13.1 Non-Sterile (USP <795>) & Sterile (USP <797>) Compounding

13.1 Non-Sterile (USP <795>) & Sterile (USP <797>) Compounding

Compounding is an indispensable component of pharmacy practice that tailors customized medications to the unique clinical needs of individual patients when commercially manufactured, FDA-approved drug products cannot meet those needs. However, the preparation of non-sterile and sterile customized medications presents inherent safety risks, including chemical degradation, incorrect dosing calculations, microbial contamination, and endotoxin exposure. To ensure uniform quality and patient safety, compounding is governed by a dual framework: federal statutory mandates under the Food, Drug, and Cosmetic Act (FD&C Act) and national standards established by the United States Pharmacopeia (USP), enforced in Oklahoma through the Oklahoma State Board of Pharmacy (OSBP) under Title 59 O.S. § 353 and OAC Title 535 Chapter 15 Subchapter 10.

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Federal Statutory Framework: Section 503A vs. Section 503B

The Drug Quality and Security Act (DQSA) of 2013 reaffirmed and clarified the boundaries of pharmacy compounding by establishing two distinct statutory pathways under Title I (the Compounding Quality Act):

+-----------------------------------------------------------------------------------------+
|                   FEDERAL STATUTORY DUAL PATHWAY (FD&C ACT)                             |
+-----------------------------------------------------------------------------------------+
|  SECTION 503A: Traditional Pharmacies       |  SECTION 503B: Outsourcing Facilities     |
|  - Patient-specific prescription required   |  - No patient-specific Rx required (Bulk) |
|  - Anticipatory compounding in limited qty  |  - Office-use / hospital stock supply     |
|  - Primary oversight by State Boards (OSBP) |  - Direct oversight by Federal FDA        |
|  - Governed by USP <795>, <797>, <800>      |  - Governed by FDA CGMP (21 CFR 210/211)  |
|  - Exempt from FDA CGMP, NDA, Labeling      |  - Subject to routine FDA inspections     |
+-----------------------------------------------------------------------------------------+

Section 503A — Traditional Compounding Pharmacies

• Patient-Specific Mandate: Section 503A applies to state-licensed community, hospital, and clinic pharmacies that compound medications pursuant to a valid, patient-specific prescription or medication order.
• Anticipatory Compounding: Pharmacies may compound limited quantities of a medication before receiving a valid prescription if the preparation is based on a history of receiving valid prescriptions generated by an established relationship between the pharmacist, patient, and prescriber.
• Statutory Exemptions: Compounded preparations that meet Section 503A requirements are exempt from three major federal provisions:
  1. FDA Current Good Manufacturing Practice (CGMP) regulations (21 CFR Parts 210 and 211);
  2. Labeling with adequate directions for use (FD&C Act § 502(f)(1));
  3. New Drug Application (NDA) pre-market approval requirements (FD&C Act § 505).
• Prohibitions: Section 503A facilities cannot engage in regular or bulk compounding for office-use distribution without patient-specific prescriptions, nor may they compound drug products that have been withdrawn or removed from the market for safety or efficacy reasons, or compound regular copies of commercially available FDA-approved drug products without a significant medical distinction documented by the prescriber.

Section 503B — Outsourcing Facilities

• Voluntary Registration: A facility that compounds sterile medications may voluntarily register with the FDA as an Outsourcing Facility under Section 503B.
• Office Use & Bulk Distribution: 503B facilities are legally authorized to compound sterile (and non-sterile) drugs in bulk and distribute them to hospitals, clinics, and practitioners for "office use" without receiving patient-specific prescriptions in advance.
• Regulatory Rigor: Unlike 503A pharmacies, 503B outsourcing facilities:
  • MUST strictly comply with FDA CGMP regulations, mirroring commercial pharmaceutical manufacturers;
  • Are subjected to risk-based, mandatory federal FDA inspections;
  • Must report all compounded products, active ingredients, and batch numbers to the FDA every six months;
  • Must report adverse events to the FDA MedWatch program within 15 calendar days;
  • Must be licensed by the OSBP as an Outsourcing Facility if shipping into or operating within Oklahoma.

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USP <795> Non-Sterile Compounding Standards

USP Chapter <795> establishes standards for compounding non-sterile preparations (pharmaceutical preparations that do not require sterility, such as oral liquids, capsules, tablets, topicals, suppositories, and troches).

Documentation: Master Formulation Record vs. Compounding Record

Every non-sterile compounding operation relies on two foundational documentation instruments:

Water Activity (a_w) and Formulation Stability

Water activity (a_w) is the ratio of the vapor pressure of water in a formulation to the vapor pressure of pure water under identical conditions. Formulations with high water activity (a_w ≥ 0.60) are highly susceptible to microbial proliferation, chemical hydrolysis, and mold proliferation. Formulations with low water activity (a_w < 0.60), such as anhydrous ointments, suppository bases, and dry powders, naturally inhibit microbial growth.

USP <795> Beyond-Use Date (BUD) Rules

Under updated USP <795>, beyond-use dates are established based on the presence of water, chemical stability, antimicrobial preservation, and storage temperature, provided no specific stability-indicating study dictates an alternate BUD:

+-----------------------------------------------------------------------------------------+
|                    USP <795> NON-STERILE DEFAULT BEYOND-USE DATES (BUDs)                |
+-----------------------------------------------------------------------------------------+
| Formulation Type / Water Activity             | Storage Temperature     | Maximum BUD   |
+-----------------------------------------------+-------------------------+---------------+
| Non-preserved Aqueous Dosage Forms (aw >= 0.60)| Refrigerator (2°C - 8°C)| 14 Days       |
| (e.g., aqueous oral suspensions/solutions)    |                         |               |
+-----------------------------------------------+-------------------------+---------------+
| Preserved Aqueous Dosage Forms (aw >= 0.60)   | Controlled Room Temp    | 35 Days       |
| (e.g., emulsions, gels, preserved lotions)    | (20°C - 25°C) or Cold   |               |
+-----------------------------------------------+-------------------------+---------------+
| Non-aqueous Oral Formulations (aw < 0.60)     | Controlled Room Temp    | 90 Days       |
| (e.g., capsules, tablets, anhydrous liquids)  | (20°C - 25°C) or Cold   |               |
+-----------------------------------------------+-------------------------+---------------+
| Non-aqueous Non-Oral Formulations (aw < 0.60) | Controlled Room Temp    | 180 Days      |
| (e.g., anhydrous ointments, suppositories)    | (20°C - 25°C) or Cold   |               |
+-----------------------------------------------+-------------------------+---------------+

Governing Shorter Expiration Rule: If any individual active pharmaceutical ingredient (API) or inactive component in the compounded preparation has an expiration date from the manufacturer that is shorter than the calculated default BUD, the assigned BUD cannot exceed that component's earliest expiration date.

Raw Material Quality & Sourcing

• Pharmacopeial Sourcing: Active Pharmaceutical Ingredients (APIs) must be sourced from FDA-registered facilities and comply with official USP-NF (United States Pharmacopeia - National Formulary) or FCC (Food Chemicals Codex) monographs.
• Certificate of Analysis (CoA): Every lot of raw chemical substance must be accompanied by a valid Certificate of Analysis (CoA) verifying purity, identity, and potency.
• Undated Chemical Reagents: If a component is received without a manufacturer-assigned expiration date, the pharmacist must assign an expiration date not to exceed 3 years from the date of receipt, provided the container remains sealed and stored properly.

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USP <797> Sterile Compounding Standards

USP Chapter <797> establishes comprehensive requirements for the preparation of Compounded Sterile Preparations (CSPs), including injectables, ophthalmics, otics for perforated eardrums, inhalations, and tissue implants.

Compounded Sterile Preparation (CSP) Categorization

Updated USP <797> categorizes sterile compounding operations based on environmental controls, facility engineering, personnel testing rigor, and sterility assurance:

+-----------------------------------------------------------------------------------------+
|                        USP <797> CSP CATEGORY COMPARISON MATRIX                         |
+-----------------------------------------------------------------------------------------+
| Attribute        | Category 1 CSPs        | Category 2 CSPs        | Category 3 CSPs     |
+------------------+------------------------+------------------------+---------------------+
| Primary Control  | ISO Class 5 PEC        | ISO Class 5 PEC        | ISO Class 5 PEC     |
| (PEC)            | (LAFW, BSC, CAI)       | (LAFW, BSC, CAI)       | (LAFW, BSC, CAI)    |
+------------------+------------------------+------------------------+---------------------+
| Secondary Control| Unclassified           | ISO Class 7 Buffer +   | ISO Class 7 Buffer +|
| (SEC / Area)     | Segregated Area (SCA)  | ISO Class 8 Anteroom   | ISO Class 8/7 Ante  |
+------------------+------------------------+------------------------+---------------------+
| Sterility Test   | Not Required           | Optional (extends BUD) | Mandatory for Batches|
+------------------+------------------------+------------------------+---------------------+
| Personnel Requal.| Every 6 Months         | Every 6 Months         | Every 3 Months      |
+------------------+------------------------+------------------------+---------------------+
| Max Room Temp BUD| <= 12 Hours            | 1 to 45 Days (per test)| Up to 60 - 90 Days  |
| (Controlled RT)  |                        | & component sterility  | (with stability)    |
+------------------+------------------------+------------------------+---------------------+
| Max Cold BUD     | <= 24 Hours            | 4 to 60 Days (per test)| Up to 90 - 120 Days |
| (2°C to 8°C)     |                        | & component sterility  | (with stability)    |
+------------------+------------------------+------------------------+---------------------+
| Max Frozen BUD   | PROHIBITED (N/A)       | 45 to 90 Days          | Up to 180 Days      |
| (-25°C to -10°C) |                        |                        |                     |
+------------------+------------------------+------------------------+---------------------+

Immediate-Use Compounded Sterile Preparations

Immediate-use CSPs are exempted from standard Category 1 and Category 2 cleanroom requirements only when compounding is performed in urgent or emergent clinical scenarios (e.g., cardiopulmonary resuscitation, emergency department intubation, battlefield trauma):

• Compounding must involve no more than 3 different commercial sterile non-hazardous products;
• Aseptic technique must be maintained;
• Administration must commence within 4 hours from the start of preparation;
• If administration does not begin within 4 hours, the preparation must be immediately discarded;
• No storage, refrigeration, freezing, or batching is permitted for immediate-use CSPs.

Cleanroom Architecture & ISO Particle Classifications

Air quality is measured by the concentration of airborne non-viable particulate matter ≥ 0.5 µm per cubic meter of air under ISO 14644-1 standards:

• ISO Class 5 (Class 100): ≤ 3,520 particles/m³. Required for the direct compounding zone inside Primary Engineering Controls (PECs).
• ISO Class 7 (Class 10,000): ≤ 352,000 particles/m³. Required for sterile non-hazardous buffer rooms, hazardous secondary engineering controls, and anterooms opening into negative-pressure rooms.
• ISO Class 8 (Class 100,000): ≤ 3,520,000 particles/m³. Required for anterooms opening into positive-pressure non-hazardous buffer rooms.

Pressure Gradients & Engineering Controls

• Positive Pressure Cleanrooms (Non-Hazardous Sterile): To prevent unclassified air from entering the buffer room, the buffer area must maintain continuous positive pressure of at least +0.020 inches of water column (5.0 Pascals) relative to the adjacent anteroom. The anteroom must maintain at least +0.020 inches of water column relative to unclassified external corridors.
• Unidirectional Airflow: Laminar Airflow Workstations (LAFWs) must maintain a constant, uniform unidirectional velocity of 90 feet per minute (±20%) across the direct compounding area.

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Personnel Garbing Hierarchy & Aseptic Technique

Contamination is overwhelmingly introduced by compounding personnel. USP <797> mandates an orderly garbing sequence executed in the anteroom, moving progressively from the "dirtiest" to the "cleanest" activities:

[ENTERING ANTEROOM]
       |
  1. Remove outer garments, jewelry, makeup, nail polish, artificial nails
       |
  2. Don dedicated shoe covers (or dedicated cleanroom shoes)
       |
  3. Don head and facial hair covers
       |
  4. Don surgical face mask and eye shield (if required)
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  5. Cross the "Line of Demarcation" from dirty side to clean side of Anteroom
       |
  6. Perform hand hygiene: Wash hands & forearms to elbows with soap & warm water
     for at least 30 SECONDS. Clean underneath fingernails with disposable pick.
       |
  7. Dry hands completely with low-lint disposable towels or electronic hand dryer
       |
  8. Don non-shedding, disposable cleanroom gown with snug cuffs and neck closure
       |
  9. Sanitize hands with alcohol-based hand rub (70% sterile IPA)
       |
 10. Enter Buffer Room / ISO Class 5 area
       |
 11. Don STERILE, powder-free gloves (cuffs pulled over gown sleeves)
       |
 12. Routinely sanitize gloved hands with sterile 70% IPA throughout compounding

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Quality Assurance: Personnel Qualification & Environmental Sampling

Personnel Competency Testing

1. Gloved Fingertip and Thumb Sampling (GFS):
   • Initial Qualification: Before being permitted to compound sterile preparations independently, personnel must successfully pass 3 consecutive gloved fingertip tests, yielding 0 Colony-Forming Units (0 CFUs) on both hands immediately after garbing and hand hygiene.
   • Ongoing Competency: Personnel must undergo gloved fingertip testing at the conclusion of media-fill testing at least every 6 months for Category 1 and 2 CSPs, and at least every 3 months for Category 3 CSPs. The action level for ongoing testing is > 3 CFUs total for both hands combined.
2. Media-Fill Testing:
   • Personnel must simulate the most challenging compounding procedures using sterile soybean-casein digest (tryptic soy) broth.
   • Filled containers are incubated for 14 calendar days (typically 7 days at 20°C–25°C followed by 7 days at 30°C–35°C).
   • Passing Result: Zero turbidity (no visible microbial growth). Conducted initially and at least every 6 months (Category 1 & 2) or every 3 months (Category 3).

Environmental Monitoring Matrix