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Microbial CDMO

Stability Studies

Biological drug substances are complex large molecules, particularly sensitive to environmental factors: temperature, oxidation, light, ionic content, and shear. It is critical to conduct stability studies on the drug substance and drug product under intended storage conditions, accelerated conditions, and forced degradation conditions. The stability data is usually used to support the shelf-life, expiration date and storage conditions.

Following the ICH Q5C guidance, Yaohai Bio-Pharma offers stability study services for proteins, peptides, plasmids, and mRNAs, involving long-term stability studies, accelerated stability studies, and forced degradation studies. In addition, we have all the necessary capabilities for sample storage and Critical Quality Attributes (CQA) analysis to collect stability data.

Regulatory Requirements for Stability Studies

According to the ICH Q5C guideline, “The proper supporting stability data should be developed for biotechnological/biological product, as many external conditions can affect the product’s potency, purity and quality. It is also strongly suggested that studies be conducted on the drug substance and drug product under accelerated and stress conditions.

Real-Time (long-term) Stability Studies

In real-time (long-term) stability testing, the drug substance or drug product is stored under intended storage conditions and monitored until the biological characteristics change beyond the acceptable limits. As a result of long-term stability studies, the shelf-life, expiration date, storage conditions, and sampling/testing intervals can be established.

Table 1. The testing frequency in long-term stability studies of pre-approval biologics

Shelf-life Testing intervals Time points
1 year or less

Monthly for the first 3 months;

Every 3 months thereafter

 At 0, 1, 2, 3, 6, 9, and 12 months
More than 1 year

Every 3 months for the first year;

Every 6 months for the second year;

Annually thereafter

 At 0, 3, 6, 9, 12, 18, 24, 36 months, and annually thereafter
Accelerated Stability Studies

The recommended storage temperature of injectable biopharmaceutics is usually between 2 and 8℃. Accelerated stability studies are conducted with shorter duration under accelerated conditions, such as high temperature. The stabilities data is recognized as supportive information for product stability and widely used in shelf life and expiration date determination, as well as formulation development.

Tabel 2. Examples of Accelerated Stability Studies

Stability Studies Accelerated conditions Sampling points
Accelerated Stability Studies

elevated temperature

relative humidity

 At 0, 1, 2, 3, 6 months
Forced Degradation Studies

The aim of forced degradation studies is to collect stability information under stress conditions, such as high temperatures, humidity, light, oxidation, freeze-thaw or mechanical stress (shaking, shear). Forced degradation studies of the drug substance or drug product under extreme conditions can help recognize key factors/parameters leading to biologics degradation. This data is useful for robustness assessment for the formulation and manufacturing process.

Tabel 3. Examples of Forced Degradation Studies

Stress Stress conditions Duration time
Temperature High temperature (e.g., 25℃, 30℃, 37℃, 40℃) Days-months
Humidity Relative humidity (0~100%) Days-months
Light A minimum of 1.2 million lx h and 200 W h/m2 Several days
Freeze-thaw freeze–thaw (from -20℃, -80℃ to 15℃) 1~5 cycles
Shaking, stirring 50~500 rpm Hours-days
Analytical Methods Supporting Stability Studies
Critical Quality Attributes (CQAs) Analytical Methods
Total protein content UV, BCA, Bradford, Lowry
Visible particles Visual inspection
Aggregation, fragments Dynamic light scattering Size-exclusion chromatography (SEC) HPLC/UPLC, Capillary electrophoresis CE (CGE, CZE, cIEF/iCIEF), Non-reducing SDS-PAGE
Peptide mapping and sequencing LC-MS/MS
Disulfide bonds LC-MS/MS
PTM (oxidation, isomerization, deamidation, glycosylation) LC-MS/MS
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