Method for the evaluation of the colloidal stability of liquid biopolymer solutions

xyli83
Feb 5, 2018
4 min read

Medicilon has extensive experience of performing stability studies on active pharmaceutical ingredients, early prototype formulations and finished dosage forms. Stability testing is performed according to FDA-ICH guidelines, client approved protocols and standard operating procedures. Email:marketing@medicilon.com.cn web:www.medicilon.com

The invention concerns the field of biomolecule formulation screening and stability testing. It concerns a method for the evaluation of the colloidal stability of liquid biopolymer solutions. The present invention describes a method for determining the stability of a liquid pharmaceutical composition comprising: a) providing a liquid pharmaceutical composition in a container, b) shaking said container on a shaker, whereby the shaker performs an oloid movement, c) determining the stability of said liquid pharmaceutical composition.

Technical Field

Background

The overall stability of biopharmaceutical formulations depends on various stability parameters like colloidal stability at the water/air interface, ice/water interface or its chemical stability, just to name a few.

In the early development phase time-to-clinic is crucial to be able to show proof of clinical concept of the development candidate. Any upfront loading of development activities should be avoided.

An important aspect for the development of a liquid formulation/liquid biopolymer solution, especially a protein formulation, is its sensitivity against mechanical stress and its chemical or colloidal stability. To determine these key criteria of a liquid formulation/liquid biopolymer solution, especially of a protein formulation, different mechanical stress studies can be conducted like a shear force study, a freeze/thaw study or a shaking study. Especially in early development phases it is of importance to perform such studies in a short time period. The overall development goal is to realize a short time lines until start of the first clinical trials. New and improved testing and screening methods are needed to help in realizing the tight time schedules of early stage development phases. There is, therefore, a need to accelerate the development of suitable biopharmaceutical formulations, especially for liquid formulations/liquid biopolymer solutions, such as protein formulations.

One important aspect for the development of a liquid protein containing formulation is the prevention of protein aggregation induced by e.g. shear stress, shaking stress, thermal stress or the like. For the evaluation of the behavior of a protein against stress it's very common to prove its sensitivity by carrying out stress studies like a storage stability study at elevated temperature, e.g. 40° C. or shaking studies. One other important aspect especially in early development phases is to realize a short time to clinic for clinical phases 1 or 2. Therefore it's necessary to have meaningful and fast development tools for the formulation development.

Furthermore it is an advantage to prove stress parameters, which are realistic or which can occur during the life cycle from manufacturing of the drug product until administration to the patient. Therefore, it is necessary to carry out a storage stability study of a protein formulation at different temperatures. Stress on the drug product can also happen during shipment particularly due to shaking of the product. In addition, the stress conditions during shipment are very important to understand because the way of the drug product after manufacturing to the patient can take several days up the weeks. This means also that the drug product can be exposed to stress over the duration of the shipment. Altogether, a shaking stress study is a mandatory tool for a successful formulation development.

Firstly, during shaking protein aggregation can occur due to protein denaturation at hydrophobic surfaces or layers like glass, plastic, ice or air. Because of the relative movement of the liquid in relation to the container the liquid surface, especially at the interface air/liquid, is rebuilt continuously. Consequently the denaturation rate is accelerated at this interface.

Secondly, based on shaking, shear forces into the liquid can built up, which result in protein denaturation or aggregation. Nevertheless Bee et al.examined the influence of shear forces on the denaturation of proteins and assumed that the forces on the protein are small compared to the forces acting at the air/liquid interface, because of the shear gradient, and therefore this factor can be assumed to be negligible.

For assessing the protein sensitivity against denaturation at hydrophobic layers different techniques are mentioned in the literature. Mahler et al. (European Journal of Pharmaceutics and Biopharmaceutics 59 (2005) 407-417) described the aggregation of IgG1 after stirring or after shaking. The protein solutions were exposed to shaking stress using a horizontal movement of a shaking plate with 150 amplitudes per minutes. In comparison to this the liquids were stirred using small reaction vials and Teflon coated stirring bars. The magnetic stirrer was adjusted to 600 rounds per minutes. Both methods showed a protein aggregation after 48 h depending on the used protein formulation.

Kiese et al. described the effects of shaking stress and stirring on antibodies using a horizontal shaker and a magnetic stirrer. The duration of the stress given to the system was up to 7 days. As a result is was found that both stress methods induced protein aggregation and particle formation depending on the protein formulation.