A smart solution for Biopharmaceutical Development – by Hayashibara

TREHALOSE SG JP, USP-NF, Ph. Eur., CP

High-purity and low endotoxin injectable grade trehalose

TREHALOSE SG is an injectable grade pharmaceutical excipient and is monographed as being low endotoxin and high purity. It is supplied as powdered dihydrate crystals produced by the enzymatic saccharification of starch. Hayashibara has achieved exceptionally high quality and stable supplyby production of trehalose and removal of endotoxin in our manufacturing plant in Japan. TREHALOSE SG is stable to heat and acid, and as a non-reducing disaccharide, does not participate in the Maillard reaction, so it stabilizes biopharmaceutical formulations.

Introduction

Biopharma consists of molecules from organisms that can be used as active pharmaceutical ingredients (APIs). Many modalities such as antibodies, peptides and nucleic acids have been developed, and their market is rapidly expanding every year. In general, biopharmaceuticals are considered to be more specific and safer than small molecule drugs. However, most biopharmaceuticals are administered as injectable drugs due to their lower stability and absorption compared to small molecules. Currently, there are many studies being conducted with the aim of improving the precision of quality control, extension of storage periods, and simplifying storage conditions. A typical biopharmaceutical formulation contains various excipients including osmotic regulators, buffers, and surfactants. Among them, saccharides are added to many products to regulate the osmolality and stabilize the API1,2. Some of the saccharides (especially sucrose and trehalose) are also used as API protectants during cryopreservation and lyophilization1,3. In this white paper, Hayashibara proposes the use of trehalose as a strategy to improve the storage stability of antibodies, nucleic acids and exosomes. In the case of antibodies, Hayashibara introduces data to not only improve stability during storage, but also provides benefits during manufacturing processes such as culture and purification.

Trehalose For Biopharmaceuticals

Trehalose is a non-reducing disaccharide consisting of two glucose molecules linked by an α,α‒1,1 bond (Figure 1), and its unique molecular structure gives it properties such as low-reactivity and acid resistance. Trehalose is known to stabilize proteins, especially with regards to antibodies, and both its anti-aggregation effect and function as a chemical chaperone have been widely reported4,5. Further, it is commonly used as a cryoprotectant, and many reports have shown that it protects biomolecules such as proteins and lipid bilayers from physical stress during lyophilization3,5,6.

TREHALOSE SG JP, USP-NF, Ph. Eur., CP

TREHALOSE SG is an injectable grade pharmaceutical excipient and is monographed as being low endotoxin (<0.3 EU/g) and high purity (≧99.0 %). It is supplied as powdered dihydrate crystals produced by the enzymatic saccharification of starch. As shown in Figure 2, unlike Maltose and Sucrose, TREHALOSE SG does not participate in the Maillard reaction and is stable to heating such as autoclave. Thus, TREHALOSE SG can contribute to quality stabilization of various biopharmaceutical formulations.

For Antibody Stabilization

During antibody production and storage, physical and chemical stress can cause denaturation and/or aggregation, but trehalose has been reported to protect antibodies from the stress4,7. TREHALOSE SG not only contributes to the stabilization of final formulations as an excipient, but also contributes to quality improvements in each upstream to downstream manufacturing process.

Inhibition of aggregation during upstream processing

Chinese hamster ovary (CHO) cell lines are widely used as a host cell for antibody production. While CHO cells have a high antibody producing ability, the high antibody concentrations tend to aggregate in the culture medium. In a study adding TREHALOSE SG to a medium of bispecific single-chained diabody (scDb-Fc)-producing CHO cells, antibody aggregation was suppressed (Figure 3).

Inhibition of aggregation during downstream processing

During downstream processing of antibodies, there are various physical or chemical stressors which can cause aggregation. Common aggregation stressors include acidic buffers and high salt concentrations. In a study, monoclonal antibody (mAb-TNF-β) was incubated with TREHALOSE SG, Sucrose, D-Mannitol or Sorbitol in glycine HCl buffer (0.1 mol/L, pH 2.7) or lithium chloride buffer (5 mol/L) at 25°C for 30 min. TREHALOSE SG showed the highest anti-aggregation effect of all the carbohydrates (Figure 4, 5).

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Hayashibara ― A world leading supplier of pharmaceutical grade Maltose PH

Founded as a starch syrup manufacturer in 1883, Hayashibara has grown into a company with strong research and development expertise, engaging in original and creative research. Utilizing our technological background in biotechnology and in-depth knowledge of saccharide production, Hayashibara became the first company in the world to succeed in the mass production of “Trehalose”, a unique disaccharide recognized as a beneficial excipient for the biopharmaceutical industry. In addition to trehalose, Hayashibara has been supplying for many years other high purity ingredients to the pharmaceutical industry worldwide.