It is a general trend to develop a formulation for preclinical and early clinical studies first and further refine the formulation for Phase III clinical trials while conducting earlier clinical studies.
Formulations for preclinical / early clinical studies
Preclinical/Phase I/II clinical trial formulation can be frozen liquid, refrigerated liquid or lyophilized formulation dependent on intrinsic stability of each product.
Frozen liquid formulation can be used to support early clinical studies. It is recommended that real time stability at actual storage temperature as some complex physicochemical changes can complicate the stability of drug product in frozen state.
Refrigerated liquid formulation would be preferred if product is stable.
Lyophilized formulation can be used for products that may not be stable in liquid state or for product development strategies demanding best product stability.
Formulations for Phase III/commercial application
It is preferred that a commercial formulation is identified before entering into Phase III clinical trials. Anticipated expiry should be 24 months. Various factors supporting product presentation will evaluated at this stage of development:
- Routes of delivery (intravenous, subcutaneous, intramuscular, local, etc)
- Delivery devices (infusion, syringe, pump, etc)
- Container closure system (vial, prefilled syringe, cartridge, etc)
- Dosing schedule (fixed, variable, continuous, etc)
Liquid formulation would be preferred, especially when presented in a refilled syringe. Sufficient stability information is required to achieve liquid formulations as most biopharmaceuticals have limited stability in liquid state. It is also important to understand that product stability in prefilled syringe may be different from the same formulation filled in vials.
Lyophilized formulation is useful when better product stability is required. In order to achieve good lyophilized formulations, the following additional formulation factors need to be considered above and beyond storage stability:
- Efficient lyophilization cycle
- Elegant appearance of the lyophilized cake
- Good stability during the freeze-drying process
- Easy, rapid and thorough reconstitution
Multi-dose formulation can be used when multiple dosing from a single vial is beneficial. In general, the addition of preservative(s), regardless of the type and amount utilized, significantly changes the stability profiles of proteins. In some extreme cases, visible precipitation and aggregation have been reported from the introduction of these materials. Therefore, the effect of various preservatives on the stability of protein should be carefully examined. Other experiments are also required to qualify a protein product for multi-dose formulation capabilities. The most notable tests include analyses for antimicrobial preservative effectiveness and stopper resealing. As proteins have limited stability in the presence of preservatives, dual chamber syringes or dual chamber cartridges containing bacteriostatic diluents are routinely used.