Sterile Compounding & BUD

Sterile Compounding & BUD

Master sterile compounding standards and beyond-use dating with free flashcards and spaced repetition practice. This lesson covers USP 797 requirements, cleanroom classifications, aseptic technique, and beyond-use date (BUD) assignment—essential concepts for NAPLEX success and safe pharmacy practice.

Welcome to Sterile Compounding Mastery 🧪

Sterile compounding represents one of the highest-risk activities in pharmacy practice. A single lapse in aseptic technique or improper beyond-use dating can lead to serious patient harm, including bloodstream infections, sepsis, and even death. The 2012 fungal meningitis outbreak linked to contaminated methylprednisolone injections resulted in 64 deaths and over 750 infections—a stark reminder of why USP Chapter 797 exists.

For the NAPLEX, you'll need to know USP <797> standards inside and out, including risk levels, environmental quality standards, personnel requirements, and BUD assignment. These aren't just test questions—they're the foundation of safe sterile compounding practice.

💡 Pro Tip: The revised USP <797> (effective November 2023) made significant changes to category classifications and BUD tables. Make sure you're studying the CURRENT standards!

Core Concepts: USP <797> Framework 🏗️

The Purpose of USP <797>

USP Chapter 797 establishes mandatory standards for compounding sterile preparations (CSPs) to prevent:

• Microbial contamination (bacteria, fungi, endotoxins)
• Chemical contamination (incorrect ingredients, degradation)
• Physical contamination (particulates, broken glass)
• Excessive bacterial endotoxins
• Variability in strength beyond acceptable limits

These standards apply to ALL settings where CSPs are prepared: hospitals, home infusion pharmacies, physician offices, and community pharmacies.

CSP Risk Categories (2023 Revision)

USP <797> classifies preparations into four categories based on contamination risk:

⚠️ Critical Change: The old "Low/Medium/High" risk levels were replaced with "Category 1/2/3" in 2023. Don't confuse them on the exam!

Immediate Use CSPs: The Exception

Immediate Use is NOT a risk category—it's an exception with strict criteria:

✅ All criteria must be met:

1. In the presence of a patient emergency or immediate need
2. Prepared using aseptic technique (even if not in ISO environment)
3. Simple transfer manipulations (limited to 3 entries per container)
4. Administration begins within 4 hours of preparation
5. Preparation occurs in an ISO Class 5 or better environment OR if not available, in a clean area with risk mitigation
6. Not batched or stored for future use

❌ If ANY criterion is not met: The CSP must be assigned a regular category (1, 2, or 3) and follow full USP <797> requirements.

🧠 Mnemonic - IMMEDIATE:

• Immediate need present
• Maximum 4 hours until administration
• Minimal manipulations (≤3 entries)
• Exception, not a category
• Don't batch
• ISO Class 5 preferred
• Aseptic technique required
• Temporary solution
• Emergency situations

Environmental Quality: Cleanroom Standards 🌬️

ISO Classifications

ISO (International Organization for Standardization) classifies air quality by particles per cubic meter:

Primary Engineering Controls (PECs)

The PEC is where the actual compounding occurs. Must maintain ISO Class 5 air quality:

Types of PECs:

1. Laminar Airflow Workbench (LAFW) 🌊

   • Horizontal or vertical airflow
   • Horizontal: NOT for hazardous drugs (air blows toward compounder)
   • Vertical: Acceptable for some HDs with proper containment

2. Biological Safety Cabinet (BSC) 🛡️

   • Class II BSC most common for HDs
   • Negative pressure inside cabinet
   • HEPA-filtered exhaust (recirculated or externally vented)

3. Compounding Aseptic Isolator (CAI) 📦

   • Closed system with glove ports
   • Positive pressure (for non-HDs)
   • Can be placed in unclassified space if externally vented

4. Compounding Aseptic Containment Isolator (CACI) 🔒

   • Closed system for hazardous drugs
   • Negative pressure with HEPA filtration
   • Provides both aseptic environment AND personnel protection

💡 Quick Decision Tree:

┌─────────────────────────────────────────┐
│  Are you compounding hazardous drugs?   │
└───────────────┬─────────────────────────┘
                │
     ┌──────────┴──────────┐
     │                     │
    YES                   NO
     │                     │
     ▼                     ▼
┌─────────┐         ┌──────────┐
│  CACI   │         │   CAI    │
│   or    │         │   or     │
│Class II │         │Horizontal│
│  BSC    │         │  LAFW    │
└─────────┘         └──────────┘

Segregated Compounding Areas (SCA)

For facilities with Category 1 compounding only and limited volume:

• PEC (ISO Class 5) placed in unclassified space
• Must be externally vented (CAI or CACI with external exhaust)
• Restricted to Category 1 CSPs only
• Maximum BUDs: 12 hours at room temp OR 24 hours refrigerated
• No buffer area or anteroom required

⚠️ Common Mistake: Students think SCA can be used for all categories. SCA = Category 1 ONLY with reduced BUDs!

Beyond-Use Dating (BUD): The Critical Calculation 📅

What is BUD?

The Beyond-Use Date (BUD) is the date/time after which a CSP must not be used. It's assigned based on:

• CSP category (1, 2, 3, or Immediate Use)
• Storage temperature
• Available stability/sterility data
• Type of compounding environment

BUD ≠ Expiration date! BUD accounts for sterility risk, not just chemical stability.

BUD Tables (2023 USP <797>)

In a Controlled Environment (ISO Class 5 PEC in ISO Class 7/8 buffer/anteroom):

*2023 revision reduced Category 2 room temp from 12 to 4 hours!

In a Segregated Compounding Area (SCA):

BUD Extension with Testing

Maximum BUDs can be extended beyond table values if:

1. Sterility testing per USP <71> is performed
2. Stability data supports the extended dating (chemical, physical, microbiological)
3. Documented evidence from peer-reviewed literature OR direct testing
4. Quality assurance program validates the process

Example: A hospital compounds batches of morphine 50 mg/mL in 0.9% NaCl. With validated sterility testing and stability data showing no degradation for 90 days refrigerated, they can extend Category 2 BUD from 24 hours to 90 days.

Manufacturer's Expiration Date Rule

BUD cannot exceed:

• The manufacturer's expiration date of any ingredient
• When using a multi-dose vial (MDV): BUD cannot exceed 28 days after opening (or manufacturer's guidance if shorter)

🧠 BUD Hierarchy (most restrictive wins):

         BUD = SHORTEST OF:
              │
    ┌─────────┼─────────┐
    │         │         │
    ▼         ▼         ▼
┌────────┐ ┌────┐ ┌─────────┐
│ Table  │ │MFR │ │ Opened  │
│ Values │ │EXP │ │MDV (28d)│
└────────┘ └────┘ └─────────┘

💡 Pro Tip: If a question gives you stability data, use it! But if no data is provided, default to the table values.

Personnel Requirements & Garbing 👨‍⚕️

Training & Competency

ALL personnel involved in sterile compounding must:

1. Complete initial training on:

   • Aseptic technique
   • Facility-specific SOPs
   • Cleaning and disinfection
   • Garbing procedures
   • Environmental monitoring

2. Pass competency assessments:

   • Media Fill Test (MFT) (also called Process Simulation): Compound using sterile growth medium instead of drugs, then incubate to check for contamination
   • Gloved Fingertip Sampling (GFS): Test gloved fingers after compounding to ensure no contamination
   • Initial assessment: Before compounding independently
   • Annual reassessment: Every 12 months
   • Re-assessment if: Process failure, long absence, or observed poor technique

3. Demonstrate knowledge via written testing on USP <797> requirements

Garbing Order (Critical Sequence!) 🧤

Garbing must occur in the anteroom (or designated area) before entering the buffer room. The order matters:

┌─────────────────────────────────────────────┐
│  ANTEROOM GARBING (in order)               │
├─────────────────────────────────────────────┤
│  1️⃣  Remove outer garments, jewelry        │
│  2️⃣  Don shoe covers                       │
│  3️⃣  Don hair cover (covers all hair)      │
│  4️⃣  Don face mask (covers nose & mouth)   │
│  5️⃣  Perform hand hygiene (wash/sanitize)  │
│  6️⃣  Don non-shedding gown                 │
│  7️⃣  Enter buffer room                      │
│  8️⃣  Perform hand hygiene AGAIN            │
│  9️⃣  Don sterile gloves (over gown cuffs)  │
└─────────────────────────────────────────────┘

🧠 Mnemonic - SHOE HEAD HANDS GOWN GLOVES:

• SHOE covers first (dirtiest)
• HEAD cover (hair/beard)
• HANDS wash (#1)
• GOWN after clean hands
• GLOVES last (after entering buffer room and washing hands again)

⚠️ Key Points:

• Gown cuffs must be tucked inside gloves (prevents skin shedding into CSP)
• Gloves must be sterile and powder-free
• If gloves touch anything non-sterile → re-sanitize or change gloves
• No jewelry, artificial nails, nail polish (harbors bacteria)

Aseptic Technique Fundamentals 🎯

Critical Sites & Critical Areas

Critical Site: Any opening that allows direct contact between CSP and environment

• Needle tips
• Syringe tips
• Vial stoppers
• Ampule necks
• IV bag ports

Critical Area: The ISO Class 5 environment where manipulation occurs (inside PEC)

Golden Rule: NEVER touch or obstruct airflow to a critical site!

Disinfection Protocol

70% Isopropyl Alcohol (IPA) is standard for disinfecting:

1. Vial stoppers: Spray and let air dry (10-30 seconds)
2. Ampules: Swab neck before breaking
3. IV ports: Scrub vigorously for 10-15 seconds
4. Work surfaces: Clean with IPA before/after compounding

⚠️ Common Error: Not allowing adequate drying time! Alcohol needs contact time AND evaporation to be effective.

First Air / Shadow Contamination

HORIZONTAL LAMINAR FLOW (Top View)

 HEPA Filter
━━━━━━━━━━━
 → → → → → →   AIRFLOW (ISO 5)
 → → → → → →
 → → ⊗ ← ← ←   ⊗ = Vial
 → → ↓ → → →   ↓ = SHADOW (contaminated!)
 → → → → → →
━━━━━━━━━━━
 Work Surface

❌ WRONG: Placing sterile item in shadow
✅ RIGHT: Keep critical sites in FIRST AIR
          (direct, uninterrupted HEPA flow)

First Air: The initial, uninterrupted flow of HEPA-filtered air that reaches the critical site

Shadow: The turbulent, contaminated air created when an object blocks first air

💡 Technique: Work from back to front in horizontal flow (items toward filter, manipulation toward you). In vertical flow, don't work directly over open critical sites.

Zone of Turbulence

Any object >1 inch in diameter creates a zone of turbulence extending 3X the object's diameter behind it (in horizontal flow).

Example: A 2-inch diameter bottle creates a 6-inch zone of turbulence behind it.

Spacing Rule: Keep sterile items at least 6 inches apart AND 6 inches from walls of the hood.

Examples: BUD Calculations & Scenarios 📊

Example 1: Category 1 CSP in Controlled Environment

Scenario: A pharmacist prepares a single IV bag by transferring 2 grams of cefazolin (from a previously unopened vial) into a 100 mL 0.9% NaCl bag. The compounding occurs in an ISO Class 5 horizontal laminar flow hood located in an ISO Class 7 buffer room. The CSP will be stored at room temperature.

Question: What is the maximum BUD?

Solution:

Answer: 12 hours

💡 Key Teaching Point: Category 1 + Controlled environment + Room temp = 12 hours (most common scenario)

Example 2: Category 2 CSP with Refrigeration

Scenario: A home infusion pharmacy prepares a batch of 20 TPN bags. Each bag contains dextrose, amino acids, lipids, electrolytes, vitamins, and trace elements from multiple vials. Compounding occurs in an ISO Class 5 BSC within an ISO Class 7 cleanroom. The TPNs will be refrigerated at 4°C and delivered to patients the next day.

Question: What is the maximum BUD for these TPNs?

Solution:

Answer: 24 hours from the time the first bag was started

⚠️ Important: For batch compounding, the BUD clock starts when you begin preparing the FIRST unit, not when you finish the last one!

Example 3: Multi-Dose Vial Limitation

Scenario: A pharmacy receives a 50 mL multi-dose vial of methylprednisolone with an expiration date of December 31, 2025. The vial is opened on March 15, 2025, and stored at room temperature. On April 10, 2025, a pharmacist withdraws medication to prepare a Category 1 CSP that will be refrigerated.

Question: What is the latest BUD for the CSP?

Solution:

Answer: 24 hours from preparation (April 11, 2025 at same time)

💡 Teaching Point: Compare ALL potential limits. If the MDV had only 12 hours left before its 28-day limit, THAT would become the BUD (even though table says 24 hours).

Example 4: Segregated Compounding Area

Scenario: A small community pharmacy installs a compounding aseptic isolator (CAI) with external venting in their regular pharmacy space (unclassified room air). They prepare a simple vancomycin 1g in 250 mL NS bag. The preparation will be stored at room temperature.

Question: What is the maximum BUD, and what category restrictions apply?

Solution:

Answer: 12 hours (same as controlled environment for Category 1, but NO Category 2 or 3 allowed in SCA)

⚠️ Critical Distinction: If this were a TPN (Category 2), it could NOT be prepared in the SCA at all—would need a full controlled environment.

Common Mistakes to Avoid ❌

Mistake #1: Confusing Old vs. New Risk Levels

❌ Wrong: "This is a medium-risk CSP, so the BUD is 30 hours."

✅ Right: "The old Low/Medium/High terminology was replaced in 2023. This is Category 2, so the BUD is 4 hours at room temp or 24 hours refrigerated."

Why it matters: Using outdated standards will result in wrong answers on NAPLEX and unsafe practice.

Mistake #2: Ignoring the Most Restrictive BUD

❌ Wrong: "The USP table says 24 hours refrigerated for Category 1, so that's my BUD."

✅ Right: "I must also check: (1) manufacturer expiration dates of all ingredients, (2) MDV opened date + 28 days, (3) stability data. The SHORTEST of all these becomes my BUD."

Example: If your MDV was opened 27 days ago, you only have 1 day left—even though the table says 24 hours, your actual BUD is 1 day.

Mistake #3: Wrong Garbing Order

❌ Wrong: Gloves → gown → hair cover → shoe covers

✅ Right: Shoe covers → hair cover → mask → hand hygiene → gown → enter buffer room → hand hygiene again → gloves

Why it matters: Contamination! If you put on gloves before your gown, you'll contaminate them when donning the gown. If you don't wash hands between anteroom and buffer room, you bring contamination into the compounding area.

Mistake #4: Misunderstanding Immediate Use

❌ Wrong: "I'm in a hurry, so I'll call this Immediate Use and skip the cleanroom."

✅ Right: "Immediate Use requires a genuine patient emergency AND all 6 criteria must be met. Just being busy doesn't qualify."

Red flags:

• Batching (❌ not allowed for Immediate Use)
• Administration >4 hours later (❌ exceeds time limit)
• Routine scheduled doses (❌ not an emergency)

Mistake #5: Category 2 Room Temperature BUD

❌ Wrong: "Category 2 CSPs can sit at room temp for 12 hours."

✅ Right: "As of the 2023 revision, Category 2 at room temp is only 4 hours (down from 12). Refrigeration extends it to 24 hours."

Pro tip: This is a HIGH-YIELD change for NAPLEX. Expect questions testing whether you know the updated timeframe!

Mistake #6: Touching Critical Sites

❌ Wrong: Steadying a needle by holding the tip, touching vial stopper with gloved finger, allowing syringe tip to touch the hood surface.

✅ Right: Critical sites must NEVER be touched. Use proper technique: hold needle by hub, never touch disinfected stoppers after cleaning, keep syringe tips pointed up or in first air.

Mistake #7: Shadow Zone Contamination

❌ Wrong: In a horizontal flow hood, placing a vial downwind (toward you) and then manipulating a syringe directly behind it.

✅ Right: Items should be spaced ≥6 inches apart. Critical sites must be in direct HEPA airflow (first air), not in the turbulent shadow created by other objects.

❌ CONTAMINATED SETUP:
HEPA → → → [Vial] ← ← [Syringe]
                    ↑
              Shadow zone!

✅ CORRECT SETUP:
HEPA → → → [Syringe]    [Vial]
           (6" spacing minimum)

Key Takeaways 🎯

Memory Aid: The Sterile Compounding Checklist 📝

Before compounding ANY sterile preparation, mentally run through this checklist:

✅ ENVIRONMENT: Am I in the right ISO class for this category?

✅ GARBING: Did I follow the correct sequence and technique?

✅ EQUIPMENT: Is my PEC certified and running? Pre-cleaned?

✅ MATERIALS: Are all ingredients within expiration? MDVs within 28 days?

✅ TECHNIQUE: Am I maintaining first air? Not touching critical sites?

✅ DOCUMENTATION: Label with date, time, preparer initials, BUD?

✅ BUD: Did I calculate using the most restrictive limit?

📚 Further Study

1. USP Chapter 797 Official Text: USP.org - USP <797> - The authoritative source; review the 2023 revision highlights

2. ASHP Sterile Compounding Resources: ASHP.org - Compounding Resource Center - Includes practice guidelines, FAQs, and case studies

3. FDA Compounding Guidance: FDA.gov - Human Drug Compounding - Regulatory perspective and enforcement priorities

🎓 You've completed Sterile Compounding & BUD! This is one of the highest-yield topics for NAPLEX—master these BUD tables and category classifications, and you'll confidently handle any sterile compounding question on exam day. Practice with the flashcards above, and don't forget to review the common mistakes section before your test! 💪