Compounding Pharmacy (USP 795): The Art of Non-Sterile Compounding, How to Make Creams, Gels, and Suspensions Correctly

Compounding Pharmacy (USP 795): The Art of Non-Sterile Compounding, How to Make Creams, Gels, and Suspensions Correctly

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Non-sterile compounding is a hands-on craft with real clinical impact. Done right, it turns APIs and excipients into safe, effective medicines tailored to patients. USP 795 sets the minimum standards so every compounded cream, gel, or suspension is consistent and reliable. This guide explains the “how” and the “why,” with practical steps you can apply at the bench.

What USP 795 Covers and Why It Matters

USP 795 governs non-sterile compounding. It focuses on patient safety through process control, documentation, and quality checks. The goal is not perfection in theory, but predictable quality in practice. That means:

  • Validated process: Use repeatable methods so outcomes don’t depend on who is compounding that day.
  • Controlled environment: A clean area reduces contamination and mix-ups.
  • Right beyond-use date (BUD): Water and heat drive degradation and microbial growth. Default BUDs exist because we rarely have full stability data.
  • Documentation: If it’s not written, it didn’t happen. Records prove what you made, how you made it, and that you checked it.

Set Up a Compliant Non-Sterile Compounding Workflow

  • Space and hygiene: Use a designated compounding area with smooth, cleanable surfaces. Keep it uncluttered. Control traffic to limit mix-ups.
  • Water: Potable water for handwashing and initial equipment rinse; Purified Water for compounding and the final equipment rinse. This reduces microbial and mineral load.
  • PPE: Gloves, coat or gown, hair restraint. Follow USP 800 for hazardous drugs.
  • Equipment: Calibrated balance, mortar and pestle (glass for liquids; porcelain/wedgewood for powders), spatulas, homogenizer, sieves, volumetrics, pH paper/meter, thermometers.
  • Cleaning: Written SOP for cleaning and frequency. Clean before and after each batch to prevent cross-contamination.
  • Documentation: Maintain a Master Formulation Record (MFR) for each formula; create a Compounding Record (CR) for every batch. Record ingredients, lot numbers, quantities, calculations, equipment ID, checks, and signatures.
  • Release checks: Define what you will check (appearance, pH, weight, uniformity, packaging, label). Verify before releasing.

Choose Ingredients and Vehicles Wisely

  • API properties: Know solubility, pH stability, and sensitivity to heat, oxidation, or light. This dictates method and packaging.
  • Base compatibility: Choose o/w or w/o cream bases based on drug solubility and skin feel. Ionic excipients can destabilize some gels (e.g., carbomers dislike high electrolytes).
  • Wetting and levigating agents: Use glycerin/propylene glycol for hydrophilic systems; mineral or castor oil for oleaginous systems. This reduces particle clumping and improves uniformity.
  • Suspending agents: Sodium CMC, xanthan gum, or methylcellulose slow settling so the dose stays uniform.
  • Preservatives: Needed when water is present and the product will be used multiple times. Match pH range to preservative efficacy. Avoid certain preservatives in neonates.
  • pH and buffers: Keep API in a stable pH zone and ensure preservative activity. Small pH shifts can crash gels or degrade drugs.

Core Techniques You Must Master

  • Trituration: Reduce particle size with a mortar and pestle. Finer particles disperse better and reduce grittiness.
  • Geometric dilution: Combine small amounts of API with base in doubling increments. This prevents “hot spots” of drug.
  • Levigating: Wet powder with a small amount of compatible liquid to form a smooth paste before incorporation. This helps uniformity and texture.
  • Dissolution: If a drug is soluble, dissolve it for better uniformity. Watch heat and solvent limits.
  • Emulsification: For creams and lotions, bring oil and water phases to similar temperatures, then combine with mixing. This stabilizes the emulsion.
  • Homogenization: Improve texture and distribution using an ointment mill or homogenizer. Too much shear can thin some gels; monitor viscosity.

How to Make a Cream Correctly

Example: 2% w/w drug in an o/w cream base (100 g batch)

  1. Calculate and plan: Determine 2 g API, 98 g base. If the API is a powder, decide on a levigating agent (e.g., glycerin for o/w base). Plan to account for any mass of levigating agent by displacing base.
  2. Prepare equipment: Clean and dry mortar, pestle, spatulas, and homogenizer. Tare the balance.
  3. Triturate the API: Pulverize to a fine, uniform powder to reduce grittiness.
  4. Levigate: Add just enough glycerin to wet the powder and make a smooth paste. Avoid overwetting, which can thin the cream and destabilize the emulsion.
  5. Geometric dilution: Incorporate a small portion of the cream base into the paste. Mix until uniform. Double the amount of base each time until all base is incorporated.
  6. Homogenize: Use an ointment mill or homogenizer for a smooth, consistent texture. Limit passes to prevent over-processing.
  7. QS to weight: Check final weight and add base if needed to reach 100 g. This ensures the labeled strength.
  8. Assess: Look for uniform color, absence of visible particles, and acceptable feel (no grittiness). Record observations.
  9. Package: Use a wide-mouth, tight, light-resistant jar or a collapsible tube to reduce air exposure.
  10. Label: Include drug strength (w/w), BUD, storage, and “For external use only.”

Why these steps? Particle size and uniform mixing govern dose uniformity and patient experience. Geometric dilution prevents localized high concentrations. Homogenization improves spreadability and consistency.

How to Make a Carbomer Gel Correctly

Example: 1% carbomer gel with dissolved API

  1. Hydrate polymer: Sprinkle carbomer into Purified Water while stirring to avoid clumps. Allow time to fully hydrate (often 30–60 minutes). Hydration time prevents later lumps and air pockets.
  2. Add cosolvents: If the API needs alcohol/propylene glycol for solubility, add after hydration to avoid premature thickening or precipitation.
  3. Dissolve API: Dissolve in a suitable solvent within the gel vehicle, considering pH and maximum solvent percentage for skin tolerance.
  4. Neutralize: Slowly add neutralizer (e.g., sodium hydroxide or triethanolamine) to raise pH into the thickening range of the carbomer, typically around pH 6–7. Mix gently to avoid air.
  5. Deaerate: Allow the gel to stand or use vacuum to remove bubbles. Bubbles trap air, which impairs dosing and appearance.
  6. Preservative and finish: Add compatible preservative at the effective pH range. QS to final weight.
  7. Check: Verify pH, clarity, viscosity (by flow or spread test), and uniformity.
  8. Package: Use airless pump or tube when possible to limit contamination and oxidation.

Key cautions: Carbomers lose viscosity with high electrolytes and cationic ingredients. Add salts last and test viscosity. Excess shear can reduce thickness.

How to Make an Oral Suspension Correctly

Example: 25 mg/mL API, 100 mL total

  1. Calculate: 2.5 g API for 100 mL. Choose a vehicle with buffer, sweetener, and preservative, or make one with Purified Water, buffer, sweetener, and a suspending agent.
  2. Triturate the API: Reduce to a fine powder. Pass through a sieve if needed to break aggregates.
  3. Wetting: Levigate the powder with a few milliliters of glycerin or a small amount of surfactant solution to overcome hydrophobicity. This improves dispersion and reduces floating clumps.
  4. Make a paste: Add a portion of the vehicle to form a smooth slurry.
  5. Add suspending agent: Pre-disperse sodium CMC or xanthan gum in vehicle to avoid clumps, then combine with the slurry. Mix thoroughly.
  6. pH check: Adjust to the API’s stability range and preservative effectiveness. Avoid extremes that irritate the GI tract.
  7. QS to volume: Transfer to a calibrated cylinder or volumetric flask and bring to 100 mL with vehicle. Mix by inversion to avoid excessive foaming.
  8. Assess: Test redispersibility after settling for 24 hours. The suspension should redisperse with 10 gentle inversions.
  9. Package: Use a tight, light-resistant bottle with a child-resistant cap. Provide an oral syringe with an adapter for accuracy.
  10. Label: Include strength (mg/mL), “Shake well,” storage, and BUD.

Why this works: Wetting reduces interfacial tension so particles disperse. A suspending agent slows sedimentation (Stokes’ Law), keeping each dose consistent.

Quality Checks Before Release

  • Calculations verified: Independent check of weights, volumes, concentrations.
  • Appearance and texture: Uniform color, no phase separation, no grittiness for creams/gels.
  • Weight/volume: Final mass or volume matches label. Adjusted for levigating agents and solvent losses.
  • pH: Within target range for stability, comfort, and preservative efficacy.
  • Uniformity: Sample from multiple points in the batch if feasible; mix further if non-uniform.
  • Container-closure: Compatible, tight, and clean. Correct cap and seal.
  • Label accuracy: Includes list of active ingredients with strengths, BUD, storage, route, and auxiliary labels.

Beyond-Use Dating, Packaging, and Storage

When no stability data are available, USP 795 default BUDs for non-sterile preparations are:

  • Nonaqueous formulations (e.g., many ointments and capsules): up to 90 days.
  • Water-containing oral liquids: up to 14 days refrigerated (2–8°C).
  • Water-containing topicals (dermal, mucosal) and semisolids: up to 30 days.

Use tighter BUDs if the formulation or packaging is at higher risk (e.g., minimal preservative, high water activity, frequent hand contact). Extend BUDs only if you have reliable stability data for the specific formula, container, and storage.

Choose packaging that protects from light, air, and moisture. Tubes or airless pumps reduce contamination for semisolids. For oxidizable drugs, minimize headspace and consider antioxidants.

Labeling and Patient Counseling

  • Auxiliary labels: “Shake well” for suspensions; “For external use only” for topicals; storage (“Refrigerate” if required); “Do not freeze.”
  • Measuring: Provide an oral syringe and adapter for liquids. Never rely on household spoons.
  • Use directions: Clear, simple steps. For topicals: apply a thin layer, wash hands before and after, avoid broken skin unless directed.
  • What to expect: Normal texture, scent, and appearance. When to stop and call if irritation or separation occurs.
  • BUD and disposal: Explain that BUD is not the same as expiration. Discard after the BUD to avoid reduced potency or contamination.

Common Pitfalls and How to Avoid Them

  • Skipping geometric dilution: Leads to dose variability. Always stepwise mix for powders in bases.
  • Wrong levigating agent: Oil in a water-based system (or vice versa) causes separation or clumps.
  • Not accounting for added liquids: Levigating agents and cosolvents change final weight/volume. QS at the end.
  • Using tap water: Introduces microbes and minerals that destabilize formulations.
  • Over-shearing gels: Thins the product irreversibly. Mix gently after gel forms.
  • Poor documentation: Missing lot numbers or calculations breaks traceability and violates USP 795.
  • Weak preservation: Inadequate preservative or wrong pH encourages microbial growth. Match preservative to pH and water activity.

Equipment Checklist for Reliable Results

  • Balances: Calibrated, with readability appropriate to batch size.
  • Mortars and pestles: Glass (liquids); porcelain or wedgewood (powders).
  • Homogenizer/ointment mill: For smooth creams and uniform dispersions.
  • Volumetric tools: Class A glassware or calibrated syringes/cylinders.
  • Sieves: For de-agglomerating powders (e.g., 60–100 mesh).
  • pH meter or high-quality pH paper: For pH-critical formulations.
  • Thermometer: For phase-temperature control in emulsions.

Compounding under USP 795 is about control: of ingredients, process, and outcomes. When you understand why each step matters, you can build creams that spread well, gels that hold their body, and suspensions that deliver the same dose every time. That is the art—and the responsibility—of non-sterile compounding.

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