Section 1: USP <797>, <800>, and Hazardous Drug Management

22.1.1 The “Why”: Beyond the Bottle and the Vial

As a pharmacist, you are the undisputed guardian of the final medication product. In your community practice, this responsibility is focused on ensuring the correct drug, in the correct dose, goes to the correct patient, with the correct counseling. Your entire workflow is a series of critical checkpoints to prevent errors in dispensing. This is the foundation of medication safety.

Now, in the world of specialty and hospital pharmacy, your responsibility expands exponentially. You are no longer just the guardian of the dispensed product; you are the guardian of the compounded product, from the moment its components enter your pharmacy to the second it is administered to the patient. This requires a profound shift in mindset, from a focus on dispensing accuracy to an obsession with process integrity.

The United States Pharmacopeia (USP) provides the standards for this integrity. These are not “guidelines”; they are, in most states, the law. Failure to comply with them is not just poor practice; it is a violation of your license and a direct threat to public health. The catastrophic 2012 fungal meningitis outbreak from the New England Compounding Center (NECC), which killed 64 people and infected over 750, was a direct result of ignoring these fundamental principles. Those pharmacists were not just negligent; they were manufacturing and shipping contaminated products that were tantamount to poison.

This module is designed to translate your existing skills in quality assurance into this new, high-stakes environment. We will explore the two pillars of compounding safety:

• USP General Chapter <797>: The standard for Sterile Compounding. This chapter’s entire purpose is to protect the patient from us (and our environment). It is a framework to prevent microbial contamination (bacteria, fungi, endotoxins) from entering a product that will be injected directly into a patient’s bloodstream or body cavity.
• USP General Chapter <800>: The standard for Hazardous Drug (HD) Handling. This chapter’s entire purpose is to protect us (the healthcare workers) from the medications. It provides a framework to prevent occupational exposure to drugs that are carcinogenic, teratogenic, or otherwise toxic.

For a specialty pharmacist, these two chapters are not optional reading; they are the blueprint for your daily operations. You will be handling high-cost, high-risk biologics (governed by <797>) and often, oral or injectable chemotherapy and immunomodulators (governed by both <797> and <800>). Your expertise is no longer just clinical; it must be procedural, environmental, and microbiological. This section is your masterclass in becoming that expert.

22.1.2 Masterclass: USP <797> — Protecting the Patient

USP Chapter <797> provides the minimum standards for preparing sterile compounded products. Its goal is to prevent patient harm from five potential sources:

1. Microbial Contamination: The introduction of bacteria, fungi, or viruses.
2. Endotoxins/Pyrogens: The remnants of bacteria that can cause a fever response, even if the bacteria are dead.
3. Chemical Contamination: The unintended introduction of chemicals, like cleaning residues.
4. Physical Contamination: The introduction of physical matter, like glass shards, rubber cores, or fibers.
5. Incorrect Strength/Ingredients: The wrong drug or the wrong amount of drug.

The entire chapter is a system of controls designed to mitigate these risks. We will break down the most critical components for you as a pharmacist.

A. Personnel: The Biggest Source of Contamination

The single greatest threat to a sterile product is not the air or the surfaces; it is the compounding personnel. Humans shed millions of particles and thousands of bacteria per minute. The entire garbing process is designed to “contain” the human operator.

Training and Competency: Before any person can enter the buffer room, they must pass both didactic (book) training and practical skills tests, including:

• Gloved Fingertip and Thumb Sampling: This is the ultimate test. After garbing, you press your gloved fingertips and thumb onto a sterile agar plate. This is incubated to see if you contaminated your own gloves while putting them on. A new compounder must pass three times with zero (0) colony-forming units (CFUs) before they can compound. This competency must be re-validated semi-annually (for most compounding).
• Media-Fill Test: This is a simulation of your most complex compounding procedure using a sterile soybean-casein digest medium (SCDM), also known as tryptic soy broth (TSB). Instead of drug, you transfer this “microbial growth food.” If your technique is bad, you will introduce bacteria, and the broth will turn cloudy after incubation. This must also be passed initially and then re-validated.

B. The Garbing Process: A Non-Negotiable Ritual

Garbing is a ritual performed in a specific order, moving from “dirtiest” to “cleanest.” The 2023 revision of USP <797> clarifies this process significantly. It must be performed in the anteroom (ISO 8 area).

Masterclass Table: Step-by-Step Garbing Process (Non-Hazardous)

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Step	Action	Location	Pharmacist’s “Why”: The Critical Rationale
1	Don Shoe Covers	Line of Demarcation (Anteroom)	This is the FIRST step. You apply “dirty” items in the “dirty” area. You step *over* the line of demarcation, one foot at a time, applying the cover before your “dirty” street shoe touches the “clean” side.
2	Don Hair/Beard Cover	Anteroom (Clean Side)	Your hair and beard are massive particle generators. This cover must contain *all* hair, including ears.
3	Don Face Mask	Anteroom (Clean Side)	Masks are for patient protection, not personal protection (in <797>). They block moisture and microbes from your mouth and nose.
4	Hand Hygiene (First)	Anteroom (Clean Side)	This is the most critical step. Wash hands and forearms up to the elbows with soap and water for at least 30 seconds. Dry with low-lint towels. This removes gross soil.
5	Don Gown	Anteroom (Clean Side)	The gown should be low-lint and resistant to fluids. It must close fully in the back. Cuffs must be snug at the wrist.
6	Hand Hygiene (Second)	Buffer Room (ISO 7) or Anteroom	After donning the gown, you must perform hand hygiene again using a waterless, alcohol-based surgical hand scrub. Rub until dry. This sanitizes your hands immediately before gloving.
7	Don Sterile Gloves	Buffer Room (ISO 7)	Sterile gloves are the last item. They must be donned without touching the outside of the glove with your bare hand. The cuff of the glove must go over the cuff of the gown.
8	Sanitize Gloves	Buffer Room (ISO 7)	Immediately after donning, and frequently throughout compounding, gloves must be sanitized with sterile 70% Isopropyl Alcohol (IPA) and allowed to dry. This kills any microbes transferred during donning.

C. The Environment: A Cascade of Air Pressure and Purity

The entire cleanroom is a system designed to move “dirty” air *out* and keep “clean” air *in* the most critical areas. This is achieved through HEPA filters and air pressure differentials.

HEPA Filter: The “High-Efficiency Particulate Air” filter is the heart of all clean air technology. It removes 99.97% of all particles $0.3 \text{ microns}$ in size or larger. The air that passes through a HEPA filter is essentially sterile.

ISO Classes: Air purity is classified by the International Organization for Standardization (ISO). The smaller the number, the cleaner the air. The classification is based on the number of particles of a certain size per cubic meter of air.

Masterclass Table: ISO Classes in a Non-Hazardous Cleanroom

Room / Device	ISO Class	Particles ($\ge 0.5 \text{ \textmu}m/m^3$)	Air Pressure	Purpose
Primary Engineering Control (PEC) (e.g., LAFW, BSC, CAI)	ISO 5	3,520	N/A (Uses first-pass air)	The “sterile cockpit” where all manipulations occur. Bathed in HEPA-filtered air.
Buffer Room (SEC) (Secondary Engineering Control)	ISO 7	352,000	Positive (to Anteroom)	The “clean room” that *houses* the PEC. Its job is to provide a clean environment for the PEC to operate in.
Anteroom	ISO 8	3,520,000	Positive (to Pharmacy)	The “gowning room.” Its job is to separate the dirty pharmacy from the clean buffer room. All garbing occurs here.
Pharmacy / Outside Air	Unclassified	> 3,520,000	Neutral	The “dirty” general environment.

Visualizing the Non-Hazardous (<797>) Cleanroom

Air pressure is the key. Air must always flow from cleanest to dirtiest. This “cascade” of positive pressure ensures that any particles from a dirtier area are pushed *out* and away from the cleaner area.

D. Categories & Beyond-Use Dating (BUD): The 2023 Revision

The 2023 revision of USP <797> (which became official November 1, 2023) completely changed how we assign Beyond-Use Dates (BUDs). The old “Low/Medium/High Risk” levels are gone. They have been replaced by Category 1, Category 2, and Category 3.

This new system is simpler. The BUD is determined by two factors:

1. The Environment: Is the product made in a cleanroom (SEC/PEC) or a segregated compounding area (SCA)?
2. Sterility Testing: Has the final product been sent out for sterility testing?

Masterclass Table: BUDs by <797> Category (2023 Revision)

Category	Compounding Environment	BUD (Aseptically Prepared, No Sterility Test)
Category 1	Made in an unclassified Segregated Compounding Area (SCA). An SCA is just a “room with a hood” (PEC). There is no ISO 7 buffer room. This is for urgent use only.	$\le$ 12 hours at Room Temp $\le$ 24 hours Refrigerated
Category 2	Made in a full cleanroom suite: PEC (ISO 5) …inside a SEC (ISO 7) …with an Anteroom (ISO 8)	BUD depends on starting components and preservatives. If any component is non-sterile: $\le$ 4 days at Room Temp $\le$ 7 days Refrigerated $\le$ 45 days Frozen If all components are sterile: $\le$ 10 days at Room Temp $\le$ 14 days Refrigerated $\le$ 45 days Frozen
Category 3	Made in a full cleanroom suite (same as Category 2). PLUS: More rigorous garbing/cleaning. Final product passes sterility testing. Endotoxin testing passed.	Up to 180 days (or as per stability data) at any temperature. This is for batch compounding, like a 503B facility. Most specialty pharmacies operate as Category 2.

22.1.3 Masterclass: USP <800> — Protecting the Handler

USP <800> is an entirely different philosophy. Its sole purpose is to protect healthcare workers from exposure to Hazardous Drugs (HDs). This chapter applies to every location that handles HDs—pharmacies, clinics, hospitals, and physician offices. It covers the entire lifecycle of the drug, from receipt to disposal.

A. What is a Hazardous Drug? The NIOSH List

A drug is considered hazardous if it meets one or more of the following criteria in humans or animals. This is the NIOSH (National Institute for Occupational Safety and Hth) list.

• Carcinogenicity (causes cancer)
• Teratogenicity or other developmental toxicity (causes birth defects)
• Reproductive toxicity
• Organ toxicity at low doses
• Genotoxicity (damages DNA)
• …or… New drugs with a structure/toxicity similar to existing HDs.

The NIOSH list is split into three tables, and as a pharmacist, you must know the difference:

• Table 1: Antineoplastic drugs (e.g., Paclitaxel, Cyclophosphamide, Methotrexate). These have the *strictest* handling rules.
• Table 2: Non-antineoplastic HDs (e.g., Warfarin, Azathioprine, some hormones).
• Table 3: HDs with reproductive-only risk (e.g., Finasteride, some anticonvulsants).

Your pharmacy must maintain a list of all HDs it handles, specific to its own inventory.

B. The Core Concept: Containment (C-PECs and C-SECs)

While <797> uses positive pressure to push air *out* and protect the product, <800> uses negative pressure to pull air *in* and protect the handler. This is the single most important, and expensive, part of USP <800>.

All sterile and non-sterile compounding of HDs must be done in a Containment Primary Engineering Control (C-PEC) located inside a Containment Secondary Engineering Control (C-SEC).

Masterclass Table: Hazardous Drug Containment

Room / Device	Purpose	Key <800> Requirements
C-PEC (Containment-PEC) (e.g., Class II BSC, CACI)	The “chemo hood.” This is the ISO 5 device where manipulations occur.	Must be externally vented (air pumped *outside* the building). Must be negative pressure (to its own surroundings). Uses vertical laminar airflow to protect the product and the user.
C-SEC (Containment-SEC) (The C-Buffer Room)	The “chemo room” that *houses* the C-PEC.	Must be negative pressure (to the anteroom). Must have external exhaust. Must have more Air Changes Per Hour (ACPH) (e.g., 30 ACPH for sterile). Must be ISO 7.
Anteroom	The gowning room.	Must be positive pressure (to the C-SEC). This creates a “clean air” wall to protect the C-SEC from the dirty pharmacy. Must be ISO 7 (stricter than <797>’s ISO 8).

Visualizing the Hazardous (<800>) Cleanroom

The airflow is more complex. The Anteroom is positive to the C-SEC (to protect the sterile environment), but the C-SEC is negative to the Anteroom (to contain the drug). This requires a “sink” of air in the C-SEC, where air is pulled from both adjacent rooms and then exhausted to the outside.

C. Personnel Protective Equipment (PPE): The Armor

Garbing for HDs is different and more extensive. The goal is to leave no skin exposed and to create disposable layers that can be safely removed, taking the contamination with them.

Masterclass Table: PPE for Compounding Sterile HDs

PPE Item	<797> Non-Hazardous	<800> Hazardous	Pharmacist’s “Why”: The Critical Rationale
Shoe Covers	One Pair	Two Pairs	You don two pairs in the anteroom. One pair is doffed (removed) when leaving the C-SEC to avoid tracking contamination out.
Gown	Low-lint Gown	Chemo Gown (ASTM D6978)	Must be disposable, resistant to chemotherapy, close in the back, and have long, snug cuffs. Must be changed every 2-3 hours or per mfr. Cannot be re-used.
Gloves	One Pair (Sterile)	Two Pairs (Sterile, ASTM D6978)	You must wear two pairs of chemo-rated gloves. The inner glove goes *under* the gown cuff. The outer glove goes *over* the gown cuff.
Face/Eye	Face Mask	Face Mask + Face Shield	A face shield (or goggles) is required *in addition* to the mask to protect your eyes from splashes, which are a real risk.
Hair/Beard	One Cover	One Cover	Same requirement. All hair must be contained.

D. The HD Lifecycle: From Receiving to Disposal

USP <800> governs every step. As a pharmacist manager, you are responsible for designing this entire workflow.

• Receiving: HDs must be delivered in clearly marked containers. They should be unpacked in a neutral or negative pressure room (NOT in a positive pressure sterile area). Staff must wear gloves (and a gown, if the container is damaged) just to open the shipping tote.
• Storing: All HDs must be stored separately from non-HDs.
  • Refrigerated HDs must be in a dedicated HD-only refrigerator (which must be in a negative pressure room).
  • Table 1 (antineoplastic) HDs that require manipulation must be stored in the C-SEC (negative pressure room).
• Compounding: Must occur in the C-PEC/C-SEC with all appropriate PPE. A key tool is the Closed System Transfer Device (CSTD), which is a needle-free system that mechanically prevents the escape of vapor or liquid. <800> *requires* CSTDs for administration and *recommends* them for compounding.
• Dispensing: The final, compounded HD (e.g., an IV bag) must be wiped down. It must be placed in a transparent, sealed bag and labeled as a hazardous drug.
• Transport: Must be in a container designed to prevent breakage and contain leaks.
• Disposal: All items contaminated with HDs (vials, needles, gloves, gowns) must be disposed of in designated yellow (trace) or black (bulk) waste containers. This is an EPA requirement.

E. The Assessment of Risk (AoR): The “Specialty Pharmacy” Clause

This is one of the most important, and most misunderstood, parts of <800>. The *full* force of <800> (negative pressure rooms, etc.) is designed for manipulating HDs (e.g., crushing tablets, drawing up injections). But what about just *dispensing*? What about a specialty pharmacy that dispenses oral Gilenya (fingolimod) or Xeloda (capecitabine) tablets in their original bottles?

USP <800> allows a pharmacy to perform an Assessment of Risk (AoR) for some HDs (mainly Table 2 and 3 drugs in final dosage forms) to determine if alternative containment strategies are acceptable.
An AoR allows you to document your process and potentially avoid having to handle these drugs in a full negative pressure room.

22.1.4 Masterclass: Environmental Monitoring (EM) — Proving Your Process Works

How do you *know* your cleanroom is clean? How do you *know* your staff’s garbing and aseptic technique is perfect? You can’t just trust the process; you must test the process. This is Environmental Monitoring (EM), also called Environmental Sampling. It is a core requirement of <797>.

EM is broken into two main parts:

• Viable Sampling: Testing for living microbes (bacteria, fungi). This is the “germ” test.
• Non-Viable Sampling: Testing for non-living particles (dust, dander, fibers). This is the “particle” test that certifies your ISO class.

A. Viable Sampling (The “Germ” Tests)

This is your performance report card. It must be done every 6 months (at minimum) for all cleanroom categories.

Masterclass Table: Viable Sampling Methods

Sample Type	Method	Purpose (What it Tests)	Frequency
Gloved Fingertip & Thumb Sampling	After garbing (and before sanitizing), press all 10 digits onto an agar plate.	This is the #1 test of garbing competency. It checks if you contaminated your own sterile gloves.	Initially (3x), then semi-annually for Category 1/2. Quarterly for Category 3.
Surface Sampling	Use a contact plate or swab to sample “high-touch” surfaces (e.g., PEC work surface, cart handle, doorknob).	This is a test of your cleaning and disinfecting process. Are you leaving microbes behind?	Monthly (for Category 1/2). Weekly (for Category 3).
Active Air Sampling	Use a calibrated air sampling machine to suck in a known volume of air (e.g., 1,000 liters) and impact it onto an agar plate.	This is a test of your HEPA filters and air handling system. Is the air truly “clean”?	Semi-annually (for Category 1/2). Monthly (for Category 3).

B. Actionable Levels: What to Do When You Fail

You will have a sample fail at some point. A “failure” means you grew more colony-forming units (CFUs) than the chapter allows. The key is not to panic, but to investigate, correct, and re-test.

Masterclass Table: Viable Sampling Action Levels (per plate/sample)

Sample Type	ISO 5 (PEC)	ISO 7 (Buffer)	ISO 8 (Anteroom)
Gloved Fingertip	$ > 0 \text{ CFU} $ (for initial test) $ > 3 \text{ CFU} $ (for ongoing)	N/A	N/A
Surface Sample	$ > 3 \text{ CFU} $	$ > 5 \text{ CFU} $	$ > 50 \text{ CFU} $
Active Air Sample ($/m^3$)	$ > 1 \text{ CFU} $	$ > 10 \text{ CFU} $	$ > 100 \text{ CFU} $

C. Non-Viable Sampling & Certification

This is the particle count test. You don’t perform this yourself; you hire a certified company to do it. They bring in a calibrated particle counter and test all your ISO-classified spaces.

This certification must be performed:

• Every 6 months (semi-annually).
• Any time the PEC or room is moved.
• Any time major service is performed on the HEPA filters or HVAC system.

The certifier will give you a report that states your PEC is ISO 5, your Buffer Room is ISO 7, etc. This report is the “license” for your cleanroom. You must have it on file and available for any inspector. You cannot legally compound sterile products in a room that has not been certified.

22.1.5 Putting It All Together: The Specialty Pharmacist as Quality Manager

You have now seen the full, complex ecosystem of compounding. As a specialty pharmacist, you are not just a clinical expert; you are the designated quality manager. Your responsibilities are vast and non-delegable. You are the final backstop for patient safety.

Your Daily, Weekly, and Monthly Responsibilities

Daily Pharmacist Checklist:

• Review Logs: Check the refrigerator/freezer temperature logs. Check the room pressure logs (are your rooms holding pressure?). Check the cleaning logs (was the daily clean done?).
• Order Verification: For every sterile compound:
  • Is it clinically appropriate? (Your clinical skill)
  • Is the dose/diluent/volume correct? (Your pharmacy skill)
  • Is the assigned BUD correct per <797> AND manufacturer stability? (Your <797> skill)
  • Is this an HD? If so, are all <800> precautions being used? (Your <800> skill)
• Final Product Check: Before a product leaves the pharmacy:
  • Is it free of particles, cores, or precipitates?
  • Is the label correct?
  • Is it bagged and labeled per <800> if hazardous?

Weekly Pharmacist Checklist:

• Review Cleaning: Ensure the weekly deep clean was performed and documented.
• Supply Check: Are you low on chemo gowns? Sterile gloves? Are any cleaning agents expiring?

Monthly Pharmacist Checklist:

• Review EM Reports: Your surface sample reports will come back this month. You must review them, sign them, and open a CAPA for any failures.
• Review Cleaning: Ensure the monthly ceiling/wall clean was performed.

Semi-Annual / Annual Pharmacist Checklist:

• Manage Certification: Schedule and oversee the semi-annual cleanroom certification.
• Manage Competencies: Schedule and perform the semi-annual gloved fingertip sampling and media-fill testing for your entire compounding staff (and yourself!).
• Review AoRs: Review your Assessment of Risk documents annually and update them as needed.
• Training: Conduct your annual staff training on <797> and <800> procedures.

This is the true work of an advanced specialty pharmacist. It is a demanding, high-accountability role that combines high-level clinical knowledge with the procedural rigidity of a manufacturing engineer. Your community pharmacy experience gave you the bedrock skill—an unwavering attention to detail. This masterclass has given you the blueprint to apply that skill to this new and critical environment. You are not just dispensing drugs; you are guaranteeing their integrity.