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European Biopharmaceutical Review

Best Laid Plans

Minimising stability evaluation prior to the conduct of First in Man (FiM) studies poses many problems. However, through careful consideration and planning, it is possible to effectively manage the time spent and reduce the financial investment at this critical stage of development.

In order to develop a new API into a dosage form suitable for human administration, in its appropriate pack with a proven shelf-life, an enormous amount of work has to be completed.The aim, therefore, must be to produce a FiM product as cost-effectively as possible. Indeed,drug development statistics show that most novel pharmaceuticals fail at this stage, therefore managing the investment up to this point is important. Stability data should be sufficient for the period and conditions that the FiM will experience.The objective is to obtain clinical data, which often triggers the release of more funds for further clinical development.Any dosage form is a combination of the three arms of pharmaceutical development – the API, the formulation recipe and the manufacturing process; these three are inseparable.The process is often overlooked as most clients will ask about formulation skills, but rarely ask about processing skills.A cookery book provides a useful analogy – we can all copy the recipe, but how many of our efforts resemble the end result featured in the glossy photograph.This is a good example of the importance of the process.However, processes take time to perfect; for FiM products the means of reducing cost is to have as simple a process in place as possible. Likewise, the formulation recipe should be equally simple – perhaps just the API on its own.

FiM Formulation Strategies for Oral Products
Drug-in-capsule or drug-in-bottle products are being used more widely following the pressure on resources and the introduction of equipment to speed up production, such as Xcelodose® and QuantosTM.This is an obvious direction to take, but illustrates the risks of most FiM strategies.The API will not have had any assistance from the formulation specialist, which is an obvious risk. It also raises the spectre of ‘clinical temptation’ – that is to say, to become so excited with the clinical data that formulation and process development remains dormant while further clinical studies are carried out with increasingly large numbers of drug-in-capsule products.

At some stage, however, more time will need to be allocated to develop a commercially viable dosage form with the clinical cross-over trial in order to tie the two formulations together in any data review.

Minimising Stability Evaluation
At the FiM stage, stability data has the single objective of supporting the shelf-life assigned to the product by the qualified person (QP). Opinions differ as to whether the API stability data will be sufficient, but it seems likely that it will depend on the circumstances of the study and the nature of the API.

However, a common approach for the assigning of shelf-life to a formulation is the conduct of an accelerated stability study on feasibility batches, whereby the FiM clinical formulation is stored for up to six months at high temperature and humidity conditions (for example 40°C and 75 per cent relative humidity) to attempt to ‘force’ the formulation out.An appearance and analytical timepoint at one month, which shows that the product has not degraded or changed in any way, allows a two-fold shelf-life.This is often an indicative timepoint and can be useful for FiM product manufacture in order to schedule subsequent GMP manufacture and release for a FiM study, which is likely to be completed within a twomonth period if conducting a classical Phase 1 study.

The requirement for dissolution data is also questionable – the data may be ‘useful’, but to have it as part of the release specification may tie the project in knots, which is rather ironic given that the outcome of the clinical study will provide in vivo ‘dissolution data’.Therefore, data for release does not necessarily have to be all the data you can possibly measure.



Sterile Dosage Forms
The requirements for sterility demand that an injectable product is sterilised by moist heat, unless there are reasons that preclude the method – for example if it is thermally unstable.The growth in the number of large molecule dosage forms and the increasing vulnerability of new small molecules has seen the rise of aseptic processing, sometimes coupled with lyophilisation (freeze drying).Often these molecules will be unstable in water or aqueous-based buffer (that is the solvent by which they will be administered to the volunteer or patient).The cost and time taken to create a useful lyophilisation process is substantial, as is the formulation project to produce a stable product with a useful shelf-life.

If freeze drying is the likely route for a commercial product, it is worth considering the option of ‘freeze-only’ for the FiM product. The dissolved API is frozen and shipped to the clinic immediately. Stability data will be generated to support the ‘frozen-time’ and the ‘life after thawing’. It is perfectly possible for pharmaceutical development service companies to produce and ship the products with tight timelines in order to reduce the ‘frozentime’. These products can be made and shipped within 24 hours, but sterility testing takes a finite period and can affect this approach.However, an exemplary aseptic record of the manufacturing unit would support a ‘ship-immediately’ strategy with the agreement of the QP.

Other Dosage Forms
Most dosage forms can follow a similar direction: reduce the formulation (and therefore the associated processing), and generate stability data that is appropriate for the clinical study. Oral liquids can be fashioned from commercial drinks (although juices should be avoided because they are vulnerable to the variation of natural products).Their viscosity can be increased by the addition of, for example, hydroxypropyl methylcellulose (HPMC) to hold the dose on the spoon.

Inhaled products can be assessed as nebulising solutions and if necessary the frozen methods described for large molecule injectables can be used.

Topical products are perhaps the dosage forms where this strategy can become unstuck. It is tempting to bring together an API with a commercially available carrier cream; however at their simplest, topicals are designed to deliver on, in or through the skin, and this semicommercial product may be completely unsuitable. If the carrier cream is preserved, it can be calamitous to use it for a study of an antibacterial API because the study may result in assessing the preservative and not the precious new API.

Scheduling is Key
At the start of any novel pharmaceutical development project, deciding when to manufacture the clinical batch that will be administered in the FiM study is key and affects both timings and costs.When seeking to effectively reach FiM clinical trials, detailed planning and management of the project is vital to its success.The process is often more complex and time-consuming than expected, but partnering with an experienced and qualified formulation development company can provide reassurance and enhance efficiency throughout all stages of the process.




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Paul Titley is Managing Director of Aesica, R5, Formulation Development, and a chemist by training, with over 30 years of experience in the development and manufacture of pharmaceuticals. Paul joined Wellcome to work extensively in industrial pharmacy in the pharmaceutical development laboratory. During this time Paul helped set up pharmaceutical manufacturing at Wellcome plants in Africa and South America. He left Wellcome in 1996 to join Quintiles as Senior Director of Business Development in Scotland, and then in 2002 worked as General Manager of Encap Drug Delivery. Email: info@aesica-pharma.com
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