USP <697> and FDA MAPP Guidelines: Ensuring Container Content Integrity for Injections
Injectable drug products demand the highest standards of quality and safety—not just in formulation but also in the volume they deliver.
Ensuring that injectable containers provide the full labeled dose is the core principle of USP <697> and the FDA’s MAPP 5019.1 and 5019.2.
This article offers detailed guidance for pharmaceutical professionals on container content evaluation for lyophilized, single-dose, multi-dose, and large-volume injections.
📘 What is USP <697>?
USP <697>, titled “Container Content for Injections”, is an informational chapter in the United States Pharmacopeia that outlines best practices for ensuring injectable containers hold sufficient withdrawable volume as labeled.
- Applies to all injectable dosage forms, including solutions, lyophilized powders, emulsions, and suspensions.
- Ensures compliance with USP <1151>, 21 CFR 201.51(g), and international compendia (Ph. Eur, JP).
- Focuses on withdrawable volume accuracy using standard administration techniques.
🧪 Applicability of USP <697>
USP <697> covers container content expectations for:
- Single-dose injections: Must allow 100% withdrawal of labeled volume.
- Multi-dose vials: Require accurate dose withdrawals multiple times.
- Lyophilized injections: Must yield full labeled volume upon reconstitution.
- Large Volume Parenterals (LVPs): Full volume must be infusible, even with hold-up volumes.
✅ Acceptance Limits Under USP <697>
| Labeled Volume | Containers to Test | Minimum Withdrawable Volume |
|---|---|---|
| ≤ 3 mL | 5 | 100% from each |
| 3–10 mL | 3 | 100% from each |
| > 10 mL | 1 | 100% from the unit |
Measurements should be done using gravimetric or volumetric methods, simulating standard withdrawal conditions (e.g., syringe and needle).
💊 Special Case: Lyophilized Injections
- Reconstitution volume must enable full dose withdrawal after mixing.
- Vial headspace, stopper design, and reconstitution procedure must support dose accuracy.
- Should meet USP <905> (Uniformity of Dosage Units) post reconstitution.
🧴 Single vs Multi-Dose Injections
Single-Dose Vials:
- Contain a single, fully deliverable dose.
- Overfill should account only for minor dead space loss.
Multi-Dose Vials:
- Contain preservatives for multiple uses.
- Each dose must be consistently withdrawable during the in-use period.
- Partial loss through stopper absorption or handling must be evaluated.
🧊 Large Volume Parenterals (LVPs)
- Volumes range from 100 mL to 1000 mL.
- Must deliver full labeled dose via infusion pump or gravity feed.
- Overfill must compensate for hold-up in IV tubing or administration sets.
📑 FDA MAPP Guidelines
MAPP 5019.1 – Delivered Dose Requirements
- FDA expects full delivery of labeled dose using the methods described in product labeling.
- Applicable to all injectable drug forms including lyophilized and reconstituted products.
- Supports consistency in reviewer expectations across NDA, ANDA, and BLA filings.
MAPP 5019.2 – Maximum Fill Volume Policy
- Excessive overfill (beyond what is needed for accurate dosing) must be justified.
- Prevents risk of overdose, misuse, or misleading labeling.
- Supports FDA’s goal of promoting accurate and safe dosing in clinical use.
🏭 Best Practices for Manufacturers
- Document and justify overfill volumes in submissions.
- Perform container content studies for each container closure system.
- Ensure reconstitution procedures are validated for lyophilized products.
- Include USP <697> compliance in the CMC section or Type III DMF.
🔬 Regulatory Summary Table
| Product Type | Key Requirement | Guidance |
|---|---|---|
| Single-dose injections | Full 100% volume must be withdrawable | USP <697> |
| Multi-dose vials | Repeatable dose withdrawal accuracy | USP <697>, MAPP 5019.1 |
| Lyophilized injections | Dose consistency post reconstitution | USP <697>, <905> |
| LVPs | Infusible full labeled volume | USP <697>, <645> |
| Overfill control | Not excessive or misleading | MAPP 5019.2 |
📎 References
- USP <697> – Container Content for Injections
- USP <1151>, <905>, <645>, <1663>, <1664>, <1207>
- FDA MAPP 5019.g1 and 5019.2
- 21 CFR 201.51(g)
- ICH Q8, Q9, Q10
Extractable and Leachability study