Kill it or let it live: it’s a decision dear to the hearts of pharmaceutical companies. The earlier a compound can be killed, or proved ineffective, the better. Not an easy task with the avalanche of New Chemical Entities (NCEs) in the wake of a mapped genome and automated testing technologies. Enter formulation development, always an important step in the drug development process, now even more crucial to a compound’s lifecycle.

As pharmaceutical companies continue to focus on R&D and commercialization, drug development is being farmed out to contract providers. This is nothing new; it’s been happening for years, but contract providers aren’t just dealing with Big Pharma anymore. Emerging biotech companies lack drug development capabilities, giving more business to a burgeoning pharma and biopharma outsourcing industry.

Having worked with pharma companies for years, the drug development contract service providers were more than ready to take on new business. By the late 1990s, these companies had become experts at small molecule formulation development. Companies that performed preformulation and regular formulation development services could tell their clients when to “kill” a compound and when to let it survive, offering key money- and time-saving decisions.

New automated technologies, as well as the biotechnology industry, have created a mountain of new drug targets waiting to be sifted through. Now, however, in addition to small molecule drug targets, formulation development is a puzzle that applies to large molecule protein and peptide drug targets. This presents a whole new set of complications never seen before.

The biggest problem facing formulation development providers is solubility. Ask anyone in the industry, and this is the first response. Each person contacted for this article mentioned it, cutting me off before I could finish my question about hot topics in formulation development. Large molecule targets are water insoluble and formulators are working hard to tackle that problem.

Ian Smart, director of operations at Niro Pharma Technologies, commented, “Solubility is obviously the hottest, the biggest trend.” He added, “Biotechnology companies are usually very difficult because they tend to look at different types of molecules. They are looking at large molecules that tend to have solubility problems. If you’ve got solubility problems then it’s difficult to get that product released. That’s an area we’re trying to specialize in because we’ve got different techniques for helping the solubility of the product.”

Elsie Melsopp, Ph.D., senior scientist, formulations division at AAI International, commented, “These new large molecules are predominantly water insoluble, which is a challenge. It is difficult to do conventional preformulation studies on these molecules and develop the right formulation for the clinic. A lot of our clients come to us with these types of molecules.”

Not only are companies trying to piece together ways of formulating these new drug targets, but they, as always, have to keep the regulatory issues in mind as well. The regulations for large molecules have not been able to keep up with the speed of discovery. Vijay Aggarwal, Ph.D., president, AAI International, illustrated that point. “Many regulations were written with the small molecules in mind. Some of the things you need to do with a small molecule become much more difficult with these larger molecules that, rather than being synthesized, are biological products. They are purified from some fermentation source or other biologic source. The levels and types of impurities are different, the types of characterizations are different, the analytical techniques are different and, sometimes, not directly amenable to regulations written with small molecules in mind.”

Recently, the FDA placed the review of drugs that come from living organisms into the same unit that handles chemical-derived therapies. The biologics unit has lagged behind the agency’s drug unit over the years. While the agency’s drug unit has halved it’s approval time over the last couple decades, the biologics segment languished. Industry insiders are hoping this move will speed up the approval process while making the two types of review processes more consistent. Not an easy task. Making sure batches are consistent is a lot easier for small molecule drugs than it is for biologics. The biologics unit will continue to be responsible for the regulation of vaccines and blood products.

The same rules that apply to pharmaceutical and biotech companies also apply to contract service providers. In addition, however, a company such as AAI not only has to follow FDA requirements, but those of its clients as well. Service providers have to stay on top of regulatory changes, sometimes informing their clients that what may have passed as compliance a few years ago, may not work today. Regulations will eventually catch up to new technology and new molecules.

The FDA is constantly trying to keep up with innovation. New process analytical techniques are coming from the agency to establish online process analytical testing. Dr. Melsopp commented, “Some companies are doing typical in-process blend and bulk product testing, as well as on-line. In order to stay competitive, contractors and companies have to start thinking about process analytical technologies and to put them in place during manufacturing.”

Another hot area of formulation development is early stage preformulation and the benefits of it. This goes back to the idea of trying to kill compounds early. Although it may take more time in the long run, doing some initial work can help the critical decision as to whether a compound goes on to the next step or not. Dr. Aggarwal said, “We’ve seen examples where companies haven’t done enough exploration at the initial stages of different formulation options and therefore end up with something that dies later in the process.”

Although the amount of preformulation done for compounds varies from project to project, factors such as time (the most valuable thing to drug companies) and money (the second most valuable thing) dictate how much initial work is done. In the best of all possible worlds, a company with ample time and money should spend both on preformulation, according to Dr. Ingallinera.

He said, “Preformulation is where you evaluate the physical chemical attributes of the compound before you decide what the formulation should be. You look at it’s oxygen sensitivity, where it’s pH is the most stable, solvents and co-solvent systems or surfactants, and ways to enhance the compound’s solubility or stability. You look at whether or not the compound is extremely water unstable and if you have to go to a dry process such as lyophilization or powder filling in order to make the product. You look at various methods of sterilization, and evaluate whether or not the product can withstand the heat or the radiation or other attributes of sterilization during preformulation. Considering these variables at a very early stage allows you to develop a better formulation.”

Preformulation services are not the only things sponsors are looking for from contract providers. Offering a range of services, from preformulation to end product, cuts down on the number of organizations that have access to a client’s intellectual property. Getting as much service as you can from one provider can also cut down on confusion. Dr. Ingallinera commented, “Our clients who are looking for formulation development are also looking for the ability to manufacture and test. They like ‘one-stop-shopping’.”

Suketu Desai, Ph.D., director, AAI’s formulations division, added, “It’s a very competitive environment. If a client goes to a CRO that can provide one-stop processing, then the confidential information around the compound will only be shared by one entity instead of a bunch of companies. If someone can provide one-step processing, there is an advantage to that.”

According to Mike Nason, associate director of marketing, applying novel drug delivery technologies usually occurs late in the life of the product in its enhancement stages. The decision to incorporate novel delivery systems may have come from the trend in the industry to make a product dramatically different than what’s out there.

Dr. Aggarwal commented, “I think the era of being the 23rd drug on the market in a particular category is over. Companies need to have something markedly different and better in order to even consider spending the time and money to develop it.” He added, “The newer technologies that you see, from transdermal patches to extended release preparations, these formulations have dramatically increased patient convenience and extended the length of actions.”

Generic companies are also following that trend. They no longer need the formulation of the name brand drug, they want something better. Mr. Smart commented, “The generic companies are certainly looking to be more clever, rather than just bringing out the cheapest copy. If you’ve got a two times a day tablet, the generic companies are trying to make it a once a day tablet. By the time the generic comes on the market, the name brand pharma has already started developing the one a day. It’s a constant battle that is interesting to watch.”

Newly discovered large molecules, as stated earlier, have their own set of formulation problems. Mr. Nason said, “There’s not a lot of development experience and expertise coming out with the new compounds and molecules. In other words, emerging companies are looking to the more established companies who have experience and expertise with the development process.”

The formulation puzzle for these new biological therapies is not the reason we have yet to see an influx of new large molecule drugs. The regulatory hold-ups have been a rate limiting step, but so has the sheer amount of new compounds to wade through. Dr. Aggarwal thinks expertise is the answer. “Historically, the limitation on the pipeline was not having enough good drug targets or drug compounds to take to clinic. Now, with the genomic technologies, the challenge is no longer the lack of enough targets; there are more than enough. It’s having the expertise to take it to market. Development now becomes the rate limiting step of getting drugs into the marketplace.”

When looking for a provider of formulation development, Dr. Desai believes that pharma companies should be looking beyond formulation development in a service provider. “If a provider can get a product from a vial to clinical supplies and then to the agency for drug approval, almost all of your needs can be addressed in one place,” he remarked.

More importantly, if a provider has the expertise in the early phases of drug development, key decisions will made easier for the client. Dr. Aggarwal stated, “I think this area is the ‘art’ part of drug development. The experience, creativity and access to technology at formulation development probably has more impact on the way a product succeeds than at later stages in development.”

He added, “The right decision, made by the right person at the formulations development stage, can really have a dramatic impact on the movement of that product through the rest of the development process. They can either accelerate it or slow it way down. Having organizations with that level of expertise, that creativity and access to technology is one of the key deciding factors when choosing a service provider.”

The more experience and expertise a company has, the better equipped it will be to handle the intricacies of the formulation development puzzle. This crucial part of the drug development process has been successfully outsourced for years, and providers have handled the challenges of large molecules as the projects have poured in. Whether it be the solubility of new proteins and peptides or making a “kill” decision as early as possible, the future for these service providers looks promising. The bottleneck of NCEs at the beginning of the drug development process should keep projects coming in the years ahead.

In closing, Dr. Aggarwal had this view of the formulation development industry, “We think that the future for drug development companies is very bright because of the need for new applications of existing compounds as well as further development of new compounds. There’s a huge opportunity for well-positioned companies that have a lot of expertise in drug development.”