Formulation and Dispensing of IV Admixtures

1. Definition and Types

2. Pre-formulation Considerations

a. Physicochemical Compatibility

• Drug–drug compatibility: Will the drugs precipitate, degrade, or react when combined?
• Drug–vehicle compatibility: Is the drug stable in the chosen diluent (NS, D5W, D5NS, LR, sterile water)?
• pH considerations: Most IV drugs are stable within a narrow pH range; the vehicle pH can accelerate degradation.
• Osmolarity: Solutions > 900 mOsm/L should not be given peripherally (risk of thrombophlebitis and vein damage); use a central line.
• Light sensitivity: Some drugs (e.g., nitroglycerin, amphotericin B, metronidazole) require light-protected bags/tubing.
• Temperature stability: Check storage requirements (room temp vs. refrigerated).

b. Chemical Stability

• Hydrolysis: Common with beta-lactams, esters, amides (e.g., ampicillin degrades rapidly after reconstitution).
• Oxidation: Ascorbic acid, morphine, dopamine — protect from oxygen.
• Photodegradation: Furosemide, amphotericin B, dacarbazine.
• Use stability data (Trissel's Handbook, King Guide, product monographs) to determine beyond-use dates (BUD).

c. Concentration Limits

• Each drug has a minimum and maximum concentration for stability, safety, and administration rate.
• Example: Potassium chloride should not exceed 40 mEq/100 mL for peripheral infusion; maximum rate 10–20 mEq/hr peripherally.

3. Calculation and Verification

Steps in dose calculation:

1. Confirm the order: patient name, MRN, drug, dose, route, frequency, diluent, volume, rate.
2. Calculate the drug amount needed:
   • e.g., Vancomycin 1 g in 250 mL NS: draw up 10 mL of 100 mg/mL vial = 1000 mg.
3. Calculate the final concentration: dose ÷ total volume.
4. Calculate infusion rate: volume ÷ time (mL/hr).
5. Independent double-check by a second pharmacist (mandatory in most institutions).

4. Aseptic Preparation (USP <797> Standards)

Environment

• ISO Class 5 Primary Engineering Control (PEC): Laminar Airflow Workbench (LAFW) for non-hazardous drugs, or Biological Safety Cabinet (BSC) / Compounding Aseptic Containment Isolator (CACI) for hazardous drugs (chemotherapy).
• The cleanroom itself must meet ISO Class 7 (low-risk) or ISO Class 8 (ante-room).

Personal Protective Equipment (PPE)

• Gloves (sterile, powder-free), gown, hair cover, mask, shoe covers.
• For hazardous drugs: double-gloving, chemotherapy-rated gown.

Technique

1. Hand hygiene: surgical scrub before entering clean room.
2. Surface disinfection: 70% isopropyl alcohol (IPA) on all surfaces and vials.
3. Needle technique: insert needle bevel up at 45–60°; withdraw correct volume.
4. Swab all ports and vial tops with 70% IPA and allow to dry before piercing.
5. Minimize touch contamination: work away from HEPA filter, avoid blocking airflow.
6. Remove air bubbles from syringe before injecting into IV bag.
7. Label immediately after preparation.

5. Labeling Requirements

• Patient name, date of birth, MRN
• Drug name, strength, and concentration
• Diluent and total volume
• Rate of infusion
• Preparation date and time
• Beyond-Use Date (BUD) and time
• Storage conditions
• Pharmacist's name or initials
• Auxiliary labels (e.g., "Refrigerate," "Protect from light," "Cytotoxic")

6. Beyond-Use Dating (BUD)

7. Quality Control (QC) Checks

8. Special Categories

Total Parenteral Nutrition (TPN)

• Contains dextrose, amino acids, lipids (2-in-1 vs. 3-in-1), electrolytes (Na, K, Mg, Ca, phosphate), vitamins, trace elements.
• Calcium–phosphate compatibility is critical — precipitation can be fatal if infused (particulate emboli).
• Use solubility curves (Trissel's or in-house nomograms) to confirm safety.
• Prepared using automated compounders (e.g., Baxter Exacta-Mix).

Chemotherapy

• All prepared in negative-pressure isolators.
• Pharmacist and nurse independent double-checks.
• Requires hazardous drug handling protocols (NIOSH list, ASHP guidelines).
• Closed System Transfer Devices (CSTDs) mandatory.

Antibiotic Piggybacks

• Most common admixture type.
• Reconstitute lyophilized vial → add to 50–100 mL bag.
• Critical: verify correct diluent (some antibiotics incompatible with D5W or LR).

9. Dispensing Workflow

Prescriber order → Pharmacist review → DUR/clinical check
        ↓
Dose calculation → Compatibility check → Stability check
        ↓
Preparation in cleanroom (aseptic technique)
        ↓
QC check (pharmacist) → Label → Store appropriately
        ↓
Nurse verification at bedside → Administration

10. Common Compatibility Issues to Know

11. Regulatory and Standards Framework

• USP <797>: Primary standard for sterile compounding in the US.
• USP <800>: Hazardous drug handling.
• ASHP Guidelines: IV admixture programs, hazardous waste.
• Joint Commission: Medication management standards.
• NIOSH Alert: Hazardous drug list and handling requirements.

Summary

Worked Example: IV Admixture of Vancomycin 1 g in 250 mL Normal Saline

Drug Background

Step 1 — Receive and Verify the Order

Vancomycin 1 g IV every 12 hours in 250 mL NS, infuse over 60 minutes

• Correct patient, allergy check (rare but IgE-mediated anaphylaxis possible)
• Dose appropriate? Standard adult dose = 25–30 mg/kg/day in divided doses (Goodman & Gilman's)
• Renal function review — vancomycin is 90% renally excreted; dose reduction required in renal impairment
• Frequency is appropriate for the patient's creatinine clearance
• Duration specified

Step 2 — Compatibility and Stability Check

Step 3 — Calculation

Step 4 — Aseptic Preparation (in LAFW, ISO Class 5)

1. Swab tops of both vials and the IV bag port with 70% isopropyl alcohol (IPA) — allow to dry
2. Reconstitute each 500 mg vial with 10 mL SWFI using a needle and syringe → mix gently until dissolved (do not shake vigorously)
3. Withdraw 10 mL from Vial 1 → inspect for clarity and particulates
4. Withdraw 10 mL from Vial 2 → inspect
5. Inject both syringes (20 mL total) into the 250 mL NS bag through the additive port
6. Gently invert the bag 5–10 times to mix
7. Inspect the final solution: should be clear, colorless to slightly yellow — discard if turbid, discolored, or particulate matter visible

Step 5 — Label the Admixture

Patient: [Name]           MRN: [XXXXXX]
Drug:    Vancomycin 1 g (1000 mg)
Diluent: 0.9% Sodium Chloride 250 mL
Concentration: ~3.7 mg/mL
Route:   IV Piggyback
Rate:    270 mL/hr over 60 minutes
Prepared: [Date/Time]     BUD: [Date/Time - 14 days if refrigerated]
Storage: Refrigerate (2–8°C)
Prepared by: [Pharmacist Initials]
⚠ Infuse slowly — Red Man Syndrome risk if given too fast

Step 6 — Quality Control Before Dispensing

Step 7 — Dispensing and Administration

• Dispense refrigerated if not used immediately
• Remove from refrigerator 30 minutes before infusion (allow to reach room temperature)
• Nurse performs 5 Rights check at bedside (right patient, drug, dose, route, time)
• Administer via IV pump over exactly 60 minutes
• Monitor for Red Man Syndrome (slow infusion rate if it occurs), nephrotoxicity (SCr), and ototoxicity (with prolonged use)

Summary Table

Preparation of a Medicine and Justification for Inclusion in the Hospital Formulary

Drug Selected: Morphine Sulfate Injection 10 mg/mL

PART A — PREPARATION OF THE MEDICINE (Content/Formulation)

1. Dosage Form and Strength

2. Formula (per 1 mL of injection)

Note: Some formulations are sulfite-free for patients with sulfite sensitivity (e.g., asthmatics).

3. Physicochemical Justification for Each Excipient

a. Water for Injection (WFI)

• Prepared by distillation or reverse osmosis — free of particulates, pyrogens, microorganisms.
• Morphine sulfate is highly water-soluble (620 mg/mL at 25°C) — aqueous vehicle is ideal.

b. Sodium Chloride (Tonicity Adjustment)

• Blood is isotonic at 308 mOsm/L.
• Without NaCl, the solution would be hypotonic → red cell swelling and haemolysis on IV injection.
• NaCl is added to bring osmolarity to 280–320 mOsm/L.

c. Buffer System (Citric Acid / Sodium Citrate)

• Morphine is most stable at pH 3.0–5.0.
• At alkaline pH (>6), morphine undergoes oxidative degradation to pseudomorphine (inactive, toxic).
• At very acidic pH (<2), hydrolysis accelerates.
• The citrate buffer maintains the optimal acidic-to-neutral range without irritating veins excessively.

d. Sodium Metabisulfite (Antioxidant)

• Morphine contains a phenolic –OH group susceptible to oxidation (primary degradation pathway).
• Sodium metabisulfite acts as a reducing agent — it preferentially oxidises, protecting morphine.
• Extends shelf life significantly (2–3 years when stored at 15–30°C, protected from light).
• Concentration kept low (0.1%) to avoid toxic accumulation or sulfite hypersensitivity.

e. Light-Protected Ampoule/Vial

• Morphine is photosensitive — UV light accelerates oxidation.
• Amber-coloured glass ampoules + carton packaging provide dual protection.

4. Manufacturing and Sterility Requirements

5. Storage and Handling

• Store at 15–30°C, protected from light and freezing.
• Controlled substance — stored in locked, double-locked cabinet (Schedule II/Class A opioid in most countries).
• Discard unused portions — no preservative in single-dose ampoules.
• Multi-dose vials: use within 28 days of first puncture.

PART B — JUSTIFICATION FOR INCLUSION IN THE HOSPITAL FORMULARY

Domain 1 — Clinical Efficacy (Therapeutic Need)

• WHO Step 3 of the Pain Analgesic Ladder — morphine is the reference opioid for severe pain.
• Extensive RCT evidence, systematic reviews (Cochrane), and decades of clinical experience confirm efficacy in post-operative, cancer, and neuropathic pain.
• Listed on the WHO Model List of Essential Medicines (EML) since 1977 — maintained on every revision.
• No available non-opioid achieves equivalent analgesia for severe pain; morphine remains the gold standard comparator against which all newer opioids are benchmarked.

Domain 2 — Safety Profile

Domain 3 — Pharmacoeconomics (Cost-Effectiveness)

• Morphine is off-patent — multiple generic manufacturers supply it at a fraction of the cost of newer opioids (hydromorphone, oxymorphone, tapentadol).
• Cost-effectiveness analyses consistently favour morphine as the least-cost, most-effective strong opioid for hospital use.
• Inclusion reduces hospital drug expenditure without compromising outcomes.

Domain 4 — Therapeutic Substitution / Uniqueness

• The P&T Committee must decide: Does morphine add unique value, or is a formulary alternative sufficient?
• Morphine vs. pethidine (meperidine): Pethidine accumulates a toxic metabolite (norpethidine → seizures) with repeated dosing — morphine is safer for regular dosing.
• Morphine vs. codeine: Codeine requires hepatic conversion to morphine (CYP2D6) — unpredictable efficacy, ultra-rapid metabolisers at risk. Morphine is directly active — predictable.
• Morphine vs. hydromorphone: Hydromorphone is used when morphine is poorly tolerated; morphine should be first-line.
• Conclusion: Morphine is not therapeutically duplicated on the formulary; it serves the primary opioid slot.

Domain 5 — Regulatory and Guideline Endorsement

Domain 6 — Operational Feasibility

Summary: Formulary Submission Template

DRUG: Morphine Sulfate Injection 10 mg/mL
CATEGORY: Analgesic — Opioid (WHO Step 3)
PROPOSED USE: Moderate-to-severe pain, palliative care, post-operative analgesia
EVIDENCE LEVEL: Level I (RCTs, systematic reviews, WHO EML)
ALTERNATIVES CONSIDERED: Pethidine (inferior safety), Fentanyl (higher cost)
UNIQUE VALUE: Gold-standard opioid, directly active, fully titratable IV/SC/IM
SAFETY RISK: Manageable; antidote (naloxone) co-stocked
COST: Lowest-cost strong opioid (generic)
REGULATORY STATUS: WHO EML, national pharmacopoeias, all major guidelines
RECOMMENDATION: APPROVE for formulary inclusion (core list)

Visual Overview

HOSPITAL FORMULARY INCLUSION PROCESS
──────────────────────────────────────
Drug Identification (unmet therapeutic need)
        ↓
P&T Committee Drug Request Submission
        ↓
Evidence Review:
  ├── Efficacy (RCTs, guidelines)
  ├── Safety (ADR profile, antidote)
  ├── Cost-effectiveness (pharmacoeconomics)
  ├── Uniqueness (vs. alternatives on formulary)
  ├── Regulatory approval (WHO, national)
  └── Operational feasibility (storage, training)
        ↓
Committee Vote → APPROVED / REJECTED / RESTRICTED
        ↓
Formulary Listing (with prescribing restrictions if needed)
        ↓
Periodic Review (annual reassessment)

Key Principle