Sterile Compounding: Keeping It Clean

Full update August 2019

Sterile compounding has been an especially hot topic in recent years because of new regulations and standards to ensure patient safety. United States Pharmacopeia (USP) Chapter <797> is essentially the law of the land when it comes to sterile compounding. Its purpose is to protect patients receiving compounded sterile preparations from harm or death by requiring best practices and quality standards to be in place. Chapter <797> standards are enforced by many state boards, and may be used to some extent for accreditation criteria by organizations like The Joint Commission.

In essence, the goal of USP Chapter <797> is to ensure patients get compounded preparations that are truly sterile. Using a non-sterile product that really should be sterile can cause major issues. For example, injecting a non-sterile preparation into a patient can cause very severe infections, even death. Whether or not you encounter sterile compounding in your day-to-day operations, it’s good to be aware of the types of procedures that are followed. This tutorial gives a basic overview of sterile compounding, focusing on the different ways to ensure sterility of compounded preparations.

Dwyer, Barbara

DOB 8/15/59

ICU-10

Norepinephrine 4 mg
D5W 250 mL
Infuse at 0.05 mcg/kg/minute.

You’re working the evening shift in the hospital pharmacy, preparing oral doses for patients as the pharmacist verifies orders in the main pharmacy. The pharmacist verifies an order for a norepinephrine infusion or “drip,” and a label with the above info is generated. She asks you to please prepare the drip.

What does “sterile” mean?

“Sterile” or “aseptic” refers to the state of being free from microbial contamination, or more informally, free from “germs.” Microbes include bacteria, fungus, endotoxins, spores, etc. Sterile preparations should generally also be free from other contaminants, such as particles, crystals, and other foreign matter.

What types of medications must be sterile?

The following preparations are required to be sterile:

  • Injections (i.e., colloidal dispersions, emulsions, solutions, suspensions)
    • Examples: intravenous (IV) piggybacks, IV “pushes,” IV infusions or drips, parenteral nutrition (PN), intramuscular (IM) injections, subcutaneous (SC) injections, preparations for epidural infusion
  • Ophthalmic drops and ointments
    • Example: vancomycin eye drops that are compounded using vancomycin powder for injection
  • Aqueous bronchial and nasal inhalations
  • Baths and soaks for live organs and tissues
  • Irrigations for wounds and certain body cavities, such as the abdomen or bladder
  • Tissue implants

The norepinephrine infusion that you will be mixing is for IV administration. So, it must be sterile.

What can help ensure that a medication is sterile?

Proper air quality is very important in guaranteeing that compounded preparations are sterile. This is the reason for the “clean room” set-up, with laminar airflow workbenches, etc. It’s also the reason that paper towels, cardboard boxes and packaging can’t be stored in the areas where sterile preps are compounded. These types of materials can shed particles, and increase a room’s particle count.

Proper air quality means that there are fewer than a given number of specific-sized particles per cubic meter of room size. Sterile preparation of meds is usually required to be done in an environment that’s considered ISO (International Organization for Standardization) Class 5. As ISO Class goes up, say from 5 to 6 to 7 to 8, the number of particles allowed per cubic meter also goes up. For example, the number of particles allowed for ISO Class 6 is ten times higher than the number of particles allowed for ISO Class 5.

Here are some definitions of different spaces and information related to air quality, working from the site of compounding outward:

Laminar airflow workbench or biological safety cabinet: This is where the action happens, the actual space where you compound sterile preparations. These contain the surface where you’ll be placing the necessary medication vials, minibags, syringes, etc, and doing the actual compounding. Laminar airflow workbenches and biological safety cabinets are both commonly referred to by pharmacy personnel as “hoods.” These hoods have special filters to clean the air within. They generally provide at least an ISO Class 5 environment.

Laminar airflow workbenches are used for nonhazardous meds, like antibiotics, IV infusions of electrolytes, etc. The airflow in these is horizontal, towards the compounder.

Biological safety cabinets are used for hazardous drugs like chemotherapy. These are set up to help keep the preparer from being exposed to the hazardous drug. There’s a special airflow in them that moves vertically, away from the compounder, and a glass shield on the front. Some pharmacies use a compounding aseptic containment isolator (CACI) for hazardous med compounding. This type of hood is completely closed off, and vents hazardous air and particles outside the pharmacy through proper building ventilation.

Buffer area (sometimes referred to as the clean room): This is the room where the hood is located. An ISO Class 7 is required for this room.

Ante room: This is the room between the buffer area and the common pharmacy area. An ISO Class 8 is required for this room, unless hazardous meds are being compounded, then ISO Class 7 is required.

Positive and negative pressure rooms: These represent the air flow of a room. A positive pressure room has a higher pressure than the adjacent spaces, therefore the air flows out of the room. A negative pressure room has a lower pressure than the adjacent spaces, therefore the air flows into a room. Clean rooms where hazardous meds are compounded must be negative pressure rooms. This helps ensure the inward flow of air, to minimize exposure to airborne drug.

Remember that food and drink should NEVER enter the buffer room or ante room areas, where ingredients of sterile preps are present.

What do I need to do before compounding a sterile preparation?

Once you are working in an area with the proper air quality, the three most important factors in guaranteeing sterility of a preparation are:

  1. Proper hand hygiene and garbing
    Example: handwashing and wearing a gown, gloves, etc
  2. Proper aseptic technique by compounding personnel
    Example: manipulating needles, syringes, etc, in such a way that contaminants are not introduced when you compound a sterile preparation
  3. Absence of surface contamination
    Example: cleaning the surface of the laminar airflow hood or biological safety cabinet with 70% isopropyl alcohol in the proper manner

Before compounding sterile preparations, hands and arms must be properly cleaned, and you must put on appropriate garb (also called personal protective equipment [PPE]) in the correct order. This is very important. Even though you can’t see them, skin cells laden with microbes are shed from the human body at an alarming rate! PPE will help keep these out of the clean room area, and away from any sterile preparations that you compound.

Before you get ready to enter the clean room, you will need to do the following:

  • Remove your outerwear (coat, hat, etc).
  • Remove your make-up, if you are wearing any.
  • Remove all hand and wrist jewelry, and any other jewelry that’s visible.
    • Any jewelry that cannot be removed should be covered according to your company’s policy.
  • Ensure nails are trimmed to be shorter than ¼ inch (longer nails tear gloves).
    (Please note: No artificial nails or nail polish allowed)

Then you can wash up and garb. Follow the order specified in your pharmacy’s policies and training. Below is an example:

In the ante room,

  • Put on shoe covers, a hair cover, and then a facial mask (in this order).
  • Clean your hands with warm running water and vigorous hand washing for at least 30 seconds with soap.
    • Make sure you clean all the way up to the elbows and don’t forget to clean the area under your fingernails using a disposable nail cleaner.
  • Completely dry your hands and arms with a low-lint disposable towel.
  • Put on a gown, preferably a disposable one.

In the buffer area,

  • Clean hands again with a waterless, alcohol-based surgical scrub.
  • Finally, put on sterile, powder-free gloves.

Note that for preparation of hazardous drug products like chemotherapy, you will be required to wear different PPE (e.g., gloves, gown, etc) than what you would wear when preparing nonhazardous products. For more on this and other important considerations with hazardous med compounding, check out our CE, USP Chapter <800> – Handling Hazardous Meds in the Healthcare Setting.

If you leave the ante room, you can hang up your gown so you can use it again, during the same shift (this does NOT apply to hazardous med compounding). However, you cannot reuse your mask, hat, gloves, or shoe covers. When you come back to re-enter the clean room, you should repeat the entire process, with a new gown or the one you hung up, and with fresh shoe covers, hat, mask, and gloves.

Because you’re working in the main pharmacy area when you receive the label for the norepinephrine infusion, you head into the ante room to wash your hands and garb up before you go into the clean room.

Are there different types of compounded sterile preparations?

Yes. There are three main types defined by Chapter <797>: immediate-use, Category 1, and Category 2. These classifications are based on the preparation’s potential for microbial, chemical, and physical contamination.

Immediate-use: ISO class 5 environment is NOT required for immediate-use preparations. Immediate-use preparations are for emergency use or immediate patient administration (e.g., cardiac or respiratory arrest situation, emergency room or operating room treatments, or any time where waiting too long would put the patient at risk of harm because of delays in treatment). An example of an immediate-use prep would be an epinephrine drip prepared at bedside by the nurse or pharmacist for a patient in cardiac arrest.

Immediate-use compounded sterile preps must be administered within four hours from the start of preparation. If administration has not begun within four hours, the prep should be discarded. For example, an antibiotic, such as azithromycin, is mixed by a nurse in the emergency room for immediate use for a patient. Administration is delayed beyond four hours because the patient has no IV access. The original prep needs to be thrown out, and a new one mixed.

Category 1: Category 1 preps must be compounded in an ISO Class 5 air quality environment or better; however, this Class 5 environment (i.e., hood) does not have to be located within an ISO Class 7 clean room. An example of this would be when a hood is located directly in a regular pharmacy satellite. A Category 1 prep has a shorter beyond-use date (discussed below) because there’s a higher risk for contamination of a preparation when there’s not a clean room.

Category 2: Category 2 is assigned to any other prep that is compounded under a hood, within a clean room, with an ante room separating the clean room from the rest of the pharmacy. As you will see below, Category 2 compounded sterile preparations are assigned a beyond-use date based on whether they are produced from sterile products only or produced from non-sterile products, whether or not they are terminally sterilized (e.g., sterilization after the preparation has been produced using dry heat, steam, or irradiation), and whether or not sterility testing has been performed on them. Sterility testing is done to ensure there is no microbial growth in the compounded preparation.

To mix the norepinephrine drip, you will be transferring 4 mg, or 4 mL, from a 4 mL sterile vial of norepinephrine 1 mg/mL, into a 250 mL bag of D5W. Since you are doing this in a clean room environment, under a hood, this compound would be considered a Category 2 prep. If this drip were being prepared outside of a clean room environment, but still within a hood, it would be considered a Category 1 prep. And if this drip were being prepped at a patient’s bedside, it would be immediate-use.

How do I know what beyond-use date to give a compounded sterile preparation?

For compounded sterile preparations, the beyond-use date is the date or time beyond which a preparation should not be used. It is not the same as the expiration date. An expiration date is determined by the manufacturer and is based on testing of sterility and stability of an individual component when kept under specified storage conditions. Beyond-use dates (BUDs) are based on how long a compounded preparation is expected to remain sterile and stable. BUDs are determined from the date/time preparation of the compounded prep is initiated. (Note: The BUD of a compound often differs from the expiration dates of the individual components being used to make the compound. Use whichever date is shorter.)

Per Chapter <797>, determining the BUD starts with determining the type of preparation (i.e., immediate-use, Category 1, Category 2).

Immediate-use:

Administration must begin no more than four hours after preparation started.

Category 1:

Not more than 12 hours at room temp, and not more than 24 hours refrigerated.

Category 2:

The BUD will depend on if it is aseptically produced (and if components are sterile or non-sterile) versus terminally sterilized and whether or not sterility testing has been performed. See the table below for more details:

BUDs for Category 2 Compounded Sterile Preparations

Characteristics of Compound

Recommended Storage Conditions

Compounding Method

Sterility Test Performed & Passed

Room Temp

Refrigerator

Freezer

Aseptically produced

No

If made from one or more non-sterile components: 1 day

If made from one or more non-sterile components: 4 days

45 days

If made from only sterile components: 4 days

If made from only sterile components: 10 days

Yes

30 days

45 days

60 days

Terminally sterilized

No

14 days

28 days

45 days

Yes

45 days

60 days

90 days

Package labeling and other references should be used, in combination with the rules from Chapter <797>, to determine appropriate BUDs for compounded sterile preparations. For example, once Primaxin (imipenem/cilastatin) 500 mg vials for IV administration are reconstituted, they are only stable for 24 hours in the fridge per the manufacturer. Let’s assume this is a Category 2 prep (e.g., produced in a clean room environment) that is aseptically produced from only sterile components with no sterility testing. Although Chapter <797> gives a maximum BUD of 10 days under refrigeration, the shorter BUD of 24 hours provided in the product information should be used.

Be sure you are also familiar with your pharmacy’s policies, as some may have more stringent guidelines for beyond-use dating. Often, hospital pharmacies will have a nice chart or reference that lists out BUDs for commonly compounded sterile preps. This can be really handy, and save a lot of time. Find out if you are expected to indicate BUDs on compounded sterile preparations, or if the pharmacist normally does it.

The norepinephrine infusion is a Category 2 prep, produced from only sterile components. Since this product will not be terminally sterilized, and will not have sterility testing performed on it, the maximum allowable BUD per Chapter <797> is 4 days at room temp, or 10 days in the fridge.

Another important BUD is that given to multi-dose vials used to make a compound. A multi-dose vial, by definition, contains a preservative. This is the main difference between a multi-dose and single-dose (no preservative) vial. The maximum BUD for multi-dose vials is 28 days after puncturing the stopper, unless otherwise specified by the manufacturer. If any type of contamination of a multi-dose vial is suspected, discard the vial immediately.

For single use vials, the maximum BUD is 12 hours after the first entry into the vial. This is if the vial is entered in at least an ISO Class 5 environment.

Once ampules have been opened, they should not be stored for any period of time, regardless of the air quality.

What else should I consider before dispensing a compounded sterile preparation?

As for all injectables, be sure to visually inspect compounded sterile preps before they are dispensed.

You shouldn’t see particles or clumps. This might be a sign of drug incompatibility, defective drug product, or of “coring” of a vial’s stopper (i.e., a piece of the stopper broke off into the compounded sterile preparation). Double-check with your pharmacist, since these preps may need to be discarded or remade.

If a preparation is an odd color, say a dark brown, when you know that it’s usually a pale yellow, there could be a problem. Often, the product information will mention the expected color of a prep, whether or not a color change is normal, and if the product should or should not be used. Ask the pharmacist what to do if there’s an unexpected color change.

Also, make sure that the expected volume is in the final preparation. For example, if a reconstituted antibiotic is supposed to have a volume of 100 mL and you see that there’s only 50 mL of fluid in the container, there’s something wrong and the preparation should not be dispensed.

Of course, sterile compounded preps must be checked by the pharmacist before they’re dispensed. Be sure to follow your pharmacy’s procedure.

Before the norepinephrine drip is checked by the pharmacist, you look it over. You don’t see anything floating in it, and the solution is nice and clear.

(The above information reflects the recommendations from USP Chapter <797>; 2019 version.)

Project Leader in preparation of this technician tutorial (350881): Flora Harp, PharmD/Assistant Editor

Cite this document as follows: Technician Tutorial, Sterile Compounding: Keeping It Clean. Pharmacist’s Letter/Pharmacy Technician’s Letter. August 2019.

—Continue for a “cheat sheet” on sterile compounding best practices—

“Cheat Sheet” for Sterile Compounding

What does “sterile” mean and what types of compounds must be sterile?

“Sterile” or “aseptic” refers to the state of being free from microbial (bacteria, fungus, endotoxins, spores, etc) contamination, or more informally, free from “germs.” Sterile preparations should generally also be free from other contaminants, like particles, crystals, and other foreign matter. Examples of preparations that must be sterile include compounds that will be used as injections and compounds that will be used in the eye (eye drops, eye ointments, etc).

What can I do to help ensure sterility?

  • Follow company policies/procedures to maintain proper air quality in clean rooms, ante rooms, and within compounding hoods; for example:
    • Do not store or open cardboard boxes in areas where sterile preps are being compounded
    • Do not bring food or drink into the clean room or ante room
    • Complete garbing before entering the clean room
  • Follow company policies/procedures for the order of hand hygiene and garbing; for example:
    • Remove outerwear, make-up, and hand/wrist jewelry
    • Put on shoe covers, hair cover, then facial mask
    • Use warm running water to vigorously wash hands for at least 30 seconds with soap, cleaning all the way up to the elbows and underneath fingernails
    • Completely dry hands with a low-lint disposable towel
    • Put on gown
    • Apply an alcohol-based hand rub to hands
    • Once hands are dry, put on sterile, powder-free gloves
  • Assign the appropriate beyond-use date based on the category of the compound
    • Category 1 (made within a hood that is NOT located within a clean room)
      • Room Temp: BUD = 12 hours
      • Refrigerator: BUD = 24 hours
    • Category 2 (made within a hood, located in a clean room, with an ante room separating the clean room from the rest of the pharmacy)

BUDs for Category 2 Compounded Sterile Preparations

Characteristics of Compound

Recommended Storage Conditions

Compounding Method

Sterility Test Performed & Passed

Room Temp

Refrigerator

Freezer

Aseptically produced

No

If made from one or more non-sterile components: 1 day

If made from one or more non-sterile components: 4 days

45 days

If made from only sterile components: 4 days

If made from only sterile components: 10 days

Yes

30 days

45 days

60 days

Terminally sterilized

No

14 days

28 days

45 days

Yes

45 days

60 days

90 days

[August 2019; 350881]

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