Source: Link Testing Instruments Co.,Ltd.
I. The Core Significance and Key Influencing Factors of Residual Oxygen Control
Residual oxygen control in injectable drugs is a crucial process for ensuring the quality stability of oxidation-sensitive drugs (such as biologics, vitamins, and some antibiotics) within their shelf life. Excessive residual oxygen content can directly lead to degradation of the active pharmaceutical ingredient, increase of related substances, color changes, and potential safety risks. The main influencing factors include the oxygen barrier properties of the packaging material, filling process conditions, the dissolved oxygen characteristics of the drug solution itself, and the storage environment. Among these, the compatibility between the packaging material specifications and the actual filling volume is the core engineering variable determining the system's final oxygen control capability and must be fully evaluated and verified during the dosage form design stage.
II. Analysis of the Mechanism of Effect of Packaging Material Specifications and Filling Volume on Oxygen Control Efficiency
(I) Mechanism of Action: Comprehensive Balance of Headspace Oxygen, Permeable Oxygen, and Dissolved Oxygen
Residual oxygen in injectable packaging mainly consists of three parts: oxygen remaining in the headspace after filling (headspace oxygen), oxygen permeating in through the packaging material during storage (permeable oxygen), and oxygen dissolved in the drug solution itself (dissolved oxygen). The ratio of headspace volume (V_headspace) to drug solution volume (V_fill) (R = V_headspace / V_fill) is a key parameter for assessing the initial residual oxygen level and predicting its long-term trend.
Headspace Oxygen Contribution: In packaging materials of a given specification, the lower the filling volume, the larger the R value, meaning a higher absolute value of the initial headspace volume and its oxygen content. Even after inert gas replacement (such as nitrogen purging), the absolute amount of residual oxygen is still positively correlated with the R value.
Permeable Oxygen Contribution: The oxygen transmission rate (OTR) of the packaging material is an inherent property. However, the permeable area (A/V_fill) of the packaging material per unit volume of the drug solution increases as the filling volume decreases. This means that during long-term storage, the relative contribution of permeated oxygen to the total oxygen load of the drug solution is more significant under small filling volume conditions.
Dissolved oxygen contribution: The larger the volume of the drug solution, the higher its initial total dissolved oxygen may be. However, this can usually be effectively controlled after optimizing the nitrogen filling or vacuum replacement process. Its impact needs to be systematically evaluated in conjunction with headspace oxygen and permeated oxygen.
(II) Analysis of oxygen control performance data and filling volume dependence for different types of packaging materials
Specifications and OTR: Common specifications are 1-20 mL. Their OTR is extremely low and usually negligible (e.g., <0.01 cc/pkg/day/atm).
Analysis of the impact of filling volume:
Small sizes (1-2 mL): When the filling volume is significantly lower than the nominal capacity (e.g., 0.8 mL for a 1 mL ampoule, R=0.25), even with two nitrogen purgings, the initial residual oxygen level may still reach 1.5%-2.0%. Filling to near full capacity (e.g., 1.0 mL, R=0.1), the initial residual oxygen can be reduced to below 0.5%.
Large sizes (10-20 mL): When the filling volume is 50% of the nominal capacity (e.g., 5 mL for a 10 mL ampoule, R=1.0), an enhanced purging process (e.g., three purgings) is required to control the initial residual oxygen at approximately 2.0%. Filling to 80% capacity (R=0.25), the initial residual oxygen is easily controlled at around 1.0%.
Mechanism Conclusion: For glass ampoules, the bottleneck in oxygen control lies primarily in the headspace oxygen replacement efficiency. Insufficient filling volume leading to excessive headspace volume is the primary cause of increased residual oxygen.
Specifications and OTR: Common specifications range from 1-10 mL. OTR varies significantly depending on the material: Polypropylene (PP) approximately 0.6-0.8, Cycloolefin copolymers/polymers (COC/COP) approximately 0.1-0.2 cc/pkg/day/atm.
Analysis of the Influence of Filling Volume:
Small specifications (1-3 mL): For PP material, when a 1 mL specification is filled with 0.5 mL (R=1.0), the initial residual oxygen can reach 2.5%-3.0%, and may exceed 4.0% after 6 months of accelerated stability testing. COC/COP materials perform better under the same conditions, with significantly lower initial and long-term residual oxygen than PP.
Large-volume (5-10 mL): When a 10 mL PP syringe is filled with 3 mL (R≈2.33), the initial residual oxygen may be as high as 3.5%-4.0%, posing a significant risk during long-term storage. Even when using COC/COP materials, the residual oxygen level at low filling volumes needs close monitoring.
Mechanism Conclusion: For plastic packaging materials, there is a cumulative effect between headspace oxygen residue and material permeation oxygen. Low filling volumes not only increase initial headspace oxygen but also increase the risk of oxygen exposure per unit volume of medication.
Specifications and OTR: Common specifications are 100-500 mL. Single-layer polyethylene (PE) films have a relatively high OTR (approximately 6-8), while ethylene-vinyl alcohol copolymer (EVOH) multilayer co-extruded films have a relatively low OTR (approximately 0.15-0.25 cc/pkg/day/atm).
Analysis of the Impact of Filling Volume:
Regular Filling (≥80% nominal capacity): Filling 200 mL of 250 mL EVOH bag (R=0.25), initial residual oxygen can be controlled within 1.5%.
Low Filling (≤50% nominal capacity): Filling 100 mL of the same EVOH bag (R=1.5), initial residual oxygen significantly increases to 2.5%-3.0%, and continues to increase rapidly during storage. PE bags have an extremely high risk of uncontrolled residual oxygen under low filling conditions.
Mechanism Conclusion: Large-capacity packaging has a large absolute amount of headspace oxygen, and the packaging material surface area is large, so the contribution of total permeated oxygen cannot be ignored. Low filling volume amplifies the effects of both of these aspects.
III. Case Study on Oxygen Control Based on Marketed Products
Case 1: A certain ceftriaxone sodium injection (5 mL glass ampoule)
Scenario A: Filling 3.0 mL of drug solution (R≈0.67), standard two nitrogen purgings. Initial residual oxygen was approximately 2.2%, rising to approximately 3.2% after 6 months of long-term storage, with related substances increasing by nearly 20%.
Scenario B: 4.5 mL of drug solution was filled (R≈0.11), using the same process. Initial residual oxygen ≤0.8%, ≤1.2% after 6 months, with related substances increasing by ≤8%.
Implication: When using high-barrier packaging materials, optimizing the filling volume to reduce the headspace ratio is the most direct way to improve oxygen control.
Case Study 2: A pre-filled insulin injection solution (3 mL specification)
PP material: When filling 1.5 mL (R=1.0), residual oxygen exceeded the internal control standard (e.g., 3.5%) after 12 months of storage.
COC material: At the same filling volume, residual oxygen remained within the standard after 12 months of storage, and oxidative degradation products were significantly less than with PP material.
Implication: For situations requiring low filling volumes, selecting packaging materials with higher barrier properties is an effective solution.
IV. Systematic Control Strategies and Key Practical Points
Design Phase Matching Demonstration: In the early stages of drug development, the optimal combination of "packaging material system - target fill volume range" should be demonstrated and determined based on the drug's oxygen sensitivity. Highly sensitive drugs should prioritize high-barrier packaging materials, and the fill volume should be set as high as possible (e.g., 85%-95% of nominal volume).
Process Development and Parameter Optimization: Process development needs to be linked to packaging materials and fill volume. For low-fill-volume products, more stringent inert gas protection processes should be validated and adopted, such as increasing the number of purging cycles, extending the purging time, or using alternating vacuum-nitrogen purging.
Quality Control and Stability Testing: Residual oxygen quality control strategies should be established for different "packaging material-fill-volume" combinations. Stability testing schemes should fully reveal the trend of residual oxygen changes over time, especially for batches under edge conditions (such as minimum fill volume).
Advanced Packaging Material System Selection: For products with extremely high oxygen sensitivity, consider using packaging materials with higher barrier properties (such as COP syringes, aluminum-plastic composite film bags), or integrating oxygen absorbers into the packaging system (compatibility and safety need to be demonstrated).
V. Conclusion
The final oxygen control efficiency of an injectable packaging system is the result of the combined effect of the inherent barrier properties of the packaging material, the product fill volume, and the filling and sealing process. The core principles indicate that:
Under fixed packaging material conditions, the closer the fill volume is to the nominal capacity of the packaging material, the better the overall oxygen control performance and the better the long-term stability of the system.
Under fixed fill volume conditions, using packaging materials with a lower OTR provides stronger oxygen control assurance and is more tolerant of fill volume fluctuations.
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