Final Written Exam

Dr. Yang

Primary Engineering Controls (PECs)

Designed to maintain ISO Class 5 air quality in the work zone

• Laminar Airflow Workbench (LAFW)

  • Airflow hoods

  • Flow workbenches

  • Horizontal or vertical hoods

  • “Hoods”

Laminar: airflow movement

• Unidirectional, linear manner

What are Secondary Engineering Controls (SECs), and what is their role?

Direct compounding areas surrounding PECs that must be controlled to prevent contamination

• SECs work adjunct to PECs to maintain environmental quality

How do PECs and SECs work together to minimize contamination risk in sterile compounding?

They work adjunct to one another to control air quality

ISO Classifications → PEC

Class 5

ISO Classifications → Buffer Room

Class 7

ISO Classifications → Ante-area

Class 8

How does the ISO classification number relate to particulate matter?

Air quality is rated based on ISO class

• The number of particles in a given space can be measured and should be limited in compounding areas

Low ISO Class = Cleaner air/environment

First Air (AKA “clean air”)

• Air that exits the HEPA-filter to remove particles & microorganisms that are 0.3 micron or larger

• Positive velocity to prevent room air from entering the clean zone (90 ft. per min ± 20%)

• Can be easily disrupted via:

  • Normal activities that can create velocities that exceed the outward velocity of first air

  • Inward flow from room air or regurgitation of air into LAFW

Why must critical sites remain continuously exposed to first air?

To prevent contamination by ensuring only HEPA-filtered air touches the site

Types of PECs

• HLFW (horizontal airflow)

• VLFW (vertical airflow)

• BSC (for hazardous drugs)

• CAI (non-hazardous isolator)

• CACI (hazardous isolator)

Horizontal Laminar Flow Workbench (HLFW) → PEC

Airflow in a horizontal direction

• Must run at least 30 minutes prior to use if turned off

• Manipulations must be performed within the central work zone

  • 6 in. from sides

  • 6 in. from front

  • 3 in. from back

• Cleaning

  • top → bottom, back → front

  • HEPA protective screen not a part of routine (remove every 6 months and clean well)

Vertical Laminae Flow Workbench (VLFW) → PEC

Produces first air in a vertical direction

• Requires altering of manipulations and techniques

Biologic Safety Cabinet (BSC) → PEC

• Vertical laminar airflow

• Provides product, environment, and operator protection

• Inward flow of air through front opening

• Often exhausts air to outside

• Should run for at least 4 minutes if turned off

• Should be used when preparing hazardous drugs

Compounding Isolators (CAI & CACI) → PECs

• Compounding Aseptic Isolator (CAI)

  • Mostly used for nonhazardous preparations

• Compounding Aseptic Containment Isolator (CACI)

  • Mostly used to prepare hazardous agents

  • Improved protection of operator compared to BSC

  • Decreased influence of room air on sterile preparation

Which types of PECs and room conditions are required for hazardous drug compounding?

• PECs: BSC or CACI

• Room conditions: Negative room pressure

Why are negative pressure and physical separation necessary for compounding hazardous drugs?

• Protect personnel from hazardous drug exposure

• Prevent contamination of nonhazardous sterile products

• Maintain required airflow and pressure gradients

• Comply with USP <797> standards

• Protect vulnerable patients

What is SCA (Segregated Compounding Area)?

Area in the pharmacy when pharmacies don’t have enough physical space or resources for an IV room

• ISO Class 5 PEC (hood/isolator) in a segregated compounding area

• Unclassified air

• Short BUD (≤12 hrs RT) for low-risk compounded sterile products

What are the environmental limitations of a segregated compounding area (SCA)?

It’s not required to meet ISO Class 7 or 8 air quality standards

What BUD restrictions apply to CSPs prepared in an SCA?

• Room temperature → 12 hrs

• Refrigerated → 24 hrs

Activities performed in the ante-area vs. buffer area

• Ante-area (Class 8): outside of the buffer area

  • Handwashing

  • Garbing

  • Staging

  • Order entry

  • Labeling

• Buffer area (Class 7): where PECs are located

  • Compounding

  • Limited traffic flow

  • No handwashing

  • Items brought in should be limited (and must be wiped down prior to entry)

What is the positioning requirement for aseptic manipulations inside an LAFW or BSC like in PEC?

Work at least 6 inches from the outer edge

When must PECs receive certification or re-certification?

• Certification

  • Initial installation

  • If device or room is moved

  • Following a major repair

  • Major service to facility

• Re-certification

  • Every 6 months

Why is certification/re-certification of PECs critical for maintaining environmental control and patient safety?

• Ensures Class 5 air quality is maintained

• HEPA filters are intact

• Unidirectional airflow protects the sterile field

• Hazardous drug containment is functioning

• Patients are protected from contaminated CSPs

Cleaning the HLFW

top → bottom, back → front

What is the correct sequence for donning PPE?

• Remove all jewelry

• Shoe covers as you’re stepping over the line of demarcation

• Head cover (& beard cover if necessary)

• Face mask

• Handwashing and dry hands with lint-free cloth

• Non-shedding lab gown

• Antiseptic hand cleansing

• Powder-free, sterile gloves

Common critical sites

• Needle:

  • Hub

  • Shaft

  • Bevel

• Syringe:

  • Barrel

  • Plunger

  • Tip

Which parts of a needle and a syringe are considered critical sites?

• Needle: Hub, tip, and shaft

• Syringe: Plunger ribs, tip

Which part of a syringe is the ONLY part that’s safe to touch during aseptic manipulations?

Outside of the syringe barrel

How does the needle gauge relate to lumen size?

The higher the gauge, the smaller the lumen diameter

Which needle gauge is most commonly used for sterile compounding?

18G

What is a major difference between open and closed systems?

Open systems allow free exchange of air and particulates between the preparation and the environment (e.g., ampule)

When and why must a filter needle or filter straw be used in sterile compounding?

When withdrawing medication from an ampule, to prevent glass particles from being drawn into the syringe

Why must a filter needle or filter straw be replaced with a regular needle before injecting medication into an IV bag?

To avoid pushing the filtered-out particles back into the final preparation

How do syringe size and calibration marks affect the accuracy of volume measurement?

Measurement is most accurate when the syringe size is closest to the volume being measured

What are small-volume parenterals (SVPs)?

Volume threshold ≤100 mL

What are large-volume parenterals (LVPs)?

Volume threshold >100 mL

What are the advantages of adaptable systems in sterile compounding?

• Short preparation times

• Improves accuracy

• Reduction in drug waste

What are the disadvantages of adaptable systems in sterile compounding?

• COSTTTT

• Additional inventory

• Specific equipment needed

What are administration sets for sterile preparations?

To deliver medication from container to patient

• Must be changed every 3-4 days

• Includes:

  • Tubing

  • Needle adaptor

  • Clamp

  • Drip chamber

  • Spike proximal Y-site

  • Additive port of distal Y-site

What is the purpose of in-line filters in sterile compounding?

Prevents particles, air, microorganisms, and endotoxins from being infused to the patient

What size in-line filter is typically used to remove bacteria and fungi from a solution?

0.22-micron

When is a 1.2-micron filter preferred over a 0.22-micron filter?

Administration of liposomal medications

What are the factors influencing the sterility of CSPs?

• Environmental quality

• Proper handwashing

• Proper hand hygiene

• Use of PPE

• PECs and SECs

• Maintenance of equipment and environment

• Aseptic technique

What are ampules?

Glass container with injectable solution

• Break at the neck to access

• Single dose only

• Open system

What are vials?

Plastic or glass container with injectable solution or freeze-dried powder

• Rubber closure

• Single or multi-dose

• Closed system

What is the proper technique when sanitizing a medication vial for sterile compounding?

Wipe with a 70% isopropyl alcohol and allow it to air dry before continuing

What is the correct technique for entering a vial with a needle (to prevent coring)?

• Insert bevel up at a 45°- 60° angle

• Rotate to 90° as you puncture

• Use a sharp, small gauge needle

• Avoid blunt or reused needles

What is the correct technique for opening a syringe package?

Peeling the package open (NOT pushing syringe through the package)

What is the correct technique for inverting a vial during sterile compounding?

See-saw method, back and forth

• NO SCOOPING !!

What is the correct technique for handling a vial during sterile compounding?

C-method (“bunny ears”)

• NO CUPPING !!

What is the difference between positive and negative vial pressure?

• Positive:

  • When air exceeds volume of solution withdrawn

  • Results in spraying or dripping of solution from the vial

• Negative:

  • Amount of air removed exceeds volume of solution removed

  • Results in difficulty removing volume needed from vial

How can positive and negative vial pressure be managed?

• Positive: Inject an equal volume of air into the vial as the volume of liquid you plan to withdraw; invert the vial and withdraw solution

• Negative: Withdraw small amounts of drug slowly; periodically pull back slightly on plunger to equalize pressure

What is vial coring?

When tiny pieces of the rubber stopper break off and get pulled into your syringe (or sometimes are still in the vial)

What are the correct techniques for withdrawing medication from an ampule?

• No milking required as its an open system

• Disinfect neck of ampule and allow to air dry

• Grasp with thumbs point toward each other (like breaking a pencil)

• Face ampule toward side of PEC

• Apply pressure at neck of ampule (not the paint line)

• Attach filter needle/straw to syringe

• Attach regular needle after use

• Inject into diluent/solution

What is the correct technique for injecting medication into an IV bag?

• Sanitize port with alcohol swab

• Port is closest to the HEPA filter

• First air is not obstructed

• Bevel of needle is up

• Finger placement is on the flange avoiding touching the ribs of the plunger

• If first air is broken, resanitize port with an alcohol swab

What is a proper technique for recapping a needle to prevent needle-stick injuries?

Best practice → should not be recapped

• “One-handed scoop”

What are the common errors seen in sterile compounding?

• Touch contamination (i.e., cupping, touching the critical site of syringe/needle)

• Incorrect BUD

• Wrong drug or dose

How can errors in sterile compounding be prevented?

Training, cleaning habits, and double checking

What are endotoxins?

Toxic, heat-stable lipopolysaccharide substances

• Within cell wall of gram-negative bacteria

• Released upon disintegration of bacteria

• Immunogenic

Why are endotoxins clinically significant?

Causes severe pyrogenic reactions (fever) and septic shock

What are the 3 main types of contamination in sterile compounding?

• Microbial — most common source, through touch

  • Bloodstream infections

  • Other types of infections

  • Death

• Chemical — Serious adverse patient outcomes if CSP is contaminated with an endotoxin

  • Infection

  • Death

  • Aluminum → found in parenteral nutrition (PN); max. exposure limit of 5 mcg/kg/day

• Physical — presence of physical matter in final preparation

  • Causes:

    • Occlusion of vessels

    • Damage to organs from thrombus

    • Phlebitis

    • Death

How do you minimize the operator’s influence, as they’re considered the most common source of contamination?

• No sneezing, coughing, talking, eating, drinking, or chewing gum

• Nails must be trimmed — no longer than quarter of an inch; preferably <2 mm

• No artificial nails, cosmetics, or jewelry

• Operator must not compound CSPs if ill or with an open wound, rash, or sore

• Must follow USP <797> guidelines (and <800> if necessary)

What are viable particles?

Particles that contain living microorganisms

What are nonviable particles?

Particles that do NOT contain a living organism

How do both viable and nonviable particles contribute to contamination?

• Viable particles — directly cause infections

• Nonviable particles — carry microbes and disrupt airflow

Both compromise sterility and patient safety

Both must be controlled to maintain ISO-classified environments

How does particulate matter impact patient safety?

It can cause vascular irritation, phlebitis, or organ damage (embolism)

What is the purpose of ISO classification?

To define the maximum allowable concentration of particulate matter in the air

How does ISO classification relate to contamination control?

• Reduces microbial burden

• HEPA filtration removes dust, skin flakes, and fibers

• Maintains positive/negative pressure

Lower ISO number = cleaner air = lower contamination risk

What defines an “immediate-use” CSP in terms of administration timing?

Administration must begin within 4 hours of the start of preparation

• BUD → 4 hours (for any storage condition)

What is the BUD for “Category 1” CSP stored at room temperature?

≤12 hours

What is the BUD for “Category 1” CSP stored in the refrigerator?

24 hours

What is the BUD for a “Category 2” CSP that is aseptically processed without sterility testing and stored in the refrigerator?

10 days

What defines a “Category 3” CSP?

Preparations that have undergone sterility testing and satisfy stricter environment requirements

Which ISO class allows the fewest number of particles per cubic meter?

Class 5

How often should a compounder complete ongoing treating and competency tests?

Every 6-12 months, depending on risk category

What disinfectants and antiseptics are commonly used in sterile compounding?

Disinfectants → 70% isopropyl alcohol

Antiseptics → alcohol-based hand rubs, povidone-iodine

How can we prevent contamination during sterile compounding?

• Use consistent and proper aseptic technique

• Use recommended PPE and environmental controls

• Disinfect vial and ampule closures with each access with sterile 70% alcohol, including disinfecting rubber closures of MDVs with each access

• Store and discard sterile products and preparations in accordance with manufacturer recommendations

• Maintain vials in ISO Class 5 environments and use sterile seals when needed

• Do not administer drugs from a single-dose vial to multiple patients

• Do not combine residual solutions from different vials or syringes for future use

• Assign conservative BUDs based on reliable references

• Discard single-use vials after one use

• Use single-dose vials and prefilled syringes when possible

• Consider risk level and ISO classifications when compounding

Stability

Retention of properties and characteristics throughout the storage and use periods

Incompatability

When a change or degradation of the active ingredients occurs

Oxidation

Decomposition of drugs occurs through reaction with atmospheric oxygen under ambient conditions

• Happens in compounds with a hydroxyl (-OH) group directly bonded to an aromatic ring (e.g., epinephrine)

• Use antioxidant or inert gas to reduce oxidation

Hydrolysis

When water causes the cleavage of a bond in a molecule; most common functional groups susceptible to hydrolysis are esters, amides, and lactams

• Use freeze-dried powder form, avoid storing in high humidity, use desiccant to reduce hydrolysis

Photolysis

Drugs sensitive to UV light exposure — drug degradation occurs due to breakage of covalent bond

• Use amber (light-protected) vials; stored in original packaging to reduce photolysis

• Require light-protective cover during administration

If temperature ↑, the rate of drug degradation __.

↑

If pH has an acid-base environment change, what happens to stability?

Degradation occurs

If length of time in solution ↑, the likelihood of degradation __.

↑

What does light exposure do to preparations?

Causes photo-degradation; light-protective covers should be used

Expiration date vs. BUD

Expiration date: Assigned by the manufacturer; determined using extensive analytical testing

BUD: Assigned by a pharmacist; determined based on available scientific evidence or per manufacturer recommendations

How BUD is determined

USP Chapter <797> provides guidance on determining BUD. Often extrapolated based on:

• Direct testing or literature

• Manufacturer information

• USP recommendations

• Theoretical predictions

Use both stability and sterility data to determine BUD/storage

Common sources of incompatibility

• Drug-drug → between two substances

  • Calcium & Phosphate

  • Ceftriaxone & Calcium

• Drug-excipient → between a substance and an excipient

  • Only in saline, not in dextrose: Ampicillin, Phenytoin, Ertapenem

• Drug-container → between a substance or excipient with a container

  • Leaching/adsorption issues with PVC container: Lorazepam, Insulin, Nitroglycerin,

Y-site Compatibility vs. Additive Compatibility

• Y-site: Mixing drugs in the line

  • Commonly large IV bag = patient’s fluids, smaller IV piggybacks = the drugs

    • Drugs mix together briefly in the common portions of the IV tubing — the drug and solutions need to be compatible

    • Shorter contact → lower risk

• Additive: Mixing drugs in the same container

  • Need to be confirmed when putting multiple drugs together in the same container/syringe

  • More compatibility issues with mixing drugs in the same container than with Y-site:

  • Risk of precipitates → emboli → death

DEHP Leaching (container-related incompatibility)

Polyvinyl chloride (PVC) containers commonly use DEHP → can leach → toxic and causes harm to the liver & testes

Drug Adsorption

Commonly seen in PVC container → drug adheres to the container → reduces the drug concentration

What is the mechanism of calcium phosphate precipitation in PN?

When calcium salts are added to electrolytes containing phosphate, a chemical reaction physically manifests as a formation of precipitate (or haze) in the preparation

What risks are associated with calcium phosphate precipitation in PN?

• Suboptimal delivery of calcium and phosphorus

• Occlusion of in-line filter

• Microvascular embolism

• Pulmonary embolism

How do you prevent calcium phosphate precipitation?

• Utilize calcium gluconate over calcium chloride

• Maintain low pH of final admixture

• Increase amino acid concentration

• Store at lower temperatures

• Avoid higher temperatures during administration

• Do not add calcium and phosphate salts in close sequence

• Calculate solubility

How to minimize the risk of incompatibilities in PN

• Use preparation shortly after compounding

• Minimize the number of drugs in a single preparation

• Utilize references and resources to determine compatibility and stability

• Closely review preparations with high or low pH

• Closely review preparations containing calcium, phosphate, or magnesium

Utilizing resources to minimize risk of incompatibilities

• Important to utilize compatibility resources to predict incompatibilities and determine drug characteristics

  • Package inserts

  • Drug databases with compatibility features

  • Books and incompatibility charts

    • Handbook on Injectable Drugs (Trissel’s)

    • King Guide to Parenteral Admixtures (King's)

  • Primary literature

Visual inspection to minimize risk of incompatibilities

• Preparation should be adequately agitated/mixed

  • Add components that will limit visual identification of incompatibilities last

• Hold final preparation up to light to see through it

• Check against a contrasting background

• Look out for:

  • Hazy/cloudy appearance

  • Precipitate

  • Color change

  • Formation of gas

  • Separation of contents

  • Crystallization

What is the most common type of medication error in pediatric compounding?

Incorrect dosage

What strategies can reduce the risk of dosing errors during drug dilution in pediatrics?

• Policy and procedure development for dilution concentrations and steps for preparations

• Double check policies during verification

• Documentation and tracking dilution batches

Errors of even 0.1 mL can result in significant under- or overdose (10% error)