The operational processes before clinical administration of biologics and all components that come into contact with the drug can affect its stability. Therefore, pharmaceutical manufacturers must standardize the clinical handling procedures of drugs to ensure the quality of medications used by patients. ICH Q8 states that "the compatibility of the drug product with reconstitution diluents should be addressed."

The purpose of Clinical In-Use Stability Studies (CIU) is to evaluate the impact of clinical compatibility processes on the physicochemical and microbiological properties of drug products in laboratory settings. These studies typically include compatibility with diluents, dose accuracy, compatibility with delivery devices, simulated infusion conditions, and storage conditions and shelf life of reconstituted solutions. Pharmaceutical companies must submit this information as part of their regulatory submission documentation. Figure 1 illustrates potential processes that a lyophilized product may undergo during clinical preparation for intravenous administration. Each step may potentially affect the product quality and/or administered dose.

Fig. 1  Typical Clinical Drug Preparation, Handling, and Administration Process

 (Using Lyophilized IV Product as an Example)

1. Diluent Compatibility

The most commonly used isotonic intravenous diluents in clinical practice are 0.9% Sodium Chloride Injection (normal saline), 5% Dextrose Injection (D5W), and Lactated Ringer's Injection. The dilution process alters critical formulation factors of the product, such as pH, ionic strength, and excipient concentrations, all of which can potentially affect protein stability. Therefore, it is essential to evaluate the impact of diluents on proteins during research studies.

It is generally recommended to screen and enable multiple diluents, and to cover worst-case use scenarios. For instance, testing the stability of solutions at the lowest and highest dosage concentrations within the clinical dose range, and evaluating storage time under worst-case conditions at applicable storage temperatures.

For example, if the anticipated clinical dose range for a Phase I study is between 0.1 mg/kg and 1.0 mg/kg, with a patient weight range of 40-120 kg, the required doses would range from 4 mg to 120 mg. If clinical administration is planned using 50 mL infusion bags, the standard solution concentration range in these bags would be between 0.08 mg/mL and 2.4 mg/mL. The fill volumes of infusion bags vary significantly among different manufacturers; therefore, a range of approximately 0.06-2.75 mg/mL (target ± 15%) can be selected to ensure stability. Furthermore, to avoid interactions with administration components such as infusion bags, it is recommended at this stage to prepare the final product in inert glass containers as a study control.

2. Dose Accuracy

Preparation methodologies for drug reconstitution, solution extraction, and transfer exhibit substantial variability across healthcare institutions, potentially impacting preparation accuracy. These procedures typically employ disposable syringes, infusion bags, vial adapters, and closed system transfer devices (CSTDs). The dead volume inherent in the ultimately utilized components can influence dose preparation accuracy. For instance, the dimensions and gradations of syringes employed in solution preparation can induce fluctuations in solution concentration.

In-use requirements should be assessed at an early stage of formulation development. As an illustration, for a Phase I study with an expected clinical dosage range of 0.1 mg/kg to 1.0 mg/kg and a patient weight spectrum of 40–120 kg, the requisite doses would span from 4 mg to 120 mg. In this scenario, a formulation concentration of 20–50 mg/mL might be more suitable than a 100 mg/mL formulation.

3. Administration Device Compatibility

During product use, the preparation of solutions inevitably comes into contact with various drug delivery components. These components, made of materials different from the original drug packaging, can potentially affect product quality.

It’s not feasible to test each component individually in the lab; therefore, contact materials can be tested instead of individual components. If the drug solution is compatible with the evaluated material type, all commercially available materials in that category can be used. If incompatibility is observed, the use of materials in clinical studies must be restricted. For safety reasons, most infusion lines are equipped with filters, so issues such as protein adsorption, filter particle shedding, and leachables should also be considered. It is recommended to conduct comparative studies with and without 0.2μm and 1.2μm filters.

Similar to diluent compatibility studies, the design of material compatibility assessments should cover worst-case usage scenarios. The evaluation should also include worst-case simulations for infusion lines, such as when administration solutions remain in the infusion tubing longer than expected due to interruptions in administration. Currently, there are no explicit domestic requirements for studying leachables in infusion lines, but applications to European and American regulatory bodies require evaluation of extractables and leachables from administration devices.

4. Air-Liquid Interface Shear Forces

Air-liquid interfaces are introduced during various operational steps: rotating, inverting, or shaking vials during preparation or after reconstitution; inverting or shaking IV bags when preparing dosing solutions; shaking dosing solutions during transportation, etc. Surfactants such as polysorbate 20 and polysorbate 80 are commonly added to protein formulations to protect proteins from interface-induced shear forces. However, their concentrations may decrease significantly after admixture, requiring additional laboratory studies.

Recommendations for evaluating the impact of air-liquid interface shear forces during clinical use include: testing worst-case fill volumes in infusion containers (e.g., half-filled IV bags), assessing the effects of mixing and shaking-induced shear forces, and testing at planned minimum infusion times and maximum flow rates specified in clinical protocols.

5. Simulated Infusion

It is crucial to understand clinical infusion devices while simulating representative composition and shear stress conditions. It is recommended to evaluate potential pump systems. Large-volume infusion pump-driven systems typically use IV bags with volumes of 50-1000 mL, while syringe pump-driven infusion systems use syringes with volumes of 60 mL or less. In Phase I clinical studies, syringe pumps may be necessary to enable drug administration across a wide dose range. The selection of infusion devices is typically determined by the minimum stable dose solution concentration in the IV bag. For example, if the minimum stable dose solution concentration requires infusion of <25 mL solution, a syringe pump may be necessary. The minimum infusion volume and flow rate when using syringe pumps need to be discussed with clinical centers.

6. Storage Conditions and Duration During Clinical Use

Studies on storage conditions and duration during clinical use should include testing under all storage conditions. For products requiring infusion at room temperature over several hours, stability assessment of the drug solution should be conducted at 0, 4, 8, and 24 hours under conditions of 2-8°C and 30°C/75% RH.

For lyophilized drug products, post-reconstitution solution stability must be evaluated. For example, exposure at room temperature/room light conditions should be assessed at 0, 4, 8, and 24 hours. Simulated infusion studies should also be conducted to evaluate the impact on product quality before the end of administration.

Microbial considerations are a crucial factor in determining storage conditions and duration. Both FDA and EMA regulations have strict requirements for clinical solution preparation and use. Generally, drug solution preparation and infusion are required to be completed within 4 hours. If completion within 24 hours is specified, microbial challenge testing is required.

7. Summary

Clinical compatibility studies should be conducted in phases according to the above methods, which helps establish the expected clinical use process. In subsequent validation studies, worst-case conditions should be fully simulated to ensure product quality during administration (see Fig. 2).

 

References

1. Parenteral protein formulations:an overview of approved products within the European Union. Eur J Pharm Biopharm.2018;131:8–24.

2. Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies. Nat Rev Drug Discov. 2014;13(9):655–72.

3. Guidance for Industry: dosage and administration section of labeling for human prescriptiondrug and biological products — content and format. 

4. FDA 21 CFR 201.57(c)(3): dosage and administration.

5. Regulation (EU) No. 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC.