Addressing Stability Challenges in Biologic Combination Products

Biologic combination products—such as prefilled syringes, autoinjectors, dual-chamber cartridges, and drug-device systems—have transformed patient-centric care in biopharmaceuticals. While convenient and increasingly common, these complex formats pose unique stability challenges due to interactions between the biologic drug, device components, and packaging materials. This tutorial explores how to design robust stability strategies to address these challenges and meet regulatory expectations for combination products.

What Are Biologic Combination Products?

Combination products integrate a biologic drug with a device or delivery system. Common examples include:

• Prefilled syringes and pens
• Autoinjectors and on-body injectors
• Dual-chamber cartridges or reconstitution systems
• Co-formulated biologics in single containers

The interplay of drug, delivery system, and packaging materials requires careful evaluation of how stability is influenced throughout the product lifecycle.

Unique Stability Challenges in Biologic Combination Products

1. Drug-Device Interaction

Materials such as silicone oil (used for syringe lubrication), adhesives, or polymers may interact with the biologic and induce degradation, aggregation, or particulate formation.

2. Interface Stress

Interfaces such as stopper-barrel contact points or reconstitution systems are subject to shear, friction, and pressure—all of which can impact the protein’s structural integrity over time.

3. Temperature and Mechanical Stress

Wearable devices and autoinjectors may be exposed to real-world conditions like vibration, drops, and temperature cycles during storage and use. These require additional testing beyond standard ICH protocols.

4. Component Migration and Leachables

Extractables and leachables (E&L) from plastic components, adhesives, and lubricants can contaminate the formulation, especially over extended storage periods.

5. Dual Formulation Stability

Products that mix two biologics or a biologic and excipient just before administration must demonstrate individual and post-mixing stability.

Step-by-Step Guide to Stability Protocol Design

Step 1: Classify Product Type and Delivery System

Start by determining the category of combination product:

• Single biologic in prefilled syringe?
• Two-part dual chamber (lyophilized and diluent)?
• On-body wearable with heating or pump components?

This classification dictates what additional stress and compatibility testing is needed.

Step 2: Identify Materials in Contact with the Drug

Map out all materials in direct and indirect contact with the drug product, including:

• Syringe barrels (glass, COC)
• Elastomeric stoppers and plungers
• Coatings and lubricants (e.g., silicone, BPO-free coatings)
• Tubing, connectors, or valves in delivery systems

Perform risk assessments for extractables and leachables, adsorption, and chemical compatibility.

Step 3: Conduct Combination-Specific Stress Testing

Augment ICH Q5C protocols with tests specific to the combination format:

• Plunger glide force under storage conditions
• Silicone oil-induced aggregation tracking
• Mechanical shock and vibration stability (simulate drops and transit)
• On-body wear time simulation at 37°C

Ensure physical and chemical attributes (e.g., clarity, pH, potency) remain within specification throughout simulated use.

Step 4: Execute Extractables and Leachables (E&L) Studies

Per USP and FDA/EMA expectations, include:

• Controlled extraction using aggressive solvents
• Leachables testing under real-time and accelerated stability
• Toxicological risk assessments of detected species

Data must support both initial marketing authorization and post-approval changes in materials or suppliers.

Step 5: Monitor Functionality Over Shelf Life

Combination products must maintain delivery performance throughout their labeled shelf life. Include tests such as:

• Injection time consistency
• Force-to-actuate measurements
• Dose accuracy and completeness

These are critical for autoinjectors and on-body systems used in outpatient settings.

Step 6: Include Reconstituted Product Stability (If Applicable)

For dual-chamber systems or lyophilized products, conduct:

• In-use stability post-reconstitution (e.g., 6, 12, 24 hours)
• Compatibility with diluent and container materials
• Impact of reconstitution rate and method

Regulatory Framework for Combination Product Stability

Combination product guidance varies by region but commonly draws on:

• 21 CFR Part 4: USFDA rule on combination product CGMPs
• ICH Q8–Q10: Pharmaceutical development and risk management
• EMA Guideline on plastic materials and E&L studies
• ISO 11608 series: Needle-based injection systems

Document all findings in CTD Module 3 and your internal Pharma SOP system for lifecycle management.

Case Study: Autoinjector Protein Instability

A biosimilar manufacturer developing an autoinjector observed unexpected aggregation at 6 months. Investigation revealed interactions between protein and silicone oil from the syringe barrel. A change to baked-on silicone and addition of polysorbate 20 reduced aggregation by 80%, resolving the issue and allowing shelf life extension.

Checklist: Stability Testing in Combination Biologics

1. Classify product format (PFS, dual-chamber, wearable)
2. Identify and qualify all contact materials
3. Design ICH + mechanical + E&L + functionality studies
4. Test both physical and biological properties across use conditions
5. Document and trend changes in all system components

Common Mistakes to Avoid

• Relying solely on drug stability data—ignoring device impact
• Underestimating E&L risks from secondary components
• Skipping functionality testing during real-time studies
• Assuming syringe and vial stability profiles are interchangeable

Conclusion

Biologic combination products introduce additional complexity to stability testing, requiring holistic evaluation of container materials, device interfaces, and real-use conditions. By extending standard ICH protocols to incorporate mechanical, functional, and leachable-focused testing, developers can safeguard product integrity and ensure compliance across global regulatory pathways. For more in-depth guidance on biologic stability design, visit Stability Studies.