COMPOUNDING

Non-sterile compounding = traditional compounding

Sterile compounding = sterile drugs/drugs that need to be prepared in sterile environment
Outsourcing = hybrid btwn manufacturing and compounding

Non-sterile (USP 795)

For individual patients (not prepared in bulk) – must have an Rx, unique dose/formulation for a patient that is not commercially
available
- Change formulation of medication – ex. estradiol cream, calamine/HC topical ointment
- Avoid excipient that patient cannot tolerate
- Formulate something that isn’t commercially available – ex. chewable levo tablets for dog, antifungal lollipops
- Add flavor
Active drug = API (active pharmaceutical ingredient)
Physical
- Requires dedicated space
o Segregated from dispensing part of pharmacy
o Segregated from sterile compounding of the pharmacy
o Can be done in ambient air, but separated from other parts of the pharmacy
- Powder containment hood
o Ventilated compounding enclosure (VCE)
- Adequate space for orderly work
- Water/sinks
o Potable – tap water
o Purified (ex. distilled)

Sterile (797)
- IV drugs – ex. parenteral nutrition, antibiotic bags
- Eye drops, ear drops
- Irrigations – ex. gentamicin bladder irrigation solution
ISO air
- ISO 5 in the hood (PEC)
o Laminar air (parallel lines)
o Line up items correctly to prevent turbulent air
o Wipe off outside of vials, syringes, etc. with 70% IPA before bringing them into PEC (disinfecting)
o Most contamination comes from compounding staff – improper hand washing
o Waste should be removed shortly after it is created – do not let it accumulate inside PEC
o Keep air as clean as possible – work at least 6 inches from the front edge
- ISO 7 in buffer room
- ISO 8 for anteroom if opening into positive pressure SEC
o ISO 7 if opening into negative pressure SEC (hazardous)
- Ambient air not measured (appx 9)
- Direct compounding area = cleanest part of the hood
o First air (directly from HEPA filter)
Basic req.
- Smooth, impervious (fluid does not soak into them), easy to clean/disinfect
- Sampling
Hazardous (USP 800)
NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings (National institute for occupational safety and
health)
American Society of Health-System Pharmacists (ASHP) – write practical guidelines necessary to meet requirements
Non-sterile (+ 795)
- MTX tablets  ointment for topical use = non-sterile prep
- 12 ACPH
Sterile (+ 797)
- MTX IV solution  IV bag = sterile
- 30 ACPH
Pose danger to any staff that come into contact with the drug
Characteristics (at least 1)
- Carcinogenic
- Teratogenic (reproductive toxicity)
- Causes organ toxicity at low doses
- Genotoxic (damage to DNA)
Antineoplastic
- Chemo drugs
Non-Antineoplastic
- Hormones
- Transplant drugs – azathioprine, cyclosporine, mycophenolate, tacrolimus, sirolimus
- Televancin
- Warfarin
- Fluconazole, voriconazole
- Antiretrovirals for HIV– abacavir, entecavir, nevirapine, zidovudine
- Antiretrovirals for CMV - ganciclovir, valganciclovir
- Isotretinoin
- BPH – finasteride, dutasteride
- Renal disease – darbapoetin alfa
- Hyperthyroidism – methimazole, PTU
Requirements
- Prior to handling, both men and women with reproductive capability must confirm in writing that they understand
the risks associated with handling HDs
Physical space
- C = containment – containing fumes/particles inside those areas
o C-PEC
o C-SEC
- Negative air pressure
o Air flow goes from ante room to buffer room to hood – externally exhausted
- Air changes (these air hazardous requirements)
o Non-sterile: 12 ACPH
o Sterile: 30 ACPH
- External exhaust
o Sterile has to be externally exhausted
o For non-sterile, you can have redundant HEPA filters (double filtered air) if external exhaust not available

PEC – primary engineering control (hoods) = sterile hood

 - Laminar airflow workbench (LAWF) = for non-hazardous drugs
- Biological safety cabinet (C-PEC) = for hazardous drugs
- Isolators – air inside is isolated from the room air – red waste buckets
o Closed front PECs
 Glove box
o Compounding aseptic isolator (CAI) – sterile, non-HD
 Positive air pressure btwn antechamber protects CSPs
 Red waste buckets
o Compounding aseptic containment isolator (CACI) for sterile, HD
 Negative pressure
 Yellow waste buckets
o Can be in buffer room, but do not have to be
o Can be located in a segregated compounding area (SCA) – the isolator acts as the PEC
 Isolator located in a space with unclassified air
 Cannot be near busy areas
 Garb has to be complete unless manufacturer of the SCA states otherwise (like only gloves)
 Maximum BUD = 12 hours
- Clean room = 1+ PECs within a SEC with adjacent anteroom
o ISO 5 PEC (LAFW, BSC, or isolator)
o Open front PEC located inside SEC
 Sterile, non-HD = conventional LAFW (sterile hood, cabinet, workbench) – horizontal airflow
 Protects the CSPs (positive air pressure)
 No external vent
 Sterile, HD = biological safety cabinet (BSC)
 Protects CSPS and staff (negative air pressure)
 External vent
SEC – secondary engineering control = buffer room/sterile compounding room (PEC is located inside here)
- C-SEC = hazardous
Anteroom – adjacent to SEC (handwashing, garbing)
CSTDs (closed system transfer device) – used to keep hazardous drugs contained inside the device to prevent spills and fumes
from leaking out
- Recommended for pharmacists
- Nurses have to use them (USP requirement)
o Some drugs do not fit inside one, but if they do it must be used
- Syringe/vial screwed into CSTD instead of just inserting directly into the vial
CSPs- compounded sterile products
- Small volume parenteral (SVP): <100 mL
- Large (LVP): >100 ml
HEPA filters
- >99.97% efficient in removing particles as small as 0.5 microns or larger
- First air = cleanest air
o Direct compounding area (DCA)
o Ex. putting needle into vial/into IV bag – first air should hit the critical areas
o Do not block first air
Personnel training
- Initial training – didactic and hands-on (observed by supervisor/expert)
- Continuous training – whenever drugs/procedures change
- Hand hygiene, garbing and gloving
o Fingerprint test – both hands
o Tryptic soy agar (TSA)
o Incubated 2-3 days (want 0 CFUs – colony forming units)
o Passing = 3 consecutive gloved fingertip samples with zero CFUs for both hands
 Initially
 Annually for low/med risk CSPs
 Semi-annually for high risk CSPs
- Sterile drug prep (aseptic prep)
o Media-fill test
o Tryptic soy broth (TSB)
 o Incubated for 14 days – if liquid stays clear = pass
 Turbidity = contamination (cloudy)
- Cleaning/disinfection
o All PECs should be kept running at all times
o Power outage  clean with germicidal detergent and disinfect with 70% IPA
 Lint-fee sterile wipes
 Do not spray directly into PEC (makes turbulence)
o If it is a C-PEC, sanitization will need to be done if the power has been turned off
o Leave on for 30 min before compounding
o Periodically and at end of day – clean from cleanest to dirtiest (clean then disinfect)

o Hazardous drug cleaning – sanitization

 Deactivation and decontamination
 2% bleach (sodium hypochlorite) or Peroxide (do both of the steps)
o Peridox
 Cleaning
 Germicidal detergent – Quat, Ammonium, Phenolics
 Diseinfection
 70% IPA
Temperature monitoring
- SEC = daily: < 20 C, 68 F
- Fridge = BID: 2-8 C
- Freezer = BID: -50- -15 C
Air sampling
- At least every 6 months (certified person or qualified staff member)
Surface sampling
- Periodically – end of the day
- Tryptic soy agar (TSA)
- Polysorbate 80 and lecithin added to TSA to neutralize effect of disinfecting agents on the surfaces
- All surfaced that are regularly exposed to staff should be tested
o At least one sample from ISO 5, 7, 8
- > 3 CFU in ISO 5 = action
- > 5 CFU in ISO 7 = action
Air pressure testing
- Confirms differential btwn two spaces
- Each shift (preferably) or daily (sometimes it is continuous)
Risk
- 795/797 – contamination of drugs
o Sterile
 Low – 1-3 sterile additives
 Medium – more than 3 sterile additives
 High – non-sterile ingredients/equipment
 Immediate use – higher risk, but acceptable if necessary to save life
 BUD = 1 hour
o Non-sterile
 Simple
  Moderate – no established stability data/specialized calculations/procedures
 Complex
- 800 – contamination of staff
o Full USP 800 requirements
 Cannot mix HD equipment with other equipment
 Dedicated tray/spatula – decontaminate after each use
o Risk assessment – determine which a lower risk and make a plan of how to handle them without full 800
 Use ASTM rated gloves (chemo gloves)
Drug exposure - HD
o Remove clothing that was exposed
o Cleanse affected skin
o Rinse eyes for at least 15 min (if exposed)
o Medical attention if necessary
o Document exposure
- Respiratory protection – for direct HD exposure:
o Cleaning spills larger than what can be contained with a spill kit
o Sanitizing underneath work surface of C-PEC
o Exposure/suspected exposure to airborne powders/vapors
o Disposing PPE contaminated with hazardous drug residue
o N95 with side shields
o PPAR mask (needs battery)
- Spills
o Cleaned up immediately, put up a sign
o Spill kit must be in every area where HD travel
 Gloves, gown, N95 mask, scoop and scraper, booties, chemo waste bag, documentation form

Administration of HD
- IV drugs
o 2 pairs of chemo gloves
 1 pair can be used if administering intact tablets/capsules
o Chemo gown
o CSTDs must be used by nurses for drug administration
- Avoid manipulation of oral HDs – use liquid formulation if available
o If manipulation is required, should be done in plastic bag

HD Disposal
- All is considered contaminated  yellow chemo waste bin
- Bulk waste  black container
PPE
Sterile HD
- Head covers (+ beard cover)
- 2 pairs of booties
- Impermeable gown
- 2 pairs ASTM rated gloves
- Full face respirator or face shield with goggles
Non-sterile HD
- Single pair of gloves may be adequate (ex. intact tabs/caps)
- Manipulation of HDs
o Double gloves
o Gown
o Mask
o Disposable pad to protect work surfaces
Sterile compounding
- Shoe covers, head covers, mask (ante room must have mirror)  hand hygiene including fingernails (fingertips to
elbows in circular motions for at least 30 seconds)  non-shedding gown  enter buffer area  apply alcohol based
hand scrub (iodine/chlorhexidine) and let dry  gloves (one pair under cuffs, second pair over cuffs)  sanitize gloves
with 70% IPA
 - Leaving compounding area = all garb except gown goes into disposal
- If gown is not visibly soiled, it can be left in the ante area and reused
- If ante room has been exited, all re-garbing must be done
- For HD
o Respirator (N95)
o 2 pairs of ASTM rated gloves
 change every 30 min
o Eye/face protection when there is high risk for spills/splashes (full-face piece respirator or face shield with
googles)
o Chemotherapy gown (disposable, impermeable – polyethylene coated polypropylene or other laminate
material, and must close in the back)
 Change every 2-3 hours
Measuring equipment
- Should hold exact amount that you need or slightly larger
- Metric system
- Graduate – has lines on the glass
o Conical – wider the mouth = more error
o Cylindrical – more accurate, harder to mix
o Do not use to measure volumes that are less than 20% of the graduate’s capacity
- Syringes
o Hypodermic (parenteral) or oral with or without cannula can be used
o Most accurate for small volumes, especially viscous liquids
o Types
 Luer lock - for patient safety, make leak free, secure connections
 The luer taper at the end of the syringe screws into leur lock
 Prevents needles falling out
 Enable patients to get multiple IV lines without multiple pokes
 Oral syringes
 Sticker placed over tip
 Hypodermic (injection) syringes come with cannulas
- Balances
o Torsion balance (Class III/A balance)
 MWQ = sensitivity requirement/acceptable error rate
o Electronic balance (analytic balance/scale)
 Higher sensitivity
o Use weigh boat or glassline weighing paper
- Pipettes – thin plastic or glass
o Volumetric: set volume only
o Mohr: graduated – used to measure small, different volumes
Mortar and pestle – pharmacy must have glass and wedgewood or porcelain
- WW: dry crystals, hard powders
- Porcelain: smoother surface- blend powders and pulverizing gummy consistency
- Glass: for liquids
Spatulas
- Flat part – flatten and grind down
- Stainless steel, plastic, rubber
o Metal should not be used if compounding metal ions
o Rubber is for corrosive material
Ointment slabs
- Also used as work surface for things such as forming pills = pill tile
- Disposable parchment ointment slabs
Powder sieves
- Powder sifted after grinding to ensure uniform particle size – fine/very fine
o Smaller = more total surface area = better absorption
o Larger particles = gritty
Electric mixing equipment
- Ointment mills/grinders – reduce particle size to increase surface area and make homogenous
- Homogenizer – electric mortar and pestle (common: Unguator)
 - Hot plate used with stirrer bars to heat and mix – has rotating magnet
Molds
- Tablets, lozenges, troches (ODTs), suppositories
- Soft products often dispensed in disposable plastic molds, refrigeration helps retain shape
Tablets
- Tablet press = mold – two plastic/metal plates used to compress damp powder into tablets
o Tablet punch
Capsules
- Gelatin
- Hypromellose (from cellulose) – vegetarian/vegan
- Machine
o Has plates in it – put in capsule bodies and shake to make them upright, put powder and spread with plastic
spreader, then put on caps and shake and they position themselves
Tube sealers
- Heat and squeeze ends of tube shut

Ingredients: APIs and Excipients

High quality – USP-NF or FCC
If from non-FDA facility – certificate of analysis should be obtained
Missing expiration date – max 3 years from date of receipt (both need to be on label)
Surfactants – lower the surface tension btwn two ingredients (interfacial tension) to make them more miscible
- Surface active agent
- Micelle mechanisms
o Emulsions
- Non-micelle
o Film
o Electrically charged layer
- Types
o Suspending agents (dispersing agent/plasticizer) – to make suspension – particles do not dissolve in a liquid
 Gums
 Cellulose – thickening
o Emulsifiers/emulgents – liquid in liquid – keep droplets dispersed in liquid vehicle
 Pick surfactant based on HLB value
 <10 = w/o
 >10 = o/w
o Levigating/wetting – aids in grinding
 Mineral oil for liphilic
 Glycerin for aqueous (or propylene glycol)
o Foaming – lower surface tension of water
 Simethicone = anti-foaming agent
o Glycols and gels – surfactants and delivery vehicles, have both lipophilic and hydrophilic parts
 Polyethylene glycol (PEG) – osmotic
 Poloxamer – use for topical drug delivery
 Thermoreversible gel – changes form depending on temp – liquid in cold, solid at RT
 PLO gel = pluronic lecithin organogel
Stability and degradation
Reactions that cause degradation (reactions to the functional groups)
- Oxidation-reduction
o Oxidation = lose electron
 Ex. cooking onions (alcohol functional group is oxidized)
 Compounds with hydroxyl groups
 Epinephrine – can often be seen with color change to amber
 Catalyzed by heat, light and metal ions
o Reduced = gain electron
- Hydrolysis
o Avoid storing in bathroom
o Dessicants
 o Esters, amides, lactams – all have carbonyl group (C=O)
 Ex. ASA – want hydrolysis to happen in the body, not on the shelf (vingar smell)
- Photolysis
o Use light protective packaging
Limit degradation
- Excipients – buffers, preservatives (BAK), chelating agents
- Light protection – amber glass
- Packages – keep out moisture
- Proper storage

Preventing oxidation

Prevent hydrolysis

Excipients
Binders – add cohesion, with or without disintegrant
Diluents/fillers – starch, calcium salts, powdered cellulose
Disintegrants – alginic acid, placrillin potassium, cellulose, starch
Flavorings/colorings – aspartame, saccharin, glycerin, dextrose, lactose, mannitol, sorbitol, phenylalanine, stevia, xylitol
Lubricants – magnesium stearate, colloidal silica
Preservatives – chlorhexidine, BAK, cetyl, phenol/ol, parabens
- Ophthalmic – BAK, EDTA, sodium benzoate, benzoic acid
- Oral – parabens, sodium benzoate/benzoic acid
Hydrophobic solvents
- Alcohol – high miscibility with water, used to dissolve solutes that would be insoluble in water alone
- Oils/fats – delivery vehicles
- Glycols – PEG – water sol and miscible, Polybase – suppository base, emulsifier
- Emollients
o Occlusive ointments – petroleum, Theobroma (hydrocarbon – oleaginous)
o Humectants – glycerin, glycerol, PEG
o Ointments – 0-20% water – combo products w/ humectant: Polybase, Aquaphor, Aquabase
  Absorption base – to form w/o emulsion (hydrophilic petrolatum, lanolin)
 Water removable base – o/w emulsion = cream
 Water soluble base – gel (PEG ointment)
o Cream – 20-50% oil
o Lotion – most water – can have small amt of alcohol to solubilize ingredients
Adsorbents – magnesium oxide/carbonate, kaolin
Coatings – shellac, gelatin, gluten
Enteric coat – cellulose acetate phthalate
Gelling/thickening agent, stabilizer – gelatin, cellulose, bentonite, agar, gums, carbomer, acacia, alginates
Levigating/wetting agent – mineral oil, glycerin

Documentation
Each product must have:
- Master formulation record – what you should do
o Products are made according to this (compounding steps)
- Compounding record – what you did: specific to the preparation and the staff involved
o Official name/assigned name
o Reference number for master formula
o Strength, dosage form
o Ingredients – manufacturer/sources, lot numbers and expiration dates
o BUD, actual (assigned)
Quality ingredients: USP-NF, FCC (preferred from FDA regulated facility, otherwise need CoA)
Material safety data sheets (MSDS) for bulk ingredient – to determine safety procedures for a specific material, will tell which
type of PPE to wear, what the chemical can harm, what to do if there is exposure
Formulation determines the type of garb
- Minimally: clean lab coat and gloves for non-sterile, non-HD formulations
Completion steps
- Package, label, auxiliary labels. Duplicate label can be places in logs
- QC – weight, color, pH, consistency etc. add those to compounding record
- Counsel patient, add ADRs to compounding log
Unit dose repackaging BUD: whichever is earlier:
- Manufacturer’s expiration date on original container
- 1 year from the repackaging date

Powders
Comminution – reducing particle size (increased SA = increased rate of absorption)
- Trituration – grind into fine powder
- Levigation – trituration with a levigating agent
o Spatulation is similar to levigation but on ointment slab with spatula
- Pulverization by intervention – dissolve crystals in solvent and let solvent evaporate, then they recrystallize and will
be easier to crush into fine powder
After comminution, put through sieve – sieve number is based on the number of holes per sieve
Glidant/lubricant: magnesium stearate – helps powder flow easier
Surfactins: sodium lauryl sulfate – to neutralize charge and keep powder from floating away

Solutions (homogeneous)
Fick’s first law of diffusion – increase dissolution rate
- Larger SA (more, smaller particles)
- Stirring
- Heat
Buffer system to resist pH changes – prevent damage to tissues, increase stability
Preservative
Flavoring/sweetener/coloring agents
Oral agents with water: max BUD 14 days, fridge

Suspensions (hetero)
Prepare powder, wet powder, levigate to form paste, add liquid in portions, add surfactant, transfer to graduate/container and
QS to final volume
Homogenizer will make uniform suspension
Preservative
Flavorings/sweeteners
Oral sus w. water: 14 day BUD, fridge

Emulsions (hetero)
Continental (dry) gum method
- 4:2:1 – oil, water, emulsifier in order OWF
- Gum levigated with oil then water added all at once
- Mixture triturated by shaking until cracking sound is heard and mixture looks creamy white
- Add other ingredients by dissolving them first in other solution and add water QS
- Homogenize
English (wet) gum method
- 4:2:1 ratio
- Triturate gum (emulsifier) and water to form mucilage
- Add oil slowly while triturating
- Finish same as previous method

Melting point order

- Line up from lowest temp to highest temp and add them in that order

Capsules
Smaller number = larger size
Glycerol/sorbitol = plasticizers to make capsules less brittle and more flexible
Punch method
Manual capsule-filling machine

Tablets
Diluents
Binders
Disintegrants
Lubricants
Coloring agents, coating agents, flavoring agents
Molded tablets – triturate dry ingredients and mix by geo dilution, moisten with alcohol/water, pasty consistency molded into
tablets and allowed to dry

Lozenges/troches
Hard: in base of sucrose/syrup
Soft: PEG
Chewable: glycerin/gelatin

Ointments
Melt from highest to lowest melting temperatures
Pastes are thicker – do not melt at body temp

Gels
Semisolid interpenetrated by liquid
PLO gel – for transdermal drug admin
- pluronic – poloxamer polymers
- lecithin – organic lipophilic ingredient
- organogel
- thermoreversible (liquid in cold, gel at room temp)
BUD 30 days (contains water)

Suppositories
Oil bases
 - Cocoa butter (theobroma)
- Hydrogenated veg oils (palm, palm kernel, coconut)
Water-sol bases
- PEG polymers
- Glycerinated gelatin
Density factor – used to calculate the amount of base displaced
- Lower = displace more of base
- Higher = displace less of base
Hand molding
Fusion molding – heat base gently, add ingredients, pour into RT mold
Compression molding – pour into cold compressed mold
Lubricants – glycerin, PEG (for oil sol bases), mineral/veg oil (for water sol bases)

Non-sterile quality assurance

- Standard operating procedures (SOPs)
- Reviewed and updated regularly
- Periodic testing of finished preparations – in-house/outsource

Dental gel would

be 30 days

Sterile preps
Physiochemical
- IV sol = isotonic, 285 mOsm/L
 o Osmolarity = all solutes
o Tonicity = on solutes that do not cross the vasculature
o Highest allowable is 900 mOsmol/L for peripheral lines, anything higher  central line
o Hypertonic = water out of RBC
o Hypotonic = water into RBCs
- pH close to neutral
- Non-PVC for leaching/sorption issues
Ready to use meds (RTU) – no CSP risk level. BUD provided by manufacturer
Ready to use vial/bag systems (Add-Vantage) – no CSP risk
Do not inject air prior to removing cytotoxic drugs from vials/CSTDs
Visual inspection
- Correct volume before compounding for pharmacist to see actual volume in syringe
- Finished = visual inspection immediately after prep against dark background, lightly squeeze to check for leakage
Terminal sterilization
- Required for high risk CSPs
- Steam sterilization – autoclave
- Dry heat – depyrogenation
- Do not use heat on heat sensitive drugs (proteins, hormones)
Bubble point test
- Heat liable CSPs sterilized with 0.22 micron filter
o Bubble point test must be performed to test filter integrity
Labeling
- Some high risk CSPs/CSPs intended for use after BUD  sterility testing
o Tryptic soy broth OR
o Fluid thioglycollate medium (FTM)
o Bacterial endotoxin (pyrogen) testing before use
 Limulus Amebocyte Lysate (LAL)