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European Biopharmaceutical Review

Fast and Flexible

No two early development projects are alike. The active pharmaceutical ingredient (API) properties will differ, from the potency to the physical characteristics; the clinical plans will vary, from the locations, to the study centres, to the design of the study itself. Moreover, many of the activities required in early development occur just in time, with plans changing as new information comes to light.

In the midst of all this variability, a drug product is required to support early-phase research, such as single ascending dose (SAD) and multiple ascending dose studies. On top of this, timelines tend to be short as clients try to achieve clinical milestones quickly and investors seek to maximise the value of their potential products.

To meet these challenges, early development pharmaceutical manufacturers need to be flexible and fast, strengthening their capabilities and widening the offerings available.

Dosage Form Choice

In general, the aim of a Phase 1 formulation is to be fit for purpose. It does not need to be over-engineered or similar to a potential commercial presentation, but it does need to give the molecule the best chance of succeeding in the clinic. From an oral solid dosage form point of view, there are many different technologies available to deliver a new molecule to a Phase 1 trial. The key is to ensure the approach is quick, adaptable and appropriate to the API in question.

Powder in capsule (PIC), or drug in capsule, is often seen as one of the fastest routes into a Phase 1 study. This dosage form has the advantage of simplicity; there is no need for excipient compatibility studies, and drug product stability can potentially be extrapolated from API stability information.

Depending on the powder properties of the API, dose flexibility required in SAD studies can be achieved by filling the capsules with low doses (0.5-5mg depending on filling technology) to high doses (around 100-200mg depending on API density). For higher doses, an API-in-bottle approach can be considered in order to provide an option for oral dosing. Some systems used for PIC applications have the advantage of being able to fill neat API and blends into capsules, vials and bottles where required, enabling additional dosing flexibility.

However, PIC is a useful technology for only a subset of APIs; the dose range is relatively limited. Of more importance is the solubility and wettability of the API. It is important to understand these characteristics in order to determine if the PIC approach will offer the API the best chance in Phase 1 studies. For molecules which do not meet these criteria – for example, BCS Class 2 and Class 4 – a fit-for-purpose formulation is often required. Typically, this would be a blend in a capsule or bottle, depending on the dose. These approaches can be applied to a wide range of APIs for oral use.

Highly Potent Molecules

Today’s early development pharma manufacturers need the capabilities and systems in place to handle highly potent molecules – a growing area in the pharma sector and particularly relevant in early phase where toxicity information is limited. In particular, the use of flexible containment technology, designed to cover all manufacturing processes, ensures protection of the API from the environment, and of the operators from the API. In order to help accelerate the development timelines, extensive use of disposable technologies can be used, from capsule fillers to blending drums. Using disposable technologies removes the time and cost required to develop cleaning validation methods. In addition, there is no risk of cross-contamination from a quality point of view. This approach extends to containment technology for the various processes, again reducing risk and cost for clients.

These containment systems can also be designed to provide protective environments for hygroscopic actives or those sensitive to oxidation. In these cases, the critical compounding steps can take place in a low humidity or inert atmosphere and this, combined with a suitable packaging approach, can ensure a suitable shelf-life for clinical studies.

Tablets are less commonly used in early-phase clinical studies, but there are cases where they are appropriate. For example, oncology studies may rapidly progress through clinical development, and so it may be more appropriate to start with a formulation that is similar to the proposed market formulation.

Early-Phase Development

Regardless of the dosage form type, to ensure the drug product is fit for purpose, the properties of the API and the target product profile must be understood. Although the philosophies of Quality by Design (QbD) are intended for late-phase development and registration, the principles can be implemented in the early phases.

In particular, a risk assessment-based approach to dosage form development can be implemented, which takes into account prior knowledge of the API. Typically, this may be limited in early development, but an understanding of the physicochemical properties, together with any preclinical data, is important. This knowledge of the API and the desired formulation time enables development efforts to be targeted where required, minimising time and cost.

A good example is around API stability and compatibility. A conservative development approach would be to perform an excipient compatibility study in order to select the excipients to take forward into formulation development. However, it may be appropriate – depending on API characteristics – to remove this step and perform more appropriate screening during formulation development, with data on prototype formulations rather than binary mixes.

The use of a risk assessment-based approach gives a new molecule a better chance of success in the clinic. It does not mean increased experimentation or overengineering, but ensures the formulation is truly fit for purpose. Another benefit of a well-designed Phase 1 formulation is that it may be more amenable for use in later-phase studies. Whether a formulation switch occurs during the development pathway will be primarily driven by clinical and marketing considerations. Choosing the right fit-for-purpose formulation ensures the drug product is not on the critical path.

Phase 2 and Beyond

Potential scale-up to later-phase studies at other sites is also something that early development pharma manufacturers are considering when they acquire new technology. This includes the use of equipment, such as automated encapsulation, that uses the same operating principles. Scale-up from early development can therefore be managed simply all the way to commercialisation with an appropriate formulation. Scale-up for tablets tends to be more complex. To mitigate this, instrumentation/data gathering and modelling are used. It is important to understand how a formulation produced at small scale will cope with an increase in speed (decrease in dwell time) when produced at a larger scale. One approach produced at a larger scale. One approach is to design a formulation at small scale capable of compression at larger scales. This involves understanding the API and the use of modelling to demonstrate the robustness of a formulation, prior to progression. Taking a science-led approach to formulation design can help avoid costly re-formulation exercises later in development.

Quality By Design

By understanding the relationships between different scales, movement ‘the other way’ is possible. Work on late-stage projects, which typically run at larger scales, can be carried out at a small scale as long as the interaction between the experimental work and the difference in scale is understood or can be modelled. When this can be done, data can be collected on a product or process to support a QbD-style submission. For example, exploration of a formulation design space can be carried out using a small-scale process. In this way, many batches can be made and tested, allowing a significant amount of data to be gathered for relatively low API cost. By using a scientific approach to scale-up, these data can then be extrapolated back to the late-stage scale with a few confirmatory batches to demonstrate the approach, rather than having to perform the full experimental design at a large scale.

Considered Approach

Early development of oral dosage forms often involves short timelines and rapidly changing goals. In order to overcome these challenges, it is important to work in a rapid and flexible manner, but not at the expense of good science. A considered approach will ensure an efficient development pathway, resulting in a fit-for-purpose formulation that has the greatest chance of development success.

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Jon Sutch, PhD, is Manager of Formulation and Clinical Trials Manufacture at Patheon’s Milton Park facility. During his time with the company, Jon has led the development of many formulations for the clinic. He has a degree in Pharmacy from the University of London and a PhD in Pharmaceutics from the University of Nottingham. Prior to joining Patheon, Jon worked at AstraZeneca for seven years on both early- and late-stage development projects, leading the formulation component of a large QbD-based product which is now an approved medicine.
Jon Sutch
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