10.1 Tennessee Board Rule 1140-07 & Sterile Product Preparation

10.1 Tennessee Board Rule 1140-07 & Sterile Product Preparation

Quick Answer: Under Tenn. Comp. R. & Regs. Chapter 1140-07, any pharmacy compounding sterile preparations in Tennessee must prepare them within a certified ISO Class 5 Primary Engineering Control (PEC) located in an ISO Class 7 buffer room, supported by an ISO Class 7 or 8 anteroom. For non-hazardous compounding, a continuous positive pressure differential of 0.02 to 0.05 inches of water column must be maintained from the buffer area to the anteroom, accompanied by at least 30 air changes per hour (ACPH). All PECs and cleanroom facilities must be recertified at least every six (6) months by an authorized certifier. Personnel garbing follows an unforgiving dirtiest-to-cleanest sequence prior to crossing the line of demarcation. Initial personnel qualification requires three consecutive gloved fingertip samples with 0 CFUs and three successful media-fill runs, with ongoing re-testing at least every 6 months for Category 1 and Category 2 compounding and at least every 3 months for Category 3 compounding.

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1. Statutory Architecture & Scope of Board Rule Chapter 1140-07

Sterile compounding represents one of the highest-liability practice domains in pharmacy jurisprudence. In Tennessee, the compounding, preparation, labeling, and dispensing of sterile medications are strictly regulated by the Tennessee Board of Pharmacy under Tenn. Comp. R. & Regs. Chapter 1140-07 ("Sterile Product Preparation"), authorized pursuant to the Tennessee Pharmacy Practice Act of 1996 (T.C.A. Title 63, Chapter 10).

Board Rule Chapter 1140-07 applies to all pharmacy practice sites that prepare sterile products, including:

• Community retail compounding pharmacies preparing outpatient sterile infusions;
• Institutional, hospital, and clinic pharmacies preparing intravenous admixtures, parenteral nutrition, epidural injections, and ophthalmic solutions;
• Nuclear pharmacies preparing radiopharmaceuticals;
• Out-of-state mail-order pharmacies licensed by the Tennessee Board that ship sterile preparations to patients or healthcare facilities located within Tennessee.

┌─────────────────────────────────────────────────────────────────────────────┐
│               TENNESSEE STERILE COMPOUNDING REGULATORY PYRAMID              │
├─────────────────────────────────────────────────────────────────────────────┤
│ FEDERAL LEVEL:                                                              │
│   • FD&C Act Section 503A (Traditional Compounding Exemptions)              │
│   • USP General Chapter <797> (Sterile Preparations - Federally Enforceable)│
│   • USP General Chapter <800> (Hazardous Drug Handling Standards)           │
├─────────────────────────────────────────────────────────────────────────────┤
│ TENNESSEE STATE LEVEL:                                                      │
│   • T.C.A. Title 63, Chapter 10 (Tennessee Pharmacy Practice Act)           │
│   • Tenn. Comp. R. & Regs. Chapter 1140-07 (Sterile Product Preparation)    │
│   • Tenn. Comp. R. & Regs. Chapter 1140-09 (Outsourcing Facilities / 503B)  │
│   • Tennessee Board Policy Statements & Declaratory Orders                  │
└─────────────────────────────────────────────────────────────────────────────┘

[!IMPORTANT] Under Tennessee law, compliance with USP <797> standards is not merely recommended best practice—it is an express regulatory mandate incorporated by reference into Board Rule Chapter 1140-07. A violation of USP <797> standards constitutes an independent violation of Tennessee pharmacy law, subjecting both the pharmacy license and individual pharmacist license to disciplinary revocation, suspension, or civil monetary penalties.

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2. Cleanroom Architecture & ISO Particulate Standards

The fundamental goal of cleanroom engineering is the systematic exclusion and elimination of non-viable particulates and viable microbial bioburden from the compounding environment. Air cleanliness is quantified using International Organization for Standardization (ISO) standards based on the maximum allowable number of particles 0.5 μm or larger per cubic meter (or cubic foot) of air.

Air Cleanliness Classification Standards

Differential Pressure & Airflow Dynamics

Cleanroom suites maintain particulate control through pressure differentials that dictate the physical direction of air velocity:

1. Positive Pressure Regimes (Non-Hazardous Compounding):

   • The buffer room must be maintained under continuous positive pressure relative to the anteroom.
   • The anteroom must be maintained under positive pressure relative to the unclassified outer pharmacy.
   • Statutory Pressure Differential: Continuous differential pressure of at least +0.02 to +0.05 inches of water column (+5 to +12.5 Pascals) must be maintained across each room boundary.
   • Operational Purpose: Ensures that when access doors are opened, clean, HEPA-filtered air flows outwards, physically preventing particulate-laden air from intruding into cleaner zones.

2. Negative Pressure Regimes (Hazardous Drug Compounding under USP 800):

   • Hazardous drug compounding suites require negative pressure of -0.01 to -0.03 inches of water column (-2.5 to -7.5 Pascals) in the Containment Secondary Engineering Control (C-SEC) buffer room to prevent hazardous aerosol escape.
   • Because the buffer area is negative, the adjoining anteroom must maintain ISO Class 7 air cleanliness (rather than ISO Class 8) with at least 30 ACPH to prevent particulate influx.

NON-HAZARDOUS POSITIVE PRESSURE GRADIENT:
┌──────────────────────┐    +0.02 to +0.05 in. w.c.    ┌──────────────────────┐    +0.02 to +0.05 in. w.c.    ┌──────────────────────┐
│  UNCLASSIFIED AREA   │ ───────────────────────────> │  ISO CLASS 7/8 ANTE  │ ───────────────────────────> │  ISO CLASS 7 BUFFER  │
│ (General Pharmacy)   │ <═══════════════════════════ │      ROOM SUITE      │ <═══════════════════════════ │      ROOM SUITE      │
│   (Ambient Air)      │     (Outward Clean Air)      │ (Garbing & Washing)  │     (Outward Clean Air)      │  (ISO 5 PEC Inside)  │
└──────────────────────┘                              └──────────────────────┘                              └──────────────────────┘

Environmental Monitoring & Cleanroom Climate

• Continuous Pressure Gauges: Cleanroom pressure differentials must be monitored continuously using a calibrated magnehelic gauge or digital pressure sensor. Readings must be physically checked and logged on a daily operating log (or on every day compounding occurs).
• Cleanroom Temperature: The buffer room must be maintained at 20°C (68°F) or cooler to reduce worker perspiration and curtail shedding of microbial skin squames.
• Cleanroom Humidity: Relative humidity must be maintained below 60% at all times to prevent fungal and bacterial spore proliferation.

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3. Engineering Controls: Primary & Secondary Devices

Tennessee Board Rule Chapter 1140-07 establishes clear distinctions between Primary and Secondary Engineering Controls.

┌─────────────────────────────────────────────────────────────────────────────┐
│                PRIMARY VS SECONDARY ENGINEERING CONTROL MATRIX              │
├──────────────────────────┬──────────────────────────────────────────────────┤
│ Engineering Control Type │ Regulatory Classification & Operational Function │
├──────────────────────────┼──────────────────────────────────────────────────┤
│ Laminar Airflow          │ ISO Class 5 PEC; horizontal or vertical laminar  │
│ Workbench (LAFW)         │ airflow; for NON-HAZARDOUS sterile compounding.  │
├──────────────────────────┼──────────────────────────────────────────────────┤
│ Biological Safety        │ ISO Class 5 PEC; vertical laminar flow, HEPA     │
│ Cabinet (BSC)            │ filtered exhaust; Class II Type A2/B2 for HDs.   │
├──────────────────────────┼──────────────────────────────────────────────────┤
│ Compounding Aseptic      │ ISO Class 5 PEC; positive pressure glove box;    │
│ Isolator (CAI)           │ uses unidirectional HEPA air for non-hazardous.  │
├──────────────────────────┼──────────────────────────────────────────────────┤
│ Compounding Aseptic      │ ISO Class 5 PEC; negative pressure glove box;    │
│ Containment Isolator     │ 100% externally vented for hazardous drugs.      │
├──────────────────────────┼──────────────────────────────────────────────────┤
│ Buffer Room (SEC)        │ ISO Class 7 cleanroom housing the PECs; no sinks │
│                          │ or floor drains permitted; non-porous surfaces.  │
├──────────────────────────┼──────────────────────────────────────────────────┤
│ Anteroom (SEC)           │ ISO Class 7 or 8 room for staging, garbing, and  │
│                          │ handwashing; contains line of demarcation.       │
└──────────────────────────┴──────────────────────────────────────────────────┘

Critical Rules for Cleanroom Architecture

1. No Sinks or Drains in Buffer Room: Under Rule 1140-07 and USP <797>, water sinks and floor drains are strictly prohibited inside the ISO Class 7 buffer room. Sinks introduce moisture, biofilms, and microbial reservoirs (e.g., Pseudomonas aeruginosa). Sinks must be located exclusively in the anteroom, on the "dirty" side of the line of demarcation.
2. Surfaces and Finishes: Walls, ceilings, floors, fixtures, shelving, and work surfaces must be smooth, seamless, non-shedding, non-porous, and resistant to damage from sanitizing and sporicidal cleaning agents.
3. Line of Demarcation: The anteroom floor must feature a visible, clearly delineated line of demarcation physically separating the clean side (leading into the buffer room) from the less-clean side (entry from the unclassified pharmacy).

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4. Recertification & Environmental Monitoring Protocol

Under Tennessee Board Rule 1140-07-.06, cleanrooms and engineering controls are subject to rigorous semi-annual recertification and routine microbiological surveillance.

Semi-Annual Engineering Recertification

All Primary Engineering Controls (LAFWs, BSCs, CAIs, CACIs) and Secondary Engineering Controls (buffer suites, anterooms) must undergo full mechanical and particulate recertification at least every six (6) months by an authorized, qualified certification technician.

Mandatory Triggers for Immediate Recertification:

• Scheduled 6-month interval expiration;
• Physical relocation of any Primary Engineering Control (even moving a hood a few inches across the room);
• Major structural repairs, ductwork alterations, or cleanroom architectural modifications;
• Following HEPA filter replacement or motor/blower repairs.

Viable & Non-Viable Environmental Monitoring Cadence

[!NOTE] If environmental monitoring reveals any pathogenic microbial growth (e.g., Gram-negative rods, coagulase-positive staphylococci, molds, or yeasts), immediate remediation is legally required regardless of the numerical CFU count. Compounding must cease until the root cause is identified, extensive sporicidal decontamination is performed, and follow-up sampling shows zero growth.

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5. Personnel Garbing, Hand Hygiene & Staging Sequence

Personnel shedding of skin scales, respiratory droplets, and hair represents the primary vector of microbial contamination in sterile compounding. Board Rule Chapter 1140-07 and USP <797> mandate an unforgiving, step-by-step garbing and hand hygiene sequence executed in order from dirtiest to cleanest.

┌─────────────────────────────────────────────────────────────────────────────┐
│                     MANDATORY GARBING & HYGIENE SEQUENCE                    │
├─────────────────────────────────────────────────────────────────────────────┤
│ STEP 1: PRE-ENTRY SANITATION (Outer Unclassified Area)                      │
│ • Remove outer garments (jackets, sweaters), watches, rings, jewelry.       │
│ • No cosmetics, artificial nails, chipped polish, or visible piercings.     │
│                                                                             │
│ STEP 2: ANTE-AREA DIRTIEST APPAREL (Dirty Side of Line of Demarcation)      │
│ • Don dedicated shoe covers (one foot at a time over line of demarcation).  │
│ • Don head/hair cover (tuck in all cranial hair completely).                │
│ • Don facial hair cover (beard/mustache cover if facial hair present).      │
│ • Don face mask and eye protection (if required).                           │
│                                                                             │
│ STEP 3: ANTE-AREA HAND HYGIENE (At the Anteroom Sink)                       │
│ • Wash hands and forearms up to elbows with warm water and soap.             │
│ • Vigorously scrub for at least THIRTY (30) SECONDS.                        │
│ • Clean under fingernails with a disposable nail cleaner.                   │
│ • Dry hands completely with lint-free disposable wipes or electronic dryer. │
│                                                                             │
│ STEP 4: GOWNING (Clean Side of Anteroom)                                    │
│ • Don non-shedding, lint-free gown with snug cuffs and enclosed neck.       │
│                                                                             │
│ STEP 5: BUFFER ROOM ENTRY & STERILE GLOVES (Inside ISO Class 7 Buffer Room) │
│ • Enter buffer room; apply sterile 70% IPA to hands and allow to dry.       │
│ • Don STERILE, powder-free gloves (cuffs of gloves must pull OVER gown).    │
│ • Sanitize sterile gloves with sterile 70% IPA prior to working in PEC.     │
└─────────────────────────────────────────────────────────────────────────────┘

Critical Garbing Rules

• Order of Garb: Shoe covers → Head cover → Facial hair cover → Face mask → Hand wash → Gown → Sterile gloves.
• Glove Placement: Compounding gloves must be sterile and powder-free. They must be donned inside the buffer room (or the clean side of the ante-area) and pulled completely over the knitted cuffs of the gown to prevent bare skin exposure.
• Routine Sanitization: Gloves must be sanitized with sterile 70% Isopropyl Alcohol (IPA) and allowed to air dry completely before entering the PEC, after touching non-sterile items (vial caps, calculation sheets), and frequently throughout the compounding session.

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6. Personnel Qualification: Gloved Fingertip & Media-Fill Testing

No pharmacist, intern, or technician may compound sterile preparations in Tennessee without successfully completing initial and ongoing competency qualification under Board Rule 1140-07-.05.

┌─────────────────────────────────────────────────────────────────────────────┐
│               PERSONNEL COMPETENCY EVALUATION & TESTING CADENCE             │
├──────────────────────────┬──────────────────────────────────────────────────┤
│ Competency Assessment    │ Frequency & Regulatory Passing Standard          │
├──────────────────────────┼──────────────────────────────────────────────────┤
│ Initial Gloved           │ THREE (3) consecutive samples immediately after  │
│ Fingertip Testing        │ garbing; ZERO (0) CFUs total for BOTH hands on   │
│                          │ every sample plate (3 tests = 6 plates = 0 CFU). │
├──────────────────────────┼──────────────────────────────────────────────────┤
│ Ongoing Gloved           │ Category 1 and 2: At least EVERY 6 MONTHS.       │
│ Fingertip Testing        │ Category 3: At least EVERY 3 MONTHS.             │
│                          │ Action Level: > 3 CFUs total for both hands.     │
├──────────────────────────┼──────────────────────────────────────────────────┤
│ Initial Media-Fill       │ THREE (3) consecutive successful runs simulating │
│ Testing                  │ most complex manipulations; ZERO growth (turbid).│
├──────────────────────────┼──────────────────────────────────────────────────┤
│ Ongoing Media-Fill       │ Category 1 and 2: At least EVERY 6 MONTHS.       │
│ Testing                  │ Category 3: At least EVERY 3 MONTHS.             │
│                          │ Incubation: 14 days; passing = 100% sterile.     │
└──────────────────────────┴──────────────────────────────────────────────────┘

Testing Mechanics & Incubation Protocol

1. Gloved Fingertip Testing:
   • Conducted immediately following the completion of full garbing and hand hygiene.
   • Crucial Rule: The compounder must NOT apply 70% sterile IPA to gloves immediately prior to touching the agar plates, as alcohol would artificially destroy viable organisms and mask improper garbing technique.
   • Each hand touches a separate nutrient agar plate (tryptic soy agar with neutralizers). Both hands must show 0 CFUs across 3 consecutive tests during initial qualification.
2. Media-Fill Testing:
   • Simulates the most difficult, labor-intensive aseptic compounding procedures performed at that practice site using sterile growth medium (Soybean-Casein Digest / Tryptic Soy Broth).
   • Must replicate the actual number of transfers, ampul openings, syringe manipulations, and filter attachments.
   • 14-Day Incubation Mandate: Media-fill containers are incubated for a total of 14 consecutive days (e.g., 7 days at controlled room temperature 20°C–25°C to foster fungal/yeast growth, followed by 7 days at 30°C–35°C to promote bacterial growth).
   • Passing Standard: Absolutely zero turbidity or visible microbial growth across all units. Any cloudiness constitutes immediate failure.
3. Failure Remediation: An employee who fails a media-fill or gloved fingertip re-test must immediately cease compounding sterile preparations, undergo retraining in garbing and aseptic technique, and pass three consecutive gloved fingertip tests and a new media-fill evaluation before compounding privileges are restored.

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7. Sterilization Methods & Depyrogenation for High-Risk CSPs

When a compounding pharmacy prepares a sterile preparation using non-sterile bulk starting materials (such as chemical powders or non-sterile components) or uses non-sterile equipment, the preparation must be sterilized using a validated method.

Sterilization Modalities (USP <797> & Board Rule 1140-07)

| Sterilization Method | Mechanism & Parameters | Applications & Critical Verification | | :--- | :--- | :--- | :--- | | 0.22-Micron Membrane Filtration | Physical exclusion of microorganisms through a sterile, pyrogen-free 0.22-μm pore membrane | Thermolabile liquid solutions that degrade under heat; requires post-use Bubble Point Integrity Testing. | | Moist Heat (Steam / Autoclaving) | Coagulation and denaturation of microbial proteins via saturated steam under pressure (121°C at 15 psi for ≥ 20–30 min) | Thermostable aqueous solutions, glass containers, surgical instruments; verified using biological indicators (Geobacillus stearothermophilus). | | Dry Heat Depyrogenation & Sterilization | Oxidative destruction of cellular constituents via high-temperature dry air (≥ 250°C for ≥ 30 min) | Anhydrous oils, dry powders, glassware, metal equipment; destroys bacterial endotoxins (pyrogens); verified with Bacillus atrophaeus. |

The Bubble Point Integrity Test

When sterile filtration is utilized for terminal sterilization, the compounder must verify that the filter membrane remained intact throughout the filtration cycle:

• The filter is subjected to increasing gas pressure until gas bubbles break through the wetted membrane pores.
• If the membrane withstands pressure up to the manufacturer's specified bubble point threshold, the filter is validated as intact.
• If the filter fails the bubble point test (bubbles appear at sub-threshold pressure), the membrane was breached or ruptured during processing. The entire batch is deemed non-sterile, must be rejected, and cannot be dispensed.

Bacterial Endotoxin (Pyrogen) Testing

• Non-sterile active pharmaceutical ingredients (APIs) often harbor bacterial endotoxins (lipopolysaccharides shed from Gram-negative bacterial cell walls).
• Endotoxins are pyrogenic (induce severe fever, shock, and hemodynamic collapse) and are NOT removed by 0.22-micron filtration or destroyed by standard autoclaving.
• High-risk preparations prepared from non-sterile bulk powders for parenteral administration must undergo Bacterial Endotoxins Testing (BET) utilizing the Limulus Amebocyte Lysate (LAL) assay prior to patient administration.

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8. Quality Assurance, Policies & Procedures, and Documentation

Under Tenn. Comp. R. & Regs. 1140-07-.03 and .04:

1. Policy and Procedure Manual: Every sterile compounding pharmacy must maintain a comprehensive, site-specific Policy and Procedure (P&P) manual detailing garbing, environmental monitoring, calibration, cleaning, storage, and recall procedures. The P&P manual must be reviewed, signed, and dated annually by the Pharmacist-in-Charge (PIC).
2. Record Retention: In Tennessee, all compounding records, environmental test logs, certification reports, refrigerator/freezer temperature logs, pressure differential sheets, and personnel training files must be retained for at least two (2) years and be readily retrievable for Board inspection.
3. Sterile Product Labeling (Rule 1140-07-.07): In addition to standard prescription labeling mandates, sterile compounded preparations must display:
   • Patient name (if outpatient) or specific patient identifier/location (if institutional inpatient);
   • Prescriber name;
   • Pharmacy name, address, and telephone number;
   • Date and time of compounding;
   • Assigned Beyond-Use Date (BUD) and exact time of expiration;
   • Names, strengths, and quantities of all active ingredients and vehicles/diluents;
   • Total volume and intended route of administration;
   • Infusion rate (if intravenous infusion);
   • Storage instructions and required auxiliary warning labels (e.g., "Refrigerate", "Do Not Freeze", "Protect from Light", "Chemotherapy - Handle with Caution");
   • Identification/initials of the compounding technician and the verifying licensed pharmacist.

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9. Practical Exam Scenarios

Scenario 1: Magnehelic Gauge Out of Range

Case: On Monday morning, a staff pharmacist in Memphis arrives to prepare intravenous total parenteral nutrition (TPN). Upon inspecting the magnehelic pressure gauge between the ISO Class 7 buffer room and the ISO Class 7 anteroom, the reading displays +0.005 inches of water column (standard specification is +0.02 to +0.05 inches). Compounding orders are pending. Legal Analysis: Under Tenn. Comp. R. & Regs. 1140-07, the buffer area must maintain a positive pressure differential of at least +0.02 inches of water column to prevent outside air intrusion. A reading of +0.005 indicates a failure of the secondary engineering control airflow regime. Compounding must not proceed. The pharmacist must immediately notify facilities/maintenance to investigate the HVAC failure, log the deviation, and re-establish compliant pressure (≥0.02 in. w.c.) before any sterile preparations may be compounded.

Scenario 2: Gloved Fingertip Failure During Semi-Annual Testing

Case: During scheduled semi-annual competency evaluations, an experienced sterile compounding technician completes a gloved fingertip test following garbing. After 48 hours of incubation, the agar plates for the right hand show 4 CFUs of Staphylococcus epidermidis. Legal Analysis: For ongoing gloved fingertip testing, the regulatory action threshold is >3 CFUs total for both hands. A count of 4 CFUs on one hand exceeds the allowable threshold. The technician must be immediately suspended from sterile compounding duties. The technician must receive remedial training in hand hygiene and garbing, and must subsequently achieve three consecutive gloved fingertip tests with zero (0) CFUs before sterile compounding privileges can be restored.

Scenario 3: Bubble Point Failure on Sterilized Ophthalmic Solution

Case: A compounding pharmacy prepares a 50-mL batch of fortified tobramycin 15 mg/mL ophthalmic solution using non-sterile tobramycin powder. The solution is passed through a sterile 0.22-micron polyethersulfone filter into sterile dropper bottles. Following the procedure, the pharmacist performs a bubble point integrity test. The manufacturer specifies a minimum bubble point pressure of 50 psi, but bubbling occurs vigorously at 32 psi. Legal Analysis: Under USP <797> and Board Rule 1140-07, passing the bubble point integrity test is a statutory prerequisite to validate filter integrity. Bubbling at 32 psi confirms that the filter membrane was structurally compromised or torn during filtration. The entire batch is legally defective and deemed unsterile. The batch cannot be dispensed, must be destroyed, and must be re-compounded with a fresh, intact filter assembly.