Ensuring Success In Early Biopharmaceutical Formulation Development

Biopharmaceuticals tend to be highly unstable. A pilot formulation study at the early drug substance development stage can make things considerably easier at the manufacturing stage, according to Yunsong (Frank) Li, director of process development at Catalent Biologics, in this interview.

Q: Why is it important to conduct biopharmaceutical formulation development?

Li: Biopharmaceuticals are very complicated and difficult to characterize and have different features from so-called small molecule or chemical drugs. They are generally very unstable and go through many different chemical and physical degradative pathways, which can affect manufacturing, shipping, and even the end users of these drugs.

Formulation development addresses the above challenges by conducting a series of biophysical and bioanalytical studies. Understanding those mechanisms of degradation and optimized buffer, pH, and excipients to prevent or slow down those degradation is important to be able to successfully develop biopharmaceutical drugs.

Q: Why is it important to conduct formulation development in early-stage drug substance process development?

Li: Working on formulation development in the early stage helps ensure we will have a comprehensive understanding of the molecular properties, the structure, and the degradation pathways. Optimum buffer, pH and excipient composition need to be designed and screened with stability of the biologic molecule in mind.

Doing early-stage drug formulation studies also helps avoid reformulation during later-stage drug product development. As we all know, drug product development takes a very long time—from the preclinical to the clinical stage and from the clinical early stage to late stage. If you can come up with a stable formulation during the very early stages of drug substance development, you don’t have to redo those formulations and studies to further optimize it in later-stage development.

Q: What challenges do you face when conducting formulation development during early-stage drug substance process development?

Li: One challenge is that you do not really know all of the critical quality attributes for the molecule and what analytical methods must be used to characterize those attributes. And, you don’t really know which stability-indicating methods can be used for those attributes.

Another challenge is that many people feel early formulation development is very time consuming, resource consuming and labor intensive. It’s also unclear how much stability data is needed for development of a formulation at that stage and what study conditions are needed to collect the stability data you need. Compounding this issue is the fact that there’s not enough material in the early stage to do a lot of work.

Q: How do you overcome these challenges?

Li: Because Catalent Biologics provides both drug substance and drug product services, we have the ability to initiate formulation development earlier in the biologic development process. Further, we developed a strategy for overcoming those challenges using our automated high-throughput screening platform to replace labor-intensive steps. And with high throughput, we can get a lot of data about the different conditions under which one can test the molecule such as thermal, mechanical, resource or light-sensitive stress.

High-throughput analytical methods are capable of characterizing the typical critical quality attributes, such as aggregation, fragmentation, charge variants, denaturation and molecular interactions. We only need very early-stage material, even before final clone is selected, for this approach, and the quantity needed for such work is typically about several hundred milligrams.

Q: Is there anything else companies should consider in the drug product development to enable IND filing?

Li: After the initial formulation development, you can get a pretty good formulation for your toxicology batch production and even clinical drug substance production. However, more work is needed before you can manufacture the drug product and have the necessary information available for your IND filing. These studies are related to drug product process development, which includes drug product compatibility with the drug product manufacturing process, with the final container closure and with the final drug administration diluents and devices.

If the drug is not stable enough, which is estimated to falling out of specification (maximum level of aggregation, charge variants and fragmentation) after two years, we may need to lyophilize the product to make it more stable. The lyophilization process removes the water from the drug product and leaves the drug molecule in a solid-state matrix. This matrix slows down the molecular mobility and degradation speed. The lyophilization cycle development is also a key activity to ensure this process is successful.

Q: What are other applications of the high throughput formulation development platform that can be useful to small biotechnology companies?

Li: I have spoken with several small biotechnology companies when they start developing their drugs. At that stage, many of them have several good drug candidates with good activity and binding to the target.

To select the best one, we need to do a developability study or manufacturability study. Those early assessments look at the stability, solubility, sensitivity to sheer and other sensitivities to typical manufacturing processes of all good candidate molecules.

The current tool we have at Catalent Biologics for high-throughput formulation development can also be used for early-stage assessment. Instead of screening many different formulations for one molecule, we can use selected formulations for screening multiple molecules.

By doing this exercise, we can select a good molecule that is most stable, and also can have high solubility and less sensitivity to the manufacturing process. This will greatly improve the success rate for molecules going through the development process and getting to clinical trial—eventually becoming a commercial product launch.