Section 2: Sterile and Non-Sterile Compounding Practices

22.2.1 The “Why”: From Reconstitution to Formulation

In Section 1, we established the non-negotiable standards of the compounding environment (the “cockpit”) and the handler’s safety. Now, we transition to the craft itself: the advanced practices of sterile and non-sterile compounding. As a community pharmacist, you are already a compounder. You reconstitute Augmentin suspensions, mix “Magic Mouthwash,” and perhaps prepare simple topical creams. Your skills are rooted in following established recipes and ensuring accuracy.

In specialty pharmacy, this skill evolves from reconstitution to formulation. You are no longer just a “line cook” following a recipe card; you are the “master chef” who must understand the science of the ingredients. The stakes are astronomically higher. An error in a simple antibiotic admixture might lead to waste or a delayed dose. An error in specialty compounding—destabilizing a $20,000 biologic, precipitating a TPN, or miscalculating a pediatric suspension—can be catastrophic, both financially and clinically.

This section is a deep dive into the advanced techniques and clinical decision-making required for specialty products. We will explore:

• Advanced Sterile Practices: Moving beyond simple IV admixtures to the high-stakes world of biologics, chemotherapy, and Total Parenteral Nutrition (TPN), where every manipulation is a potential point of failure for a drug that costs more than a car.
• Advanced Non-Sterile Practices: Moving from simple creams to creating customized, stable, and elegant formulations from scratch for patients with rare diseases or unique needs (e.g., a 1.25 mg/mL oral suspension from a 500 mg adult tablet for a 2 kg neonate).

Your role expands to that of a formulation scientist, a quality assurance manager, and a clinical logician, all at once. You must not only know how to compound, but why you are doing it in a specific way, and how to prove it was done perfectly.

PART 1: MASTERCLASS IN ADVANCED STERILE COMPOUNDING

In this domain, we are governed by USP <797>. Our primary goal is sterility. But with specialty drugs, a second goal is equally important: stability. Contaminating a $20 bag of potassium is bad. Denaturing a $20,000 vial of a biologic is financially catastrophic. You must prevent both.

22.2.2 The High-Stakes World of Biologics & Monoclonal Antibodies (mAbs)

Specialty pharmacy is the pharmacy of biologics. These are not simple chemicals like lisinopril. They are massive, complex proteins (or fragments of proteins) grown in living cell cultures. As such, they are incredibly fragile.

The “Protein Problem”: Simple chemicals can be shaken, stirred, and mixed. Proteins are folded into a precise 3-dimensional shape (their “tertiary structure”). This shape is everything. If it’s altered (denatured), it loses all clinical activity and can even become immunogenic, causing a severe reaction.
Your job is to protect this shape at all costs.

Aseptic Technique Tutorial: How to Handle a Multi-Thousand Dollar Vial

Let’s walk through the preparation of a common mAb, infliximab (Remicade).

1. Equilibration: The vial is stored in the refrigerator. You cannot inject cold diluent into it; the thermal shock can damage the protein. You must let the vial sit at room temperature for at least 30 minutes to equilibrate. This is a common first error.
2. Reconstitution (The “Do Not Shake” Rule): The vial contains a lyophilized (freeze-dried) powder. The package insert says to add 10 mL of Sterile Water for Injection (SWFI).
   • Wrong Technique: Vigorously injecting the 10 mL of SWFI directly onto the powder “cake.” This will cause intense foaming. Foaming is shearing; it’s the physical destruction of the protein. You have just wasted $1,000.
   • Correct Technique: Use a 10mL syringe and needle. Slowly inject the 10 mL of SWFI, aiming the stream against the glass wall of the vial, not onto the powder. This lets the diluent gently wash over the powder.
3. Dissolution (The “Swirl, Don’t Shake” Rule):
   • Wrong Technique: Shaking the vial to dissolve the powder. Again, this causes foaming and shearing.
   • Correct Technique: Gently swirl the vial in a circular motion. This can take several minutes. You must be patient. The final solution should be clear to slightly opalescent. Any opaque particles mean the product is denatured and must be discarded.
4. Dilution into the IV Bag: The dose (e.g., 300 mg = 3 vials) must be added to a 250 mL bag of 0.9% Sodium Chloride (NS) only.
   • Material Compatibility: Most biologics require DEHP-free and low-protein-binding bags and tubing. This is because the protein is “sticky” and will adhere to the plastic, reducing the dose the patient receives. You must ensure the correct IV bag and tubing are used.
   • Mixing the Bag: Just like the vial, you do not shake the bag. You gently invert it 3-5 times to mix.
5. Filtration (The Final Step): Most biologics require an in-line filter during administration. This is *not* a sterilizing filter; it’s a “particulate” filter to catch any small protein aggregates that may have formed.
   • Key Detail: You must know the correct filter size. Remicade requires a 1.2 micron or smaller filter. Other drugs require a 0.22 micron filter. Using the wrong one can be disastrous.

Masterclass Table: Common Specialty Biologics & Their Handling Requirements

22.2.3 Advanced Sterile Technique: Chemotherapy (USP <800>)

When compounding chemotherapy, you have two opposing goals: protect the patient from contamination (USP <797>) and protect the handler from the drug (USP <800>). This requires mastering techniques unique to hazardous drugs.

A. The C-PEC Workflow (Class II BSC)

You are not working in a Horizontal Flow (LAFW) hood, which blows air *at* you. You are in a Class II Biological Safety Cabinet (BSC), which is a vertical flow hood. It pulls a “curtain” of air down from the top, splits it at the work surface (some goes to the back, some to the front grille), and pulls it *away* from you, protecting both you and the product.

• Working Position: All manipulations must occur at least 6 inches inside the hood, behind the front grille.
• No Blocking: You must never place vials, bags, or your hands on top of the front or back grilles. This breaks the air curtain and can pull contaminated room air *in* or blow HD aerosols *out*.
• Work Flow: Work from clean to dirty. Place clean bags/syringes in the center, and vials/used items to the side. All work must be done on a chemo-absorbent pad.

B. The “Negative Pressure Technique”: Aseptic Voodoo Made Real

Chemo vials are often over-pressurized. If you just stick a needle in, a fine spray of hazardous drug will aerosolize out of the vial. You must master the “negative pressure technique” to prevent this.

Tutorial: The Negative Pressure Draw-Up

Goal: To draw up 5mL of cyclophosphamide without spraying the drug or creating a vacuum.

1. Step 1: Draw up a small amount of “air for liquid” in your syringe, but less than the dose you need. (e.g., draw up 3-4 mL of air for a 5 mL dose).
2. Step 2: Insert the needle into the vial. With the vial upright, inject the 3-4 mL of air into the *airspace* of the vial, not the liquid.
3. Step 3: Invert the vial. Let the drug “fall” into the syringe, helped by the slight positive pressure you created. As it falls, gently pull the plunger back.
4. Step 4: Draw up *more* than your target dose (e.g., draw up 6-7 mL).
5. Step 5: With the needle still in the vial, push the excess fluid and all air bubbles back into the vial. You are left with a perfect 5 mL dose.
6. Step 6: As you withdraw the needle, the vial now has a slight negative pressure, meaning it “sucks” in as the needle leaves, rather than “spraying” out.

C. Closed System Transfer Devices (CSTDs)

The negative pressure technique is a high-skill, imperfect art. The modern, safer solution is a CSTD (e.g., PhaSeal, Equashield). These devices create a sealed, needle-free connection.

• How they work: A special adapter (a “protector”) is spiked onto the vial. A second adapter is attached to your syringe. When you connect them, they form an airtight, drug-tight seal *before* the drug path is opened.
• The “Balloon”: Many CSTDs have a built-in expansion chamber (a small balloon). When you inject air, the balloon expands. When you draw out liquid, the balloon collapses. No air or vapor ever enters or leaves the system.
• The Law: USP <800> recommends CSTDs for compounding but requires them for administration of antineoplastic HDs, if the dosage form allows. As the pharmacist, you are responsible for procuring, training, and ensuring the CSTD is used correctly from compounding all the way to the nurse’s final infusion.

22.2.4 Deep Dive: Total Parenteral Nutrition (TPN) for Specialty Nutrition

This is arguably the most complex sterile product a pharmacist will ever compound. It is a 3-in-1 or 2-in-1 admixture containing dozens of ingredients, any one of which can cause a catastrophic incompatibility. The specialty patient population (Crohn’s, short-bowel syndrome, oncology) relies on this as their sole source of life.

Your role here is 90% clinical verification and 10% compounding validation.

A. The Pharmacist’s 10-Step TPN Clinical Verification

A TPN order arrives. You are the pharmacist. You must perform this check *before* you even think about compounding.

1. Check Indication & Patient Data: Why do they need it? (e.g., NPO > 7 days, short bowel). Check weight (use actual or adjusted for obesity), allergies (e.g., soy or egg for lipids), and line access (central vs. peripheral).
2. Calculate Basal Needs: Determine total calories (e.g., 25-30 kcal/kg/day), protein (e.g., 1.2-1.5 g/kg/day), and fluid (e.g., 30-35 mL/kg/day).
3. Verify Macronutrients:
   • Dextrose: Check the Glucose Infusion Rate (GIR). $$ \text{GIR (mg/kg/\min)} = \frac{\text{Rate (mL/hr)} \times \text{Dextrose Concentration (g/L)}}{\text{Weight (kg)} \times 60} $$

     GIR Critical Limit

     The maximum GIR for an adult is typically 4-5 mg/kg/min. Exceeding this overwhelms the liver’s ability to process the sugar, leading to hyperglycemia, hypertriglyceridemia, and fatty liver (hepatic steatosis). This is a core pharmacist check.

   • Protein (Amino Acids): Does the g/kg/day match your goal? Is it a specialty formula (e.g., renal-sparing)?
   • Lipids (ILE): Check the dose. Generally < 1 g/kg/day to avoid fat-overload syndrome.
4. Verify Electrolytes (The “Big 6”): Check Na, K, Mg, Phos, Ca, and Acetate/Chloride.
   • Acid-Base: Is the patient acidotic? They need more acetate (which is metabolized to bicarb) and less chloride. Is a patient alkalotic? They need more chloride. You will be adjusting the salt forms (e.g., NaCl vs. NaAcetate) to manage this.
5. THE CRITICAL CHECK: Calcium-Phosphate Solubility.

   This is the #1 physicochemical risk. If calcium and phosphate concentrations are too high, they will precipitate as Calcium Phosphate. This creates what is essentially “cement” in the bag, which will form a pulmonary embolus and kill the patient. This is not an exaggeration.

   Solubility depends on:

   • pH: Lower pH (more acidic) is better. The amino acid solution is acidic and is your primary buffer.
   • Concentration: Higher Ca and Phos concentrations = higher risk.
   • Temperature: Risk increases as the TPN warms to room temperature.
   • Order of Mixing: This is your key safety check.

6. Check Vitamins & Trace Elements: Are they ordered? Are there shortages?
7. Check ILE Stability: Is this a “3-in-1” (Total Nutrient Admixture – TNA)? The lipids, dextrose, and amino acids are all in one bag.
   • The dextrose and electrolytes create a “cationic” charge that can “crack” the lipid emulsion (the fat droplets coalesce).
   • Look for “creaming” (a white layer) or “oiling” (visible oil droplets). This is a deadly embolus.
8. Check Line Access: A TNA or a high-osmolarity TPN must go through a central line. Peripheral administration (PPN) is only for short-term, low-concentration formulas.
9. Check the Filter:
   • A 2-in-1 (lipids separate) requires a 0.22 micron filter (sterilizing).
   • A 3-in-1 (TNA) REQUIRES a 1.2 micron filter. A 0.22 micron filter will *block* the lipid globules.
10. Final Review: Check total volume, rate, and BUD (Category 2 = 14 days refrigerated, but often shortened by stability).

B. TPN Compounding: Man vs. Machine

Automated Compounding Devices (ACD)

Most TPNs are made using an ACD (e.g., a Baxa ExactaMix). This is a “pump” with 10-20 different channels, one for each ingredient. The pharmacist’s job is to:

• Validate Setup: Ensure the technician hung the correct ingredient on the correct channel. (Hanging KPhos on the NaCl channel is a fatal error).
• Validate Calibration: Ensure the machine is calibrated and the volumes pumped are accurate.
• Validate Mixing Order: The ACD software is programmed to mix in a safe order.

Manual Compounding

For pediatric or neonatal TPNs (which have tiny, precise volumes), an ACD is not accurate enough. These must be made manually, drawing each ingredient into a separate syringe and injecting it into the final bag. This is the highest-risk sterile compounding, requiring meticulous technique and a second-pharmacist check of every single syringe and calculation before mixing.

PART 2: MASTERCLASS IN ADVANCED NON-STERILE COMPOUNDING

We now shift from USP <797> (sterility) to USP <795> (non-sterile). Here, the primary goals are accuracy, stability, and elegance. This is where you truly become a formulation scientist, creating products that do not exist commercially.

22.2.5 Deep Dive: Oral Suspensions for Pediatric Rare Diseases

The Problem: A 2-year-old child (12 kg) with a rare metabolic disorder needs sildenafil 10 mg TID for pulmonary hypertension. The only commercially available forms are 25mg tablets and a 10mg/mL IV injection. You cannot send a parent home with instructions to “crush a tablet and guess.” You must compound a stable, accurate, and palatable oral liquid.

The Pharmacist’s Formulation Process:

Step 1: Choose the Drug Source

• Pure API Powder: This is the “gold standard.” You buy pure sildenafil citrate powder from a reputable supplier. This is clean, free of excipients, and easy to weigh.
• Commercial Tablets: This is more common. You must crush the 25mg tablets. The problem? The tablets also contain fillers, binders, and coatings (e.g., microcrystalline cellulose, lactose, titanium dioxide). You must ensure these excipients won’t interfere with your suspension or harm the patient (e.g., lactose in a lactose-intolerant child).

Step 2: Choose the Vehicle (The “Base”)

This is the most critical decision for stability and palatability. You cannot just use water.

Masterclass Table: Common Non-Sterile Vehicles

Step 3: Compounding Technique (Geometric Dilution)

You cannot just dump the crushed tablets into the bottle of vehicle and shake. This will result in an uneven, inaccurate “slurry.” You must use geometric dilution.

Tutorial: Making Sildenafil 2.5 mg/mL Suspension (120 mL)

1. Calculate: Need 2.5 mg/mL * 120 mL = 300 mg of sildenafil.
   Source: 25 mg tablets.
   Need: $300 \text{ mg} / 25 \text{ mg/tablet} = 12 \text{ tablets}$.
2. Crush: Place the 12 tablets in a clean glass mortar and crush to a fine, uniform powder.
3. Levigate (The “Paste”): Add a small amount of your vehicle (e.g., 10-15 mL of Ora-Plus) to the powder. Use the pestle to rub the powder into the liquid, forming a smooth, uniform paste. This step is essential to ensure all particles are wetted and no clumps remain.
4. Geometric Dilution (The “1:1”):
   • Add an amount of vehicle *equal in volume* to the paste (e.g., another 15 mL). Mix thoroughly.
   • Add an amount of vehicle *equal in volume* to the new mixture (e.g., 30 mL). Mix thoroughly.
   • Continue this “add and mix” process until you have incorporated all your Ora-Plus (e.g., 60 mL).
5. Transfer & QS: Transfer the mixture to a calibrated prescription bottle. Rinse the mortar and pestle with your flavoring vehicle (e.g., Ora-Sweet) and add the rinsing to the bottle. Finally, add Ora-Sweet “Quantity Sufficient” (QS) to the 120 mL mark.

Step 4: Assigning the BUD (USP <795>)

This is different from <797>. If you have no published stability data, you must use the default BUDs:

• For a Water-Containing Oral Formulation: The BUD is no later than 14 days, stored in the refrigerator.
• For a Water-Containing Topical/Dermal (e.g., a cream): The BUD is no later than 30 days, at room temp.
• For a Non-Aqueous Formulation (e.g., an ointment): The BUD is no later than 6 months, at room temp.

Step 5: Labeling and Quality Control (QC)

• Labeling: Must include “Shake Well Before Use,” “Refrigerate,” the BUD, and the concentration (2.5 mg/mL).
• QC: The pharmacist must check the final product for “elegance” (is it smooth? uniform?), color, and odor. You also check the math, the ingredients, and the procedure.

22.2.6 Advanced Non-Sterile: Customized Topicals

This is a common specialty service for dermatology and pain management. The goal is to combine multiple drugs into a single, cosmetically elegant, and stable topical base. The principles are the same, but the equipment and formulation science are different.

A. Equipment: Beyond the Mortar and Pestle

• Ointment Mill: This is the key to an “elegant” (non-gritty) product. It’s a machine with two or three rollers that spin at different speeds, creating immense shear force that breaks down particles to a uniform, impalpable size.
• Electronic Mortar & Pestle (e.g., Unguator): A device with a specialized mixing blade and disposable “pot” that mixes the ingredients under high shear. It’s clean, efficient, and excellent for creating stable emulsions.
• Hot Plate / Water Bath: Necessary for melting waxy bases (like in suppositories) or for creating certain gel phases.

B. Formulation Science: Making a “PLOGel”

The most common request in pain management is a transdermal gel. The “gold standard” is a Pluronic Lecithin Organogel (PLO). This is a complex emulsion you must make from scratch.

The Science: A PLO is an emulsion.

• The Oil Phase: Contains Lecithin (an emulsifier) and Isopropyl Palmitate (a solvent and skin penetrant). This is where you dissolve your oil-soluble drugs.
• The Water Phase: Contains Pluronic F-127, a unique polymer that is liquid when cold and a thick gel at room temperature (a “thermo-reversible gel”). This is where you dissolve your water-soluble drugs.

Tutorial: Compounding a “Ketamine/Lidocaine/Gabapentin” PLO Gel

1. The API Phase: Weigh your powders (e.g., Ketamine HCl, Lidocaine HCl, Gabapentin). Levigate them with a small amount of the water phase or other solvent.
2. The Oil Phase: In a beaker, mix the Lecithin and Isopropyl Palmitate (LIPOIL) until dissolved.
3. The Water Phase: In a separate beaker, mix the Pluronic F-127 with cold water and let it sit (refrigerated) until it dissolves into a clear liquid.
4. The Emulsification: Add your dissolved API paste to the water phase. Then, add the oil phase. Mix. At this point, it will be a milky liquid.
5. The “Magic” (Shearing):
   • Syringe Method: Draw the entire mixture into a large syringe. Connect it to an empty syringe with a Luer-lock connector. Force the mixture back and forth between the two syringes 30-40 times. This shear force creates the stable emulsion.
   • Unguator Method: Place all ingredients in the Unguator jar and run the machine for 5-10 minutes.
6. Packaging: As the mixture warms to room temperature, it will thicken into a gel. Package it in topical syringes or pump dispensers, as it’s often too thick for a jar.

22.2.7 The Quality System: Documentation as Your Shield

As we’ve seen, compounding is a high-risk, multi-step process. In the community, your “check” is final verification. In compounding, there are dozens of checks, and every single one must be documented. If you are ever inspected by the FDA or Board of Pharmacy, or sued by a patient, your documentation is your only defense. If you didn’t document it, it didn’t happen.

Your quality system is built on two key documents:

1. The Master Formulation Record (MFR)

This is the “master recipe.” You create this once for each unique formulation (e.g., “Sildenafil 2.5 mg/mL Suspension in Ora-Sweet/Plus”). It must be approved by the Pharmacist-in-Charge. It is the *source of truth*.

Masterclass Table: Anatomy of a Master Formulation Record

2. The Compounding Record (CR)

This is the “log.” It is the specific worksheet you fill out every time you make a batch (even a batch of one). It proves you followed the MFR perfectly.

The CR must include:

• Reference to the MFR: (e.g., “Made per MFR #SUS-104”).
• The “Trace-Backs”: This is the most critical part for QC.
  • Lot Number for *every single ingredient* (e.g., Sildenafil Lot #123, Ora-Plus Lot #456).
  • Expiration Date for *every single ingredient*.
  • Supplier/Manufacturer.
• The “Do-ers”:
  • Signature/initials of the compounder.
  • Signature/initials of the verifying pharmacist.
• The Specifics:
  • Date of compounding.
  • Prescription number.
  • The assigned BUD (e.g., 01/15/2025).
  • Results of any QC tests (e.g., “pH = 4.5, Pass,” “Appearance = White, Opaque, Pass”).