12.2 USP Non-Sterile (795), Sterile (797) & Hazardous (800) Compounding
Key Takeaways
- Section 503A traditional compounding involves patient-specific prescriptions, falls under State Board of Pharmacy jurisdiction, and is exempt from FDA CGMP and premarket approval; Section 503B outsourcing facilities compound sterile batches without individual prescriptions, register with the FDA, and must strictly follow Current Good Manufacturing Practice (CGMP).
- Under USP <795>, the Master Formulation Record (MFR) is the permanent compounding recipe, while the Compounding Record (CR) is the execution log for each specific batch; default Beyond-Use Dates (BUDs) in the absence of stability data are: non-preserved aqueous (14 days refrigerated), preserved aqueous (35 days room temp/refrigerated), non-aqueous dosage forms (90 days room temp), and solid dosage forms (180 days room temp).
- Under USP <797>, sterile compounding requires an ISO Class 5 Primary Engineering Control (PEC) located in an ISO Class 7 Buffer Room, accessed via an ISO Class 7 or 8 Anteroom maintained under positive pressure (>= 0.020 inch water column) for non-hazardous preparations.
- Initial personnel qualification for sterile compounding mandates three consecutive gloved fingertip tests with zero CFUs, followed by media-fill and gloved fingertip testing every 6 months for Category 2 CSPs and annually for Category 1 CSPs.
- Under USP <800>, hazardous drugs (HDs) listed by NIOSH must be stored and compounded in negative pressure environments (-0.010 to -0.030 inch water column) with >= 12 to 30 air changes per hour (ACPH) externally vented, utilizing ASTM D6978 chemotherapy gloves, impermeable gowns, Closed System Drug-Transfer Devices (CSTDs), and environmental surface wipe sampling every 6 months.
Last updated: August 2026
12.2 USP Non-Sterile (795), Sterile (797) & Hazardous (800) Compounding
In the Commonwealth of Kentucky, pharmaceutical compounding is governed by 201 KAR 2:076, which expressly adopts and enforces the standards established by the United States Pharmacopeia (USP) General Chapters: USP <795> (Pharmaceutical Compounding — Nonsterile Preparations), USP <797> (Pharmaceutical Compounding — Sterile Preparations), and USP <800> (Hazardous Drugs — Handling in Healthcare Settings). Concurrently, the federal Drug Quality and Security Act (DQSA) of 2013 delineates traditional pharmacy compounding from commercial outsourcing manufacturing under Sections 503A and 503B of the Food, Drug, and Cosmetic Act (FD&C Act).
1. Federal Compounding Architecture: 503A vs. 503B Outsourcing Facilities
Enacted following the 2012 fungal meningitis outbreak caused by contaminated compounded steroids from the New England Compounding Center (NECC), the DQSA created a clear two-tier regulatory structure:
┌─────────────────────────────────────────────────────────────────────────────┐
│ FDA COMPOSITE REGULATORY DUALITY │
├─────────────────────────────────────┬───────────────────────────────────────┤
│ Section 503A: Traditional Pharmacy │ Section 503B: Outsourcing Facility │
│ • State Board of Pharmacy Primary │ • FDA Direct Regulatory Oversight │
│ • Patient-Specific Prescription Req │ • Non-Patient Specific (Office Use) │
│ • Exempt from CGMP & FDA Labeling │ • Strict CGMP Compliance (21 CFR 211) │
│ • USP <795>, <797>, <800> Standards │ • Routine FDA Risk-Based Inspections │
└─────────────────────────────────────┴───────────────────────────────────────┘
Comprehensive 503A vs. 503B Comparative Analysis
| Regulatory Parameter | 503A Traditional Compounding Pharmacy | 503B Outsourcing Facility |
|---|---|---|
| Governing Statute | Section 503A of the FD&C Act (21 U.S.C. § 353a) | Section 503B of the FD&C Act (21 U.S.C. § 353b) |
| Primary Regulator | Kentucky Board of Pharmacy (KBOP) (State jurisdiction) | Food and Drug Administration (FDA) (Federal jurisdiction) |
| Prescription Requirement | Patient-Specific Prescription Required (Limited anticipatory batch compounding allowed based on historical prescribing patterns). | No Patient-Specific Prescription Required. May compound large batches for "office use" and hospital health-system distribution. |
| Current Good Manufacturing Practice (CGMP) | EXEMPT from CGMP requirements (21 CFR Parts 210/211). Governed by USP compounding standards. | SUBJECT TO FULL CGMP COMPLIANCE (Rigorous validation, cleanroom monitoring, analytical testing). |
| FDA Premarket Approval & Labeling | EXEMPT from New Drug Application (NDA) premarket approval and standard commercial labeling rules. | EXEMPT from NDA premarket approval and adequate directions for use; must meet specialized 503B container labeling. |
| Compounding Standards | Must strictly comply with USP <795>, USP <797>, and USP <800> via 201 KAR 2:076. | Must comply with FDA CGMP (exceeds USP baselines) and USP standards where applicable. |
| Interstate Distribution | Capped at 5% of total prescription orders distributed out-of-state, unless state enters FDA Standard Memorandum of Understanding (MOU). | Unlimited interstate distribution permitted across all states where the facility holds appropriate outsourcing permits. |
| Reporting Requirements | Standard state dispensing and KASPER reporting where applicable. | Mandatory biannual reporting to FDA listing all drugs compounded, active ingredients, strengths, and package counts. |
| Kentucky Licensure | Must hold Kentucky Retail or Institutional Pharmacy Permit. | Must hold Kentucky permit / registration as an Outsourcing Facility. |
2. USP <795> Non-Sterile Compounding Standards
USP General Chapter <795> establishes mandatory quality standards for compounding non-sterile preparations (e.g., oral suspensions, topical creams, ointments, capsules, suppositories, and troches).
Master Formulation Record (MFR) vs. Compounding Record (CR)
A central requirement of USP <795> (and USP <797>) is the strict separation between the compounding recipe and the execution log:
- Master Formulation Record (MFR): The standard, permanent "master recipe" created before compounding a preparation for the first time. It details the official drug name, strength, dosage form, calculation methods, exact ingredient specifications and quality grades (USP/NF grade required), compounding equipment, step-by-step preparation instructions, container/closure systems, quality control procedures, and designated Beyond-Use Date (BUD) with scientific literature rationale.
- Compounding Record (CR): The individual "batch execution log" generated each time a compound is prepared. It documents the specific MFR reference, actual manufacturer lot numbers, expiration dates, and exact quantities weighed/measured for each component, total final yield, internal batch/prescription number, assigned BUD and storage conditions, quality control check results (e.g., pH, appearance, weight variation), and the signatures or initials of the compounding technician/intern and the verifying licensed pharmacist.
USP <795> Default Beyond-Use Dating (BUD) Framework
In the absence of a published stability study or manufacturer chemical stability data, pharmacists must assign Beyond-Use Dates (BUDs) strictly based on dosage form characteristics and water activity ($a_w$):
┌─────────────────────────────────────────────────────────────────────────────┐
│ USP <795> DEFAULT BEYOND-USE DATES │
├──────────────────────────────────────┬──────────────────────────────────────┤
│ Non-Preserved Aqueous Dosage Forms │ 14 Days (Refrigerated: 2°C to 8°C) │
│ (Oral solutions, suspensions, gels) │ │
├──────────────────────────────────────┼──────────────────────────────────────┤
│ Preserved Aqueous Dosage Forms │ 35 Days (Controlled Room Temp or Refr)│
│ (Preserved lotions, creams, gels) │ │
├──────────────────────────────────────┼──────────────────────────────────────┤
│ Non-Aqueous Dosage Forms │ 90 Days (Controlled Room Temp or Refr)│
│ (Anhydrous ointments, suppositories) │ │
├──────────────────────────────────────┼──────────────────────────────────────┤
│ Solid Dosage Forms │ 180 Days (Controlled Room Temp) │
│ (Capsules, tablets, powders, troches)│ │
└──────────────────────────────────────┴──────────────────────────────────────┘
Critical Rule — Ingredient Expiration Boundary: The Beyond-Use Date (BUD) assigned to a compounded non-sterile preparation can NEVER exceed the shortest expiration date of any individual active pharmaceutical ingredient (API) or raw component used in the formulation. If an active powder expires in 20 days, a solid capsule compound's BUD is capped at 20 days (not 180 days).
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3. USP <797> Sterile Compounding Standards
USP General Chapter <797> governs the compounding of sterile preparations (CSPs), including intravenous infusions, epidurals, ophthalmic solutions/ointments, intrathecal injections, and parenteral nutrition.
Cleanroom Engineering Controls & ISO Classifications
Sterile compounding environments rely on strict hierarchical airborne particulate cleanliness defined by the International Organization for Standardization (ISO):
| Cleanroom Zone | Maximum Particle Count ($\ge 0.5\ \mu\text{m}/\text{m}^3$) | ISO Classification | Minimum Air Changes Per Hour (ACPH) | Operational Purpose & Airflow |
|---|---|---|---|---|
| Primary Engineering Control (PEC) | 3,520 | ISO Class 5 | Unidirectional laminar flow (90 ft/min $\pm 20%$) | Laminar Airflow Workstation (LAFW), Biological Safety Cabinet (BSC), Compounding Aseptic Isolator (CAI). Provides "First Air" at critical compounding site. |
| Buffer Area (Cleanroom) | 352,000 | ISO Class 7 | $\ge 30\text{ ACPH}$ (with $\ge 15\text{ ACPH}$ HEPA filtered) | Area housing the ISO 5 PECs. Staging of sterile items only. Positive pressure relative to anteroom. |
| Anteroom (Positive Buffer Access) | 3,520,000 | ISO Class 8 | $\ge 20\text{ ACPH}$ | Area for hand hygiene, garbing, staging, and package decontamination prior to buffer entry. |
| Anteroom (Negative Buffer Access) | 352,000 | ISO Class 7 | $\ge 30\text{ ACPH}$ | Required anteroom classification when opening into a negative-pressure hazardous drug buffer room. |
| Segregated Compounding Area (SCA) | Unclassified | Unclassified | Ambient | Dedicated room housing an ISO 5 PEC without a cleanroom buffer suite. Restricted strictly to Category 1 CSPs. |
Pressure Differential Standards (Non-Hazardous Sterile Compounding)
- Cleanroom suites must maintain a continuous positive pressure differential of +0.020 to +0.050 inches of water column (+5.0 to +12.5 Pa) from the ISO 7 Buffer Area to the Anteroom, and from the Anteroom to unclassified general pharmacy areas.
- Pressure differentials must be monitored and logged at least once daily using a calibrated magnehelic gauge or continuous digital monitoring system.
Personnel Qualification, Testing & Garbing (Dirty to Clean Sequence)
- Gloved Fingertip and Thumb Sampling:
- Initial Qualification: Compounding personnel must successfully complete three (3) consecutive gloved fingertip tests with zero (0) Colony Forming Units (CFUs) on both hands immediately following hand hygiene and sterile garbing.
- Requalification Frequency: Every 6 months for Category 2 and Category 3 CSPs; every 12 months for Category 1 CSPs (action level > 3 CFUs total for both hands).
- Media-Fill Testing:
- Simulates the most complex compounding operations using sterile tryptic soy broth (soybean-casein digest medium).
- Performed initially and every 6 months for Category 2 CSPs (annually for Category 1 CSPs). Incubated for 14 days; any microbial turbidity constitutes failure.
- Mandatory Garbing Sequence (Dirty to Clean):
- Dedicated shoe covers (donned over step-over line) $\rightarrow$ Head and facial hair covers $\rightarrow$ Face mask / eye shield $\rightarrow$ Perform 30-second antiseptic hand wash up to elbows with warm water and soap $\rightarrow$ Dry with lint-free towels $\rightarrow$ Don non-shedding gown with snug cuffs $\rightarrow$ Apply alcohol hand rub $\rightarrow$ Don sterile powder-free gloves (cuffs pulled over gown sleeves) $\rightarrow$ Sanitize gloves with sterile 70% Isopropyl Alcohol (IPA).
Compounded Sterile Preparation (CSP) Categories & Beyond-Use Dating
┌─────────────────────────────────────────────────────────────────────────────┐
│ USP <797> CSP CATEGORY BUD SUMMARY │
├─────────────────────────────────────────────────────────────────────────────┤
│ Category 1 CSPs (Compounded in SCA or ISO 5 PEC outside cleanroom suite): │
│ • Controlled Room Temp (20°C to 25°C): <= 12 Hours │
│ • Refrigerated (2°C to 8°C): <= 24 Hours │
│ • Frozen (-25°C to -10°C): NOT PERMITTED │
├─────────────────────────────────────────────────────────────────────────────┤
│ Category 2 CSPs (Compounded in ISO 5 PEC inside ISO 7 Buffer / ISO 8 Ante): │
│ • Aseptically prepared (Sterile starting components, NO sterility testing): │
│ - Controlled Room Temp: 4 Days │
│ - Refrigerated (2°C to 8°C): 10 Days │
│ - Frozen (-25°C to -10°C): 45 Days │
│ • Aseptically prepared (>= 1 Non-sterile component, NO sterility testing): │
│ - Controlled Room Temp: 1 Day │
│ - Refrigerated: 4 Days │
│ - Frozen: 45 Days │
│ • Aseptically prepared WITH Sterility Testing Passed: │
│ - Controlled Room Temp: 30 Days | Refrigerated: 45 Days | Frozen: 60 Days │
│ • Terminally Sterilized WITH Sterility Testing Passed: │
│ - Controlled Room Temp: 45 Days | Refrigerated: 60 Days | Frozen: 90 Days │
├─────────────────────────────────────────────────────────────────────────────┤
│ Immediate-Use CSPs (Emergency bedside / code blue administration): │
│ • Must begin administration within FOUR (4) HOURS of starting preparation │
└─────────────────────────────────────────────────────────────────────────────┘
4. USP <800> Hazardous Drug Compounding & Containment
USP General Chapter <800> establishes comprehensive safety mandates to protect healthcare personnel, patients, and the environment from the risks associated with handling Hazardous Drugs (HDs), as identified on the NIOSH (National Institute for Occupational Safety and Health) List (antineoplastics, teratogens, carcinogens, reproductive toxins).
Containment Engineering Controls for Hazardous Drugs
- Containment Primary Engineering Control (C-PEC): Must be a Class II Type A2, B1, or B2 Biological Safety Cabinet (BSC) or Compounding Aseptic Containment Isolator (CACI) that provides ISO Class 5 air quality and is externally vented through HEPA filtration to the outside atmosphere.
- Containment Secondary Engineering Control (C-SEC / Buffer Room):
- Must be physically separated from non-hazardous compounding areas.
- Maintained under continuous negative pressure differential of -0.010 to -0.030 inches of water column (-2.5 to -7.5 Pa) relative to adjacent areas.
- Must achieve a minimum of 30 Air Changes Per Hour (ACPH) and be externally vented to the outside atmosphere.
- Associated Anteroom must be ISO Class 7 (particle count $\le 352,000/\text{m}^3$) with positive pressure relative to general areas but positive relative to the negative buffer room.
- Containment Segregated Compounding Area (C-SCA): An unclassified room under negative pressure (-0.010 to -0.030 inch w.c.) with at least 12 ACPH externally vented, housing an externally vented C-PEC. Restricted to Category 1 HD CSPs.
- Hazardous API & Antineoplastic Storage: Active hazardous pharmaceutical powders and antineoplastic agents requiring manipulation must be stored in a dedicated, externally vented, negative-pressure room with at least 12 ACPH.
Personal Protective Equipment (PPE) Mandates for HD Handling
- Chemotherapy Gloves: Two pairs of powder-free chemotherapy-rated gloves tested to ASTM Standard D6978. The inner glove is worn under the gown cuff; the outer glove is worn over the gown cuff. Outer gloves must be changed every 30 minutes (or immediately if torn, punctured, or contaminated).
- Chemotherapy Gown: Disposable, non-linting, impermeable (polyethylene-coated) gown with a closed back and long sleeves with snug elastic cuffs. Gowns must be changed every 2 to 3 hours or immediately following known contamination/spills.
- Respiratory Protection: NIOSH-certified N95 respirator is required for routine HD compounding to protect against airborne particles. An elastomeric half-mask with multi-gas/P100 cartridge or Powered Air-Purifying Respirator (PAPR) is required for spills or vapor risk.
- Eye & Face Protection: Goggles and a full-face shield are required when there is a potential risk for splashes or aerosol generation (standard safety glasses with side shields are insufficient).
Closed System Drug-Transfer Devices (CSTDs) & Environmental Wipe Sampling
- Closed System Drug-Transfer Devices (CSTDs): Mechanical devices that prevent the transfer of environmental contaminants into the system and the escape of hazardous drug or vapor concentrations outside the system. CSTDs are recommended for compounding and MANDATORY for administering antineoplastic hazardous drugs when the dosage form allows.
- Environmental Surface Wipe Sampling: Facilities handling hazardous drugs must perform surface wipe sampling for hazardous drug residue at baseline and at least every six (6) months. Sampling locations must include the C-PEC interior surfaces, pass-through chambers, staging counters, and adjacent buffer/anteroom floors.
5. Master USP Compounding Beyond-Use Dating (BUD) Comparison Table
The following master table synthesizes the Beyond-Use Dating boundaries across USP <795>, USP <797>, and USP <800>:
| Compounding Category | Dosage Form / Cleanroom Classification | Controlled Room Temp (20°C to 25°C) | Refrigerated Storage (2°C to 8°C) | Frozen Storage (-25°C to -10°C) | Mandatory Quality Controls |
|---|---|---|---|---|---|
| USP <795> Non-Sterile | Non-Preserved Aqueous Oral Formulations ($a_w \ge 0.60$) | N/A (Must Refrigerate) | 14 Days | N/A | Master Formulation Record, Compounding Record, pH check. |
| USP <795> Non-Sterile | Preserved Aqueous Topical Formulations ($a_w \ge 0.60$) | 35 Days | 35 Days | N/A | Antimicrobial preservative effectiveness or validated formula. |
| USP <795> Non-Sterile | Non-Aqueous Dosage Forms ($a_w < 0.60$, anhydrous ointments/suppositories) | 90 Days | 90 Days | N/A | Component expiration check (cannot exceed shortest API exp). |
| USP <795> Non-Sterile | Solid Dosage Forms (Capsules, Tablets, Powders) | 180 Days | 180 Days | N/A | Weight variation test, visual inspection, airtight container. |
| USP <797> Category 1 CSP | Compounded in SCA or ISO 5 PEC outside Cleanroom Suite | 12 Hours | 24 Hours | Not Permitted | Gloved fingertip test (annual), media-fill (annual). |
| USP <797> Category 2 CSP | Aseptic processing, sterile starting components, NO sterility test | 4 Days | 10 Days | 45 Days | Gloved fingertip test (semi-annual), media-fill (semi-annual). |
| USP <797> Category 2 CSP | Aseptic processing, $\ge 1$ non-sterile component, NO sterility test | 1 Day | 4 Days | 45 Days | Endotoxin testing, $0.22\ \mu\text{m}$ sterilizing filtration. |
| USP <797> Category 2 CSP | Aseptic processing WITH passed sterility testing | 30 Days | 45 Days | 60 Days | Membrane filtration sterility test (USP <71>), endotoxin test. |
| USP <797> Category 2 CSP | Terminally Sterilized (Autoclave) WITH passed sterility testing | 45 Days | 60 Days | 90 Days | Autoclave validation cycle, USP <71> sterility verification. |
| USP <797> Immediate-Use | Bedside / Emergency STAT Administration | Must administer within 4 Hours | 4 Hours | Not Permitted | Continuous single preparation, aseptic technique, immediate use. |
| USP <800> Hazardous CSP | Follows Category 1 or 2 CSP limits based on cleanroom engineering | Assigned according to USP <797> Category 1 or 2 limits | Assigned according to USP <797> limits | Assigned according to USP <797> limits | 2 pairs ASTM D6978 gloves, C-PEC negative pressure, 6-mo wipe tests. |
Test Your Knowledge
A compounding pharmacist is preparing an oral suspension of Spironolactone in Cherry Syrup (an aqueous, non-preserved vehicle) for a pediatric patient pursuant to a prescription. The chemical components have expiration dates ranging from 6 months to 2 years. In the absence of published chemical stability data, what is the maximum Beyond-Use Date (BUD) and storage condition permitted under USP <795>?
A
B
C
D
Test Your Knowledge
A hospital cleanroom supervisor in Louisville is validating personnel aseptic qualifications and engineering controls for non-hazardous sterile compounding under USP <797>. Which of the following sets of requirements accurately reflects the standards for initial personnel gloved fingertip testing and cleanroom pressure differentials?
A
B
C
D
Test Your Knowledge
A healthcare system operates both a traditional hospital pharmacy compounding patient-specific sterile infusions and an FDA-registered 503B Outsourcing Facility preparing sterile batch cardioplegia solutions for regional surgery centers. Which of the following statements correctly distinguishes the legal and regulatory frameworks governing these two compounding entities?
A
B
C
D