Preclinical Outsourcing: Test Formulations

Glop, paste, sand, mud, goo, clumps, or sludge. This is no misprint. Those who have worked in preclinical drug development recognize these terms as those that can be used to describe test formulations (i.e., the formulated version of a potential new drug). If you or your outsourcing partners are using these terms to describe your test formulation, you have a problem. Your test formulation is not suitable for initiating your preclinical toxicology study. You now have to assemble the appropriate staff, troubleshoot, implement the proposed solution, and accomplish it all before the study start date. This is hard enough to do within your own research facilities, but it is exceptionally challenging when you try to address a formulation issue with an outsourcing partner that may be hundreds or thousands of miles from your location. In fact, an informal survey of CRO colleagues showed that difficult test formulations ranked #2 among the challenges in working with sponsor companies. The #1 challenge was when the CRO did not receive the test article (i.e., the drug) from the sponsor in time to prepare the test formulation for the study.

In our recent article, “People Infrastructure” (Contract Pharma, July/August 2006), we discussed those behind-the-scenes jobs that are critical to the success of a preclinical research operation. As you will see below, the role of the formulations chemist should be added to this list. While the rest of the research operation is engaged in scheduling studies and aligning resources, it is the formulations chemists who often can make the difference between successful or unsuccessful drug development projects. These individuals assure that the drug is formulated in a way that allows researchers to achieve the goals of their testing.

Recently, I had the opportunity to learn more about the critical nature of this role from an industry veteran. Roger St. Clair retired from Eli Lilly in 2004 after a 36-year career where he spent much of that time leading the preclinical formulations group that supported internal and outsourced toxicology studies. Even in retirement, his expertise is still sought out by former colleagues who have benefited from his guidance in the past. Here is some of our conversation:

Steve Snyder: From a formulations perspective, what is the biggest challenge in supporting preclinical toxicology studies?

Roger St. Clair: Compound availability (i.e., receiving the actual drug substance in a timely manner) is one of the biggest challenges. The test formulation can’t be prepared if the compound isn’t available. Compounds that are early in the development phase need to be formulated so that samples can be taken for stability assays. Regarding the actual test formulation, the challenge is to prepare a suitable formulation at a concentration that will allow researchers to achieve their targeted exposure in toxicology studies. Among the factors that impact a preparation are solubility, pKa and particle size. Research organizations that engage their formulations chemists in the planning and study design stages will increase the likelihood of a successful outcome because these individuals will have more time to understand the chemistry of the compound.

SS: Can you explain why it so important for the formulations group to have plenty of time to prepare a test formulation prior to the start of a toxicology study?

RSC: Receiving the study protocol in a timely manner is critical to the success of a formulations group. The staff needs time to prepare paperwork, labels and glassware, and to establish schedules with the analytical groups that will process stability samples. Sufficient preparation time will mitigate the risk of procedural errors because the staff doesn’t have to rush to meet study timelines. Finally, if this is the first time they have worked with a compound, sufficient time allows members of the group to develop an optimal formulation.

SS: What formulation vehicles work best or worst and why?

RSC: An acceptable vehicle is one that allows researchers to achieve the proper exposure of the test article in toxicology studies without introducing toxicities that are related to that vehicle. Test articles that are not readily soluble can be formulated into suspensions. Excipients can be used in the formulation and those that are on the FDA’s GRAS (Generally Regarded As Safe) should be considered first.

SS: When you visit a formulations laboratory at a CRO, what areas do you review to assess the capabilities of the laboratory and its staff?

RSC: Among the areas that I review are:

    Regarding the CRO formulations staff, it is also important for a sponsor to assess their problem-solving capabilities.

SS: What observations at a CRO laboratory would cause you to not want to place work there?

RSC: From a formulations perspective, a lot depends on how well the sponsor’s needs are aligned with the CROs capabilities. For example, formulations that are intended for parenteral administration should be prepared under sterile conditions. There have been times when a CRO formulations laboratory was approved to do oral formulations but we elected not to conduct parenteral studies there because the CRO either lacked the expertise or the proper equipment to do sterile preparations. It is also important that these considerations are understood by the sponsor company’s outsourcing professionals that place studies at CROs. Just because a sponsor may have a successful relationship with a CRO, it does not mean that the formulations group is automatically capable of preparing all formulations.

Obviously, another reason for not placing work at a CRO would be if there were significant and/or multiple examples where the CRO formulations laboratory did not meet the criteria that I mentioned in my response to the previous question.

SS: What were some of your worst outsourcing experiences from a formulations perspective?

RSC: In one situation, septicemia was encountered during a toxicology study where the formulation was administered parenterally by continuous infusion. An investigation of the formulation preparation process revealed that the CRO did not follow the sterile procedures that had been specified by the sponsor.

Another time, a CRO formulations group wanted to avoid daily preparations of the test formulation to save time so they prepared a larger formulation batch from which they would remove aliquots for daily use. The problem was that the larger formulation batch size was not homogeneous and a lot of very expensive test article was wasted.

SS: What are some of the “hot” areas for regulatory scrutiny in a formulations laboratory?

RSC: Standard operating procedures; usage records; labels; inventory records; equipment maintenance; calibration records; and cleaning validation.

SS: What type of formulations errors did you always worry about during your career?

RSC: I worried the most about the preparation of an incorrect concentration of a test formulation that ultimately was administered on a toxicology study.

SS: What was one of your most difficult formulations and how did you achieve a successful outcome?

RSC: There was a compound in development that was amorphous and very insoluble. It was also very expensive to produce this form. We found that, through the use of excipients, working with the particle size, and other formulation techniques, a less expensive crystalline form of the drug could be used that also had better solubility. This change was the basis for the eventual human formulation.

SS: Why is it so important for the Discovery chemists to understand toxicology and clinical formulations?

RSC: Lets say that the Discovery chemists are working on two compounds that are targeted for the same indication, and Compound A is more potent than Compound B. However, Compound A is insoluble while Compound B is readily soluble and has better characteristics. If all other criteria are equal, sometimes the compound that is easier to formulate may be a better choice. Remember, toxicology studies require dose levels and concentrations that exceed the intended human dose, so the compound must be able to be formulated to satisfy these requirements as well.

SS: Why is it important for a preclinical research operation to have someone with formulations expertise?

RSC: Formulations chemists can help researchers achieve their goals. They have an awareness of the chemistry of the compounds and can develop the appropriate formulations procedures. As many researchers know, it seems like fewer and fewer compounds are readily soluble, so this is where the problem-solving abilities of the formulations chemist add value to preclinical research programs.


In this article, we learned the importance of suitable test article formulations and how an experienced formulations chemist can add value to a preclinical research operation. We learned about the criteria that sponsors use to evaluate CRO formulation laboratories and those areas that attract regula-tory scrutiny. Like others that work in this field, there is a high expectation that their work is perfect every time. Obviously, significant mistakes in a preclinical formulations laboratory can be devastating to a research operation whether it is in Pharma, Biopharma, or a CRO. Accordingly, formulations chemists are an essential piece of the puzzle of expertise that comprises an effective preclinical research operation.

Steve Snyder is a consultant with more than 25 years of experience in preclinical toxicology as an outsourcing customer and provider. He can be contacted at info@outsource-support.com