4.2 Extemporaneous Compounding

4.2 Extemporaneous Compounding

Quick Answer: USP <795> governs nonsterile compounding, <797> governs sterile compounding, and <800> governs hazardous drug handling. The 2023 USP <797> revision replaced low/medium/high-risk CSP labels with Category 1, Category 2, and Category 3 — memorize ISO classes, Category BUDs, and alligation/aliquot math.

Compounding is the preparation, mixing, assembling, packaging, and labeling of a customized medication based on a prescription order. The FPGEE tests the three USP chapters that define standards, plus the calculations that translate a prescription into a final product.

USP General Chapter Comparison

USP <795> Nonsterile Compounding

<795> covers oral solids, topical preparations, ointments, creams, gels, troches, suppositories, and oral liquids. Key requirements:

• Ingredient selection: use USP/NF-grade ingredients; document source, lot, and expiration for each component.
• Written procedures (SOPs) for every preparation type and cleaning/garbing process.
• Documentation: a Master Formulation Record (MFR) (the recipe) and a Compounding Record (CR) (what was actually done, with signatures).
• BUD assignment: defaults are conservative; the 2023 revision sets typical limits such as nonaqueous oral liquids (aw < 0.60) up to 90 days, other nonaqueous dosage forms (aw < 0.60; e.g., capsules, troches, nonaqueous topicals) up to 180 days, non-preserved aqueous dosage forms up to 14 days refrigerated, and preserved aqueous dosage forms up to 35 days. Always confirm against the current USP table.

Common nonsterile dosage forms

• Troches/lozenges: polybase or PEG base, molded or compressed; slow buccal dissolution.
• Ointments and creams: levigation and geometric dilution; oil-in-water (cream) vs water-in-oil (ointment) systems.
• Gels: polymers such as Carbopol (carbomer), HPMC, or Pluronic F-127.
• Suspensions: structured vehicle, controlled particle size, suspending agents (e.g., xanthan, Veegum).
• Capsules: hand-filled with lactose or starch diluent, often using a capsule machine.

USP <797> Sterile Compounding (2023 Categories)

Sterile compounding requires a controlled environment to prevent microbial, endotoxin, and particulate contamination. The revision that became official on November 1, 2023 retired the old low-, medium-, and high-risk CSP labels and replaced them with Category 1, Category 2, and Category 3 CSPs, plus an immediate-use pathway.

Cleanroom classifications (ISO 14644-1)

CSP Categories and Default BUDs

Exam trap: Do not answer with the retired 2008 labels (low-/medium-/high-risk) as if they were current USP <797> terminology. FPGEE questions after the 2023 revision expect Category 1/2/3 language.

Another trap: For Category 1 and Category 2 CSPs, USP does not allow extending BUDs past the chapter tables merely because a pharmacy has a stability-indicating HPLC assay. Longer dating requires meeting the Category 3 framework (or following an FDA-approved labeling pathway that is not ordinary compounding).

USP <800> Hazardous Drug Handling

<800> applies to all drugs on the NIOSH List of Antineoplastic and Other Hazardous Drugs, which groups hazardous drugs into antineoplastics, non-antineoplastics with reproductive risk, chemicals, endocrine agents, and others.

Engineering controls

• C-PEC (Containment Primary Engineering Control): a Class II Biological Safety Cabinet (BSC) or Compounding Aseptic Containment Isolator (CACI), operated inside an ISO 5 environment.
• C-SEC (Containment Secondary Engineering Control): an ISO 7 negative-pressure buffer area (typically 0.01 to 0.03 inches water column negative to the ante area) plus an ISO 8 ante area, both externally vented.

PPE and handling

• Double chemo-rated gloves and a chemo-rated gown with closed front and cuffs.
• Eye and face protection if splash risk exists outside the C-PEC.
• Respiratory protection (NIOSH-approved respirator) if handling outside a functioning C-PEC.
• Closed-system drug-transfer devices (CSTDs) for compounding and administration.
• Spill kits accessible; only trained personnel handle hazardous drugs.
• Segregated receipt and dedicated storage with negative pressure and external ventilation; trace chemotherapy waste is segregated and disposed of as hazardous waste.

Compounding Calculations

Alligation method

Used to mix two strengths to obtain a desired intermediate strength. The differences between the desired strength and each original strength give the parts of the other solution.

Worked example: Prepare 1% hydrocortisone cream from 2.5% and 0.5% strengths. Parts of 2.5% = 1 - 0.5 = 0.5. Parts of 0.5% = 2.5 - 1 = 1.5. Total = 2.0 parts. Ratio 0.5:1.5 = 1:3. For 60 g total: 15 g of 2.5% plus 45 g of 0.5%.

Aliquot method

Used when the drug quantity is too small to weigh accurately on the available balance. Dilute the drug with an inert diluent, weigh a portion of the dilution, and back-calculate the drug mass.

Worked example: Need 5 mg of drug; balance sensitivity is 50 mg. Triturate 100 mg drug with 900 mg lactose to make a 1:10 dilution. Weigh 50 mg of the dilution, which contains 50 mg x (1/10) = 5 mg of drug.

Powder dilution

Use C1 x W1 = C2 x W2 (concentration x weight before = concentration x weight after).

Worked example: Dilute 100 g of 10% powder to 5% strength. 10 x 100 = 5 x W2, so W2 = 200 g. Add 100 g of diluent (e.g., lactose) to the original 100 g.

Beyond-Use Dating and Stability

BUD is not the same as an expiration date. A BUD is the date after which a compounded preparation must not be used; an expiration date is the manufacturer's labeled shelf life of a commercial product. Assign sterile BUDs from the current USP <797> Category tables, and nonsterile BUDs from the current USP <795> table. Stability studies use accelerated conditions (25 degrees C / 60% RH and 40 degrees C / 75% RH) per ICH Q1A, but those studies alone do not override Category 1/2 BUD caps in <797>.

Quality Assurance and Documentation

• Master Formulation Record (MFR): recipe, ingredients, calculations, equipment, and step-by-step procedure.
• Compounding Record (CR): actual lot numbers, quantities weighed, signatures of compounder and verifier.
• SOPs for environment, cleaning, garbing, and equipment calibration.
• Quality assurance program: environmental sampling (viable air and surface, plus non-viable particle counts), media-fill challenges for sterile compounding personnel, and release testing (sterility and endotoxin) when required for the assigned Category and BUD.

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Compounding is high-yield because it blends regulation (USP chapters), math (alligation/aliquot), and patient safety (BUDs, hazardous handling). Memorize the ISO classes, Category 1 vs Category 2 environment distinction, and the C-PEC/C-SEC distinction cold before exam day.