Chris Holloway Group Director, Regulatory Affairs, ERA Consulting Group

Regulation and Compliance

"Accompanying the emergence of each of the new technologies of the 1980s and 1990s was recombinant DNA technology. We've seen advances in gene and cell therapies as well, and the regulatory authorities have largely kept pace with these changes. They've considered the technologies and developed regulations or guidelines to cover them quite rapidly. It's interesting, for example, that the European Pharmacopoeia now contains general chapters for gene therapy products where practically no gene therapy has gone to market. That's quite different from the past where monographs and general chapters followed an established technology. Another encouraging point is the increased interest and willingness of major regulatory authorities to interact with sponsors, to communicate with sponsors to discuss new technologies, and to discuss what's needed to get products to market. These interactions have benefited industry but also the regulators in their own learning process.

Edward G. Calamai Managing Partner, Pharmaceutical Manufacturing and Compliance Associates

Aseptic Processing, Facility Design

"The increasing use of disposables has done away with lifetime cleaning validation and long-term impact on leachables. Single-use has also helped with turnaround of facilities between batches, campaigns of the same materials, and different products in a multiuse facility. In addition, there has been increasing acceptance of the superiority of barrier technology for certain types of aseptic processing and sample handling. Lastly, there's been an evolution of the potential impact of leachables with regard to container–closure. Heightened awareness has emerged in the past 5 to 10 years based on studies done with trace amounts of material in stoppers and in syringes, and the impact of what a subtle formulation change might be on the product's compatibility with the system.

"Looking ahead, there will likely be increased availability and use of disposable processed materials. I also hope for a breakthrough in biosynthesis. We still rely heavily on core technologies for recombinant production, but between the time of synthesis, the development of cell banks, and the downstream processing, these methods have a big impact on initial development costs. There may be a synthetic peptide synthesis that allows us to leapfrog ahead in terms of the size of peptides that can be made synthetically and quickly."

What have been the greatest challenges facing the industry overall?

“In my opinion, our industry still does not function in a highly competitive manner when compared with other high-tech industries. Many inefficient processes still exist. The cost of quality is still too high, often because many critical business functions may not fully integrate customer needs. Other high-tech business operations, such as the computer chip industry, have been able to deliver high-quality products simply because they needed to deliver quality at lower costs to stay in business. No doubt, achieving more success in the development of biologics is more challenging than many other high-tech product types, however, some lessons can be learned from these other high-tech business operations.” —Stephan O. Krause, MedImmune

“One is that the industry is too risk adverse and waits too long to finally change. That’s part of the reason why innovation is going out from the large molecules. And this is one area where the industry is not prepared to take the risks it should. Another challenge is that we have to be careful with respect to public opinion, which hasn’t been a major focus in the pharma industry to date. Public opinion is becoming more and more important, however. Otherwise we have a good success story to tell. We’re talking about a market of around $70 billion to $80 billion. The industry has done great in general, but we have to be careful that we remain prepared to take certain risks because that’s what happened before and that’s why we have the success.” —Hans-Peter Meyer, Lonza

“I think the core challenge is dealing with the high cost of development and production as well as the lengthy clinical-trial period. This combination translates into a higher priced pharmaceutical. These factors result in most large molecule therapeutics still being extremely expensive relative to small-molecule drugs.” —Michiel E. Ultee, Laureate Pharma

“I think one of the big things that we have to look at is the public perception right now, which is that biotech products are expensive and tend to come in injectible formats. These factors are difficult for the healthcare environment of 2012 to embrace. In this model, to get a product and a therapy, one has to go to a healthcare facility, be it a hospital for infusion, or a doctor’s office for an injectible. I’d like to see the industry be able to get what I call the insulin model, which is allowing these medications and therapies to get into the hands of the patients through a more simple model than what we have right now.” —Steve Walfish, Statistical Outsourcing Services

“The greatest challenge, simplistic as it may sound, is getting a product to market. If one looks at the number of products in clinical trials, the numbers of products in clinical trials a few years ago, and the relatively small number of truly new products, not just life-cycle management products getting to market, it’s remarkably small. In spite of that vast effort and expense being invested, something seems to go wrong during the process, and the number of approved products seems to be declining. In addition, perhaps one of the greatest frustrations is the realization that entirely new technologies are progressing more slowly than what we envisaged, such as with tissue engineering. Very few of these products have made it to market so far, and there have been a number of notable products that have received regulatory rejections. One hurdle here is the regulations. In addition, many of these products are designed for rare diseases, and the potential return on investment is limited.” —Chris Holloway, ERA Consulting Group.

“In large part, the public is comfortable with genetically engineered drugs. There are a number that are on the market and many are mainstream. On the other hand, there’s still a lack of understanding of what a recombinant protein is, but there’s less anxiety about how it’s made as opposed to, say, some of the ongoing anxiety around genetically modified food or radiated foods. Another challenge has been the cost of development. It continues to rise even faster than college tuition and certainly faster than inflation because there are more expectations on the amount of safety data, animal data, characterization data and, of course, clinical data needed to get a drug into late-stage clinical development, if not on the market. “One of the last things coming up over the past few years has been the transition in new chemical entities in terms of recombinant proteins that are now going off patent and becoming biosimilars or biogenerics. The challenge, from a regulatory and technical point of view, is to come up with an acceptable way for those to be recognized, not only in Europe and the US, but also in other major markets.” —Edward G. Calamai, Pharmaceutical Manufacturing and Compliance Associates.

“One challenge is regulations. There are too many of them. Each country has different requirements. And at this stage, we are not able to have a unified regulatory submission process. These regulations take a lot of time to understand and address and require a lot of expenses. The second challenge is public perception. I don’t think the general public knows enough about what is involved in biotechnology products—how we are making them, how well we are making them. These are the two challenges the industry has to work on.” —Krish Venkat, AnVen Research

Hopes for the future

“We’re still lagging behind on the yield, especially when you compare biopharma products to the solid dosage form. The industry needs now, in the next 25 years, to look at optimization and ways for us to gain efficiencies and get yields up in the biotech process.” —Steve Walfish

“Many manufacturing and laboratory operations are still using labor-intensive, traditional (well-established) technologies. The major advantages are that these traditional technologies are readily available and can be easily transferred and globally approved. The disadvantages are that these labor-intensive processes are relatively expensive and thus make our industry less competitive. These traditional technologies are also more error-prone mostly because of the large dependence on operator performance.” —Stephan O. Krause

“Two things. First, the need for cost efficient production for affordable drugs for the broad public. Second, the same success we had with mammalian cell culture for the mass cultivation of stem cells.” —Hans-Peter Meyer

“We will still have a need for a highly educated, scientifically trained workforce. The molecules we’re working with are very complex and heterogeneous, and therefore highly technical people are required.” —Michiel E. Ultee