With a push to help clients get into the clinic faster and get their drugs on the market, contract formulators assist in all stages of the drug formulation process.
More than one-third of Drug Discovery & Development magazine readers surveyed said they outsource the complex tasks of drug formulation. Since the drug formulation process is time consuming, there is no doubt that calling in some outside help could be beneficial.
The common goal for all contract formulators—and the motto of SRI Biosciences, a division of SRI International—is "tak(ing) drugs from idea to IND (Investigational New Drug)," according to Helen Parish, senior director of Pharmaceutical Sciences at SRI International. With a push to help clients get into the clinic faster and get their drugs on the market, contract formulators assist in all stages of the drug formulation process.
"The process typically begins where the client has an active biological ingredient that they have seen biological activity on, and would like to see if they can develop animal data and then, eventually, human data," according to Tom Bradshaw, president of SP Formulations (Wareham, Mass.), a contract formulation company that is part of the Smithers Group.
In pre-formulation screening, the formulator characterizes the drug’s physical, chemical, and mechanical properties in order to choose which other ingredients (excipients), besides the active pharmaceutical ingredient (API) should be used. Pre-formulation screening includes: solubility studies, drug excipient interaction studies, degradation studies, and partition coefficient studies. Each of these studies is important to assessing the pharmacokinetics of the drug, and will eventually lead to a better idea of the direct form a drug should take.
In formulation development, the formulator will consider particle size, polymorphism, pH, and solubility, and how each of these factors affects the bioavailability of the drug. During this stage, scientists will perform solubility optimization, excipient selection, dissolution studies, toxicology studies, and stability studies.
What form to choose?
Clients turn to formulators for a wide variety of needs, including the actual form a drug will take based on the type of compound and its properties. According to Bradshaw, "most companies know ahead of time what drug product formulation they would like; they specify an oral dose, or IV, or solid dose." However, it is the formulator’s task to figure out what form of the drug will actually work. For example, if a client wants to have an oral product, the formulator could either suggest a tablet or capsule. Bradshaw says, "The specific formulation selection would depend upon the pre-formulation work we do. And, so, we would review the application and the pre-formulation ideas, and move towards selecting the best form at that point with our client."
Client’s preconceived ideas on drug form are usually based on a targeted market. Parish says, "If a drug is geared towards a hospital setting, then an IV or injection form would most likely be used. If the drug will be used in outpatient status, or will be self-administered, then usually the form will be that of a capsule/tablet." According to Paul Skultety, director, Pharmaceutical Services for Xcelience, LLC (Tampa, Florida), a privately-held contract formulation and manufacturing company, a large percentage of companies are focused on oral solid dosage forms. According to Drug Discovery & Development’s poll, about 70 percent of the companies focus on oral forms of drugs.
However, with the time constraints to bring drugs to market, especially oral formulations, some clients would opt for and easier method of formulation. Skultety expressed that "there are a number of approaches available to companies focused on Phase 1 small-molecule development. Some of these companies have the need to accelerate time-to-clinic, and opt for a strategy with minimal formulation development. They want something simple, with little API, so they can try to get their product into the clinic as fast as possible, while keeping their cost down as much as they can." That is where Xcelience uses the Xcelodose system (Xcelodose is a precision powder micro-dosing system produced by, and registered to, Capsugel, a division of Pfizer) to fill API directly into a capsule shell with no other excipients being added. Xcelience can start with very low range—sub milligram levels of API—and can go up to hundreds of milligrams. Skultety claims one advantage of using the Xcelodose system is "that one can minimize the amount of active substances needed and can vary the number of strengths delivered to people. It is very easy to go from a 1mg, to a 25mg, to a 50mg capsule. And, as long as you are doing it this way, there is minimal need for any type of formulation work."
Length of process
The length of the drug formulation process depends upon the nature of the characteristics of the drug. According to Bradshaw, "The process for the early formulation services usually takes from one to two months. The full formulation testing, including the stability studies, usually takes two to six months, which includes the early development work." For example, a powder form of a drug will take less time to formulate (and is as easy as a measured scoop), where capsule/tablets will take longer due to the many excipients at various concentration levels and their interactions with one another. When choosing the excipients that will form a drug, the formulator always needs to work with US Food and Drug Administration (FDA) and United States Pharmacopeia regulations. The APIs from the formulator are screened against "commercially relevant excipients that are generally accepted for use in drug products," according to Stephen Cypes, director of Life Science Research, Symyx (Sunnyvale, Calif.). And if the generally accepted excipients don’t work, formulators must go to more avant-garde novel excipients. Once the several hundred excipients are tested, the remaining development time is dependent of the API and its specific dosage challenges. Richard Boehner, president, Symyx High Productivity Research, says that "dosage and the desired form of the drug product will determine the amount of time it will take (contracted organizations) to optimize their formulations after the screening work is completed."
Bring in the machines
Not only do formulators need to have the knowledge for drug formulation, but they also need the correct equipment, which is a reason why drug formulation is frequently outsourced. Scientists use a wide variety of instrumentation to help them in the drug formulation process including, HPLC, DSC (differential scanning calorimetry), microscopy, particle sizing, dissolution, plus, blenders and mixers. However, formulators see HPLC as a pivotal method in drug formulation because it is a versatile analytical tool. "HPLC provides formulation scientists with information on the identity, strength, quality, and purity of materials in bulk drug, drug product, or biological matrixes … , and provides formulators with the information they need to design a dosage formulation so that the drug product has the desired in vivo and stability characteristics," according to Parish.
With the push to get drugs to market, contract formulation companies "can tackle a small piece of the process, or the entire drug formulation process for a client," according to Parish. There is no question about it, but formulators are always there to give a helping hand.
Published in Drug Discovery & Development magazine: Vol. 12, No. 3, March, 2009, pp.26-27.