Clinical trials can be extremely complex, which is why the adoption of a smooth development process is crucial in taking a drug successfully from the cleanroom to final medicine status, writes Dr Alan Baillie, technical director for Evotec (Scotland) Ltd.

The successful completion of phase 1 testing of a drug candidate is a vitally important step for all drug development companies. Within its drug formulations division, Evotec provides ‘enabling technology’ from cGMP API to cGMP drug product, to support the transition from the laboratory to the clinic for parenteral dosage forms of cytotoxic and non-cytotoxic agents. Due to the complexity of clinical trials, a fit-for-purpose approach to the formulation and manufacture of the test-dosage form should be adopted.

There are several key questions to be addressed with respect to a candidate molecule, for example:

  • What is the aqueous solubility of the molecule? (+/- solubilisation)
  • What is the predicted dose of the molecule? (+ solubilisation, dose of solubiliser)
  • What is the solution stability of the molecule? (sterilisation, liquid fill and lyophilisation)

Solubility and dose

In practice, solubility is relative and is essentially related to the predicted (often unknown) potency of the API. Parenteral formulation of a poorly water-soluble substance is often difficult, but is considerably more problematic if the predicted dose is 1000mg as opposed to 5mg. Most candidate molecules tend to be weak acids or bases, and by far the most successful strategy is to make an appropriate salt, based on the pKa of any ionisable moieties. In the more difficult cases where the candidate molecule is devoid of any ionisable functionality, Evotec is able to use its expertise in order to solubilise the candidate. For instance, co-solvents, surfactants, cyclodextrins and lipid-based systems such as emulsions, liposomes and liposome-like systems, may be used to prepare water-soluble/miscible formulations.

For some of the systems, drug loading can become a significant issue. Indeed, adverse toxicity can result when, for example, a low fixed drug dose is used in conjunction with a large dose of excipient. Investigations related to drug loading are therefore an integral part of the formulation development process.

Stability

During this stage of the formulation development, the aim is not to identify the final product, but to find a formulation with an adequate shelf-life to allow it to be manufactured, distributed and used in the clinic. The spectrum of solution stability can be, at one extreme, a stable formulation that may be terminally sterilised by autoclaving or, at the other extreme, an absolute requirement for lyophilisation. It should also be noted that lyophilisation is generally the method of choice. The alternative of freezing the formulation solution and then thawing just before use is rarely used because of the unknown stability of the API to the necessary freeze-thaw cycle and the requirement for a cold chain.

For lyophilisation to be successful, a knowledge of the key physicochemical properties of the formulation solution is required. The properties are typically acquired using differential scanning calorimetry (DSC) and freeze-drying microscopy. Depending on the nature of the active agent concerned, the solution pH, the buffer species used to control the selected pH and the cryo/lyo-protectant excipients used, are all crucial parameters.

Lyo-protectants, such as glass-forming sugars (for example, sucrose or trehalose), often play a central role in the lyophilisation of sensitive protein-based APIs by maintaining a tertiary structure in the resultant dry product. After freezing the formulation solution, the bulk of the (freezable) water is removed during primary drying at a product temperature, achieved by adjusting the chamber pressure and keeping it below the product collapse temperature. Secondary drying follows, which involves a desorption process that reduces the final moisture content of the formulation. Some APIs may require residual moisture content to be present in the final formulation at levels of, for example, <0.5%. An extreme example of this would be a pro-drug designed to be activated by in vivo hydrolysis. The residual water can also act as a plasticiser, and a temperature dependent phase change linked to API instability will occur at lower temperatures with increasing residual water content. A lyophilised product is not infinitely stable and the maximum storage temperature should be identified.

Transfer of the successful formulation to the Evotec MHRA-licensed cleanroom suites for cGMP manufacture completes another significant step on the journey from drug candidate to final medicine.

Company profile

Evotec is a leader in the discovery and development of the next generation of drugs through contract research partnerships and internal drug discovery programmes. In contract research, Evotec provides the world’s leading pharmaceutical and biotechnology companies with successful and innovative solutions. This success is achieved by using an unmatched range of state-of-the-art and integrated capabilities from the early stage assay development through medicinal chemistry to sterile drug manufacture. In its internal discovery programmes, Evotec specialises in finding new treatments for diseases of the central nervous system.