-culture standards. "You beat the heck out of [the cells] to get the product out," says Chris Mason, an academic researcher at the Regenerative Medicine Bioprocessing Unit at University College in London. "You can treat the cells as badly as you like," he says, "just as long as they produce the bioproduct." 

Figure 2: An automated cell-culture system includes a media pump and circulation pump to push fresh medium and oxygen through the CellCube module and to eliminate spent medium. Ideally, cells within the module are exposed to uniform amounts of gases and nutrients. 

Treating the cells badly means that rather than allowing them to rest on a solid substrate, as most cells "prefer," cells grown for bioprocessing are suspended in a kind of nutritive broth called medium. The suspension is contained inside either a large stainless-steel vat or a large plastic (and therefore disposable) bioreactor and somehow rocked or churned or mixed to make sure that all cells have equal access to the nutrients and gases dissolved within the medium. Because they're suspended in huge vats or bags, and because they're being roiled around, the cells ball up and bump up against each other and against the vessel in which they're growing. And, as Mason noted, this harsh treatment—destructive to many cells—is fine, because the cells are not the end game. They're not the product. 

At some point, cells will be the product. Regenerative medicine, the ability to repopulate unhealthy organs and tissues with healthy cells, is getting closer to the clinic. Mason detects a major change in interest among venture capital groups, who, he says, "now see some real commercial pressure." For their part, cell-therapy companies are also focusing more on commercializing the technology as opposed to previous years, when they were mostly researching it. Several biotech companies are either preparing to enter or are already in clinical trials with cell-based therapies. Geron (Menlo Park, CA), a biotechnology company focusing on regenerative medicine, is preparing to enter its first clinical trials with a GRNOPC1, a glial-cell product that promotes spinal-chord repair. And other cell-therapies in the service of regenerative medicine are not far behind. 

In preparation for the day cell therapy comes into commercial fruition, process engineers, cell biologists, and equipment manufacturers are working out the details of large-scale cell culturing to produce cells as end products. One thing they do know, says Mason, is that for regenerative medicine,  "the process is the product. You have to take care of the cell all the way through the process." In other words, culturing cells on a large scale requires a kinder, gentler process than does culturing them to produce protein products. And there's the rub. 

By it's very nature, industrial-scale manufacturing requires batch handling, bulk movement, and bulk treatment, which is not necessarily known for its gentleness. And cells, especially the primary and stem cells used in cell therapy, are fragile and require kid-glove treatment.  

Until recently, that kind of treatment could be maintained only when a technician performed all of the harvesting, seeding, feeding, waste removal, and packaging manually. And that was fine, even for cell therapy. In its initial iteration, cell therapy involved a patient's donation to himself of his own cells—a process called autologous cell transplant. Healthy white blood cells, for example, are often removed from patients undergoing high-dose anticancer chemotherapy, which kills all remaining white blood cells in the bone marrow—including the cancer cells. While the healthy cells remain outside the body, they are cultured to increase their numbers to a point where they can repopulate the patient's bone marrow once the course of chemotherapy has been completed. Other organs may also be regenerated by similar autologous transplants. Autodonation of cells sidesteps the problem of rejection that comes in transplanting cells from one person into another. 

Viewed as a manufacturing problem, however, the batch size of an autologous cell dose is very small. Which does not mean the process cannot be automated. If transplants are being prepared for just one patient, there's little motivation to increase production scales. But imagine a transplant facility, in which many different cell types harvested from many different patients are being cultured for reimplantation at the same time. In that case, the challenge for process engineers is the parallel growth and cultivation of many different cell lines in a sterile, automated setting without contaminating one cell line with the next. Economies of scale can be realized in this setting by multiplexing the cultivation of cell lines.  

The real opportunity to develop a large-scale process comes as researchers consider the possibility of allogeneic transplants. Here the idea is that it may be possible to create some kind of "universal" cell that can safely be transplanted in many recipients without concern for rejection. In some scenarios, the cells may be modified as to not express markers that stimulate rejection by the immune system. In others, cells may be typed in a system similar to blood typing, which allows certain classes of cells to be transplanted from one group to another without the requirement of an exact tissue match. However it's achieved, the allogeneic model will require large batches of cells to be cultured for use in cell therapy. And here's where the issues become interesting.

As researchers work to invent an industrial process to "manufacture" cells on a large scale, they draw their experience and knowledge—as well as their assumptions—from two sources. The first is the manual process by which cells have been cultured for a century. And the second comes from their experience with the bulk processing of cells for bioprocessing. What is emerging is a process that Mason likes to call "regenerative medicine 1.0," or "RegenMed 1.0," for short. 

From manual cell culture, investigators know that the vast majority of cells grow best when they are attached to a solid surface. They also know that the health of the cells depends on having the proper nutrients in the culture medium, proper gas exchange, and the proper density. If too many cells crowd the plate, some may be induced to stop dividing and enter a differentiation stage where they eventually take on the characteristics of the mature cell type. This would be enormously counterproductive, because cell therapy almost always involves some kind of immature cell type to allow the recipient tissue to continue to regenerate itself. Cell culture also requires someone to remove spent medium, which is devoid of nutrients and replete with the waste products of cellular metabolism. It requires someone to recognize whether cells are viable and when the density dictates that cultures be divided onto new culture plates—a process akin to repotting plants to give them more growing room. Of course, someone also has to remove the cells in the end, package them, transport them, and then implant them in the patient. All of these processes have to be automated. 

From bioprocessing, scientists already have gained a lot of general knowledge. They know, for example, how to work in a closed system; they know quality assessment and validation techniques. "There exists a framework in which to do process development that wasn't there when bioprocessing was developed," says Jon Rowley, director for cell therapy research and development at Lonza (Walkersville, MD). "A lot of the equipment has been developed, as well," says Rowley. "Sterile connect technology, for example. We don't have to develop these technologies now from the ground up." 

The immediate challenge as Rowley sees it is that "many cells in the cell-therapy world are adherent and don't grow in traditional [for bioprocessing purposes] suspension systems, which means that that part of the [bio]process is not transferable." The next challenge is the need to build an adhesion system that limits batch size. A state-of-the-art vessel for bioprocessing can hold as much as 20,000 L of cell suspension. "There is no 20,000 L culture dish for adherent cells," he says. And then he notes that with current technology, the highest adherent batch size is 6 L, "a far cry from 20,000," Rowley adds. 

Process developers have been working closely with equipment manufacturers to overcome the volume problem. In the manual paradigm, cells adhere to the sides of flasks or roller bottles, which typically provide about 850 cm

  of surface area on which cells can grow. "What is a mammalian cell-culture flask," asks Tim Ward, director of product management at The Automation Partnership (TAP) in Royston, UK. "It was not designed to make efficient use of its volume." And as an example, he adds that to build an industrial-sized machine equivalent to a 20,000 L bioreactor that relies on roller bottles "would require a facility the size of New York."  

To address the problem, several companies are developing culture plates that increase the adhesive surface area within a given volume. Corning Life Sciences (Lowell, MA), for example, has developed several cell culture vessels meant to be used in high-volume cell production. Its "HYPERFlask," for example, provides a total of 1720 cm

  surface area on 10 growth layers within the footprint of one of the traditional T-flasks. According to Kim Titus, business development manager and the commercial lead for HYPERFlask vessel at Corning, the cells sit on a gas-permeable film through which all gas exchange takes place. Customers who have used the flask have verified that cells grow uniformly on each of the layers, indicating that nutrients and gases are distributed evenly throughout the flask.  

Those considering even larger-scale production often turn to Corning's "CellCube Culture System." Each growth layer in a CellCube module provides 850 cm

  of surface area (the same area provided by one roller bottle) on as many as 100 growth layers for a total of 85,000 cm

 . The largest turnkey processes using the CellCube system right now uses four such 100-layer CellCube modules, but custom processes have been developed by some users to allow the use of up to 10 × 100-plate Cubes simultaneously, creating 850,000 cm

  of surface area for cell culture. Andrew Lesniak, applications specialist for bioprocess for CellCube at Corning, notes that the CellCube System, which was originally designed for bioprocessing those cells that could not go into suspension, can easily be adapted to large-scale culture of adherent cells. Culture medium and gases are pumped around the whole system, he notes, so that all of the cells in the cube have uniform access to them.

Providing adequate surface area on a reasonably-sized platform is just part of the challenge in considering large-scale cell culture. Many issues loom large when process developers consider how to automate the process in order to make it economically viable. When one considers all of the judgments that need be made in manual cell culture, it becomes clear that cell culture is more art than science. But it's that assumption says TAP's Ward that may have stymied development of automated cell-culture systems. By doing cell culture manually, "people find it difficult to get consistent results," he says. And that leads them to believe that cells are too finicky to culture industrially by machines that can't recognize every nuance of cell behavior and morphology. And that's where they make their mistake, says Ward. It's people's inconsistent handling of the cells that leads to inconsistent outcomes, he says. "If you can automate the process and treat cells consistently, you get consistent results. People's perception [of the challenge] is the reverse of reality." 

The engineers at TAP, says Ward, "started out with some naiveté. Maybe if the team knew more about growing cells, we would have never attempted to do it." What TAP engineers built into their machines was consistency. "Automation makes cell culture more predictable. If you always treat cells in precisely the same way, you know exactly where they'll be in their life cycle at any point during the process, and the outcomes will be consistent." Ward notes that among TAP's collaborations is one with Manchester, UK-based Intercytex. According to an Intercytex press release, the two companies received a grant from the British government to "develop a dedicated robotic system to support the commercial-scale production of dermal papilla cells, the main cells involved in hair regeneration." 

Even though the first generation of cell manufacturing is just starting to come on line, scientists like Rowley and Mason are looking to the future, asking how the field can get to RegenMed 2.0. Interestingly, both envision a process in the future where cell manufacture borrows even more from bioprocessing. The current paradigm, says Mason, mimics the manual procedures, but in the future, he imagines the emergence of a new paradigm. In one possible scenario, he imagines adherent cells on the surfaces of beads or wafers and then suspending the beads in bioreactors similar to the ones now being used for bioprocessing. This would truly allow enormous scale-up to bioprocess-type volumes. "That approach has not yet worked for primary stem cells," says Rowley. "But it is certainly an interesting possibility and may be a medium-to long-term goal of the industry," he says. 

Of course as the cell-culturing process becomes more and more standardized, process developers will be confronted with challenges further down the manufacturing process. For example, cites Mason, stem cells are fragile and moving them into a container can exert shear forces that will tear them if you move them too quickly. "But if you go too slowly," he cautions, "they stick to the tube. There's a window of opportunity for moving them, and you have to hit it just right. There's a big investment in producing plastics that cells won't stick to." Ultimately, says Mason, the goal after the process is all standardized is "how to make it easier and cheaper to process cells."  

1.  C. Mason and M. Hoare, "Regenerative Medicine Bioprocessing: Building a Conceptual Framework Based on Early Studies," 

2.  L. Chue and D.K. Robinson, "Industrial Choices for Protein Production by Large-Scale Cell Culture," 

3.  C. Mason, "Regenerative Medicine: the Industry Comes of Age," 

4. The Automation Partnership, "Major Research Consortium Chooses CompacT SelecT for First European Study on Automating Cell and Tissue Production," Company Press Release, Nov. 22, 2005.

Creating a kinder, gentler manufacturing process that doesn't kill the product is the goal of process developers doing large-scale cell culture for cell therapy.