Careful experiment design is essential to reach a target product profile in an efficient manner.

by Susan Thompson, Technical Director at VxP Pharma

The development of pharmaceutical formulations entails a wide range of technical complexities. Whether a given dosage takes the form of a capsule, a solution, an intravenous (IV), intramuscular (IM) or subcutaneous (SC) dose, or an ointment or gel, its formulation must be developed with attention to a number of critical interrelated factors.

Aside from the intricate delivery systems used for a growing number of transdermal, intranasal, and pulmonary drugs, even a seemingly simple oral tablet requires careful investigation and identification of risk factors, selection and testing of correct excipients, and experimentation to determine the formulation that delivers the ideal bioavailable dose.

Here is an overview of common concerns in pharmaceutical formulation development, along with a basic walkthrough of the experimental approach that should be taken in order to arrive at an optimized formulation.

Every pharmaceutical formulation begins with a target product profile.

Developers and CMOs must conduct experiments to make sure their formulation fits the TPP.

Developers and CMOs must conduct experiments to make sure their formulation fits the TPP.

The core of any drug formulation is its active pharmaceutical ingredient (API), which must be delivered in precisely the amount that can readily be absorbed by the patient’s body. Along with this key property of bioavailability, the API must also be easy for the human body to receive and break down. This is the job of excipients, the inactive ingredients in the formulation, which enable the drug to conform and perform according to specific standards.

Excipients may include such inactive ingredients as disintegrants, colorants binders, lubricants, diluents, glidants, and other ingredients listed in the National Formulary (NF). While the properties of each excipient are well understood, their interactions with the API, and wit other excipients in the formulation, can vary in surprising ways. For this reason, it is crucial for the formulation’s developers to test various combinations of excipients in conjunction with the API, in order to determine the ideal excipient from each of the necessary categories.

Such an ideal combination of API and excipients are often described in the drug’s target product profile (TPP). In addition, the TPP typically includes parameters such as the intended route of administration, the form and size of the dosage, the minimum and maximum doses, and the desired appearance of the product, as well as any special requirements involved in delivery. Other aspects of the TPP may include attributes of competing drugs currently on the market, or variations for patient populations with specific needs, such as elders or young children.

The earlier in the development process a TPP is determined, the more effectively the developers can use that profile to guide their excipient selections and testing strategies. For this reason, many pharma developers determine the TPP of a drug before the development stage even begins. Chemists, executive leaders and marketers may all play roles in the shaping of a TPP.

A clear TPP establishes guidelines for the drug’s development strategy, by placing hard limits on its physical, chemical and pharmacokinetic properties. At the same time, a TPP often comes with a certain degree of flexibility, to allow adaptation around changing market factors, logistical issues, new research findings, and other issues that may require modifications in the development process.

Because of this need for a balance between precision and flexibility, contract manufacturing organizations (CMOs) need to communicate closely with their pharma development partners, to ensure that the most up-to-date TPP guidelines are being followed.

Developers and CMOs must conduct experiments to make sure their formulation fits the TPP.

The impact of each component in a formulation is first evaluated in a formulation preliminary study.

The impact of each component in a formulation is first evaluated in a formulation preliminary study.

While a TPP serves as a useful set of guidelines, the only way to conclusively determine whether a given formulation fits those guidelines is to conduct laboratory experiments. In an ideal scenario, pharma developers and contract manufacturers should collaborate on these experiments throughout the formulation development process. This collaboration will help ensure that every aspect of the drug’s manufacture, from supply chains to storage to the actual manufacturing pipeline, are optimized for maximum efficiency and dependability.

The experimentation process includes tests of excipient compatibility, process and scale-up feasibility, manufacturing process characterization, and formulation and process optimization. In the early stages, various combinations of excipients are tested for various properties by themselves, and in combination with one another, and with the API. These tests may also be conducted on a range of dose levels and dosage forms, to ensure that no combination of excipients exerts unexpected effects on the drug’s physical properties or pharmacokinetics.

The impact of each component in a formulation is first evaluated in a formulation preliminary study, which aids in selection of the excipients; then in a formulation optimization study, in which the ideal level of each excipient is precisely determined. A systematic approach to evaluating formulation factors is essential throughout both these stages of study. Without carefully planned experiment design, significant time, money and supplies may be wasted on experiments that could have been streamlined to ensure optimal process flow.

Due to the changeable nature of a TPP, the experimental phase should ideally take the form of a feedback loop, in which market factors, experimental data, and findings from other labs all feed into the development of relevant new ideas. When resources are allocated in response to results from all these sources, research teams can establish fixed conditions, and proceed toward a viable pharmaceutical product in the most efficient manner possible.

In addition to being an author and speaker, Susan Thompson serves as the Technical Director of Indianapolis based VxP Pharma.