USP 795/797/800
Compounding is considered to be: (1) ___ a tablet (2) ___ a capsule (3) weighing and ____ (4) ____ injections (5) ___ a mess (6) ____liquid (7) ____ from a HD container
(1) crushing a tablet (2) opening a capsule (3) weighing and mixing (4) withdrawing or diluting injection (5) cleaning a mess (6) transferring/pouring liquid from one container to another (7) reconstitution from a HD container
English gum method (Wet gum method) Emulsion
- 4 parts oil: 2 parts water: 1 part emulsifier 1. Titurate the gum and water to forma mucilage 2. then add the oil slowly while titiurating to form the emulsion 3. QS w/ water 4. homogenize to make emulsion uniform
Continental gum method (Dry gum method) Emulsion
- 4 parts oil: 2 parts water: 1 part emulsifier 1. levigate gum w/ oil 2. then add water all at once, shake mixture to titurate 3. add other ingredients by dissolving them first in soln. 4. add quantity of water sufficient to make final volume (QS w/ water) 5. Homogenize to make emulsion uniform
fusion molding suppositories
- base gently heated - ingredients added - mixture poured into ROOM TEMP molds - leave to congeal
hand molding suppositories
- few to be made - grated and then mixed w/ the drug - mix then rolled into a cylinder and cut into suppository sizes
emulsion
- liquid dispersed in liquid - two-phase heterogenous mixture - oil-in-water or water-in-oil
suspension
- solid dispersed in liquid - two-phase heterogenous mixture
Solution
- solute dissolve in solvent (ie. NaCl dissolved in water) - Homogenous, consistent, uniform
compression molding suppositories
- will need to know weight of each mold - need to know drug's density factor
According to USP 797, what air quality is required when compounding CSP's?
-- Ante area must meet at least ISO Class 8 -- Buffer area must meet at least ISO Class 7 -- PEC must meet at least ISO Class 5
What are the labeling requirements for finished compounded products?
-- Assigned internal ID number (e.g. prescription or lot number) -- Chemical and/or generic names, or active ingredients, and amount or concentration -- Dosage form -- Total amount or volume -- Storage conditions -- BUD -- Indication -- Route of administration -- Any special handling info -- Any warning statements -- Name, address, and contact info of the compounding facility
What does the FDA NOT allow a pharmacy to compound?
-- Compound in anticipation of receiving prescriptions (Unless you're compounding veeeeeeeery limited quantities) -- Compound drugs withdrawn/removed from the market for safety reasons -- Compound from bulk ingredients NOT approved by the FDA -- Receive, store, or use drugs without first obtaining written assurance from the supplier that each lot of the drug was made in an FDA-registered facility -- Receive, store, or use drug components not guaranteed or determined to meet compendia requirements -- Use commercial-scale manufacturing or testing equipment -- Compound for third parties to re-sell -- Failing to operate in conformance with applicable state law -- Compound drugs that are commercially available or that are essentially copies of commercially available products NOTE: A pharmacist may compound a small quantity of a drug that is only *slightly different* that the commercially available provided that there is a medical need for the variation for the particular patient E.g. 22MG OF SIMVASTATIN VS 20 MG THAT IS ALREADY ON THE MARKET *Don't do ANY of these or you'll be considered as a manufacturer!*
Compounding supervisor
-- Develops and implements appropriate procedures -- Oversees facility -- Continuous monitoring of facility and CSPs -- Reports of all testing from contractors and labs, CSP, and/or their components
Containment segregation compounding areas (C-SCA)
-- Does NOT have to be ISO 7 -- Does NOT have to have HEPA filter air -- Min of 12 ACPH May contain C-PEC if... -- Negative pressure -- Handwashing sink at least 1 meter from C-PEC Only low to medium risk compounds made here -- Products made here must NOT exceed BUD of 12 hours
What are the components of a master formulation record (MFR)?
-- Drug name, strength, dosage form -- Final product physical description -- Ingredient identities, and amounts, and container-closure systems, including necessary characteristics of components (e.g. particle size, salt form, purity, grade, solubility) -- Quantity of ingredients used -- Complete instructions for preparing, including equipment, supplies, and a description of the compounding steps -- Equipment used -- Mixing instructions -- Labeling info -- Container info -- BUD -- Packaging + storage requirements -- Quality control procedures
What are the components of a compounding record (CR)?
-- Drug name, strength, dosage form -- MFR reference -- Name, vendor, or manufacturer, lot number, and expiration date of each ingredient and container-closure system -- Component's sources/lot numbers/expiration dates -- Weight or measurement of each ingredient -- Calculations made to determine and verify quantities and/or concentrations of components, if appropriate -- Total quantity/volume compounded -- Compounder's name -- Name of verifying RPh -- Date + time prepared -- Rx number -- Assigned BUD -- Storage requirements -- Reference source of the BUD and storage requirements -- Labeling as described by manufacturer -- Final product physical description -- Quality control procedures -- Documentation of any quality control problems -- Any deviations from the Master Formulation Record, and any problems or errors experienced
HD eye/face protection requirements
-- Goggles are the best option -- Recommended to add safety glasses with side shield -- Eyeglasses or safety glasses with side shield are NOT enough When do you need them? -- When manipulating a HD outside of C-PEC -- Working at or above eye level -- Cleaning C-PEC -- Cleaning a spill
HD chemo gown requirements
-- Made of polyethylene-coated polypropylene or other laminated materials -- Closed in back and no openings in front -- Long sleeves -- Closed cuffs that are elastic or knit -- MUST be changed every 2-3 hours or immediately after a spill or splash -- NOT reusable -- Considered as hazardous waste after used When do you need them? -- Worn whenever there is a possibility of HD contact with skin or clothes -- Do NOT wear gown outside of compounding or administration area
Can you re-use any PPE when compounding sterile products?
-- Non-sterile gown can be removed and retained in the ante room or SCA if not visibly soiled -- Can be re-donned during the same work shift only All other garbing MAY NOT be reused
What personnel requirements must be re-evaluated every 3 months (quarterly)?
-- Visual observation of hand hygiene and garbing -- Gloved fingertip sampling -- Media fill testing
What is the correct order in which personnel should sanitize a HD C-PEC?
1. Deactivation & decontamination - reduces HD toxicity, then removes HD residues (2% sterile bleach/sodium hypochloride or peroxide) 2. Cleaning - removes dirt and microbial contamination (Germidical detergent, Quat. Ammonium, phenolics) 3. Disinfection - inhibits or destroys microorganisms (70% IPA)
Training/re-certification requirement for compounding low/med risk CSP's is done every ____ months
12 months
What BUD should be assigned to *non-sterile non-preserved aqueous oral formulations (e.g. oral suspension)*?
14 days Store in fridge
What BUD should be assigned to *non-sterile solid oral dosage forms*?
180 days Store at RT
What BUD should be assigned to *non-sterile preserved aqueous topical/dermal and mucosal liquid and semisolid formulations* (e.g. cream or lotion)?
30 days Store at RT
According to USP 797, aseptic manipulation should be performed at least ______ inches inside the workbench to prevent contamination
6 inches
Training/re-certification requirement for compounding HD CSP's is done every ____ months
6 months
Training/re-certification requirement for compounding high risk CSP's is done every ____ months
6 months
According to USP 797, the storage period of medium risk CSP's cannot exceed:
9 days in refrigerated state
What BUD should be assigned to *non-sterile non-aqueous formulations* (e.g. drug in petrolatum)?
90 days Store at RT
Pharmacy Bulk Package
A container of a sterile preparation for parenteral use that contains many single doses
Where can refrigerated antineoplastic HD's be stored?
A dedicated refrigerator in a negative pressure area with 12 ACPH or in a C-SCA The compressor of the room must be adjacent to an exhaust system
segregated compounding area (SCA)
A designated space, either a demarcated area or room, that has unclassified air Can prepare low-risk CSP's here Assigned BUD must be < 12hr (797)
According to USP 800, what must be incorporated into an entity's overall occupational safety plan?
A list of HD's Facility and engineering controls Competency of personnel Safe Work Practices Proper use of PPE Policies for HD waste segregation and disposal
Critical Site
A location that includes any component or fluid pathway surfaces, or openings exposed and at risk of direct contact with air, moisture, or touch contamination
Aseptic Processing
A mode of processing pharmaceutical and medical products that involves the separate sterilization of the product and of the package and the transfer of the product into the container and its closure under at least ISO Class 5 conditions
Which zones does USP 800 require a HD-compounding facility to have?
A separate area for each of the following: 1. Receipt and unpacking 2. Storage of HD's 3. Non-sterile compounding HD area 4. Sterile compounding HD area
What PPE is required when *administering intact tabs*?
A single glove
HD chemo gloves requirements
ASTM-tested chemo gloves Powder-free Inspected for physical defects BEFORE use
What defines genotoxicity?
Ability to alter genes Greater weight given to in-vivo vs. in-vitro testing "Bad results" can cause another drug to be listed as hazardous
What defines HD carcinogenicity?
Ability to cause cancer Looking for tumors in > 1 species Looking for tumors that are in multiple organs (not rodent-specific) -- Occur outside of rodent species All human data is considered relevant
Unidirectional flow
An airflow moving in a single direction in a robust and uniform manner and at sufficient speed to reproducibly sweep particles away from the critical processing or testing area
Emollient - softens and soothes skin or mucous membranes, provides a barrier, acts as a vehicle for drug delivery
Aquaphor aquabase vaseline petroleum jelly polybase eucerin cetaphil
Can you prepare sterile and non-sterile preparations in same room? Can you store them together?
Areas must be separated by at least a meter; you cannot do non-sterile compounding while sterile compounding Can store the final forms together
In-Time Use (ITU)
Assigned to ready-to-use products Created by manufacturer For sterile compounds NOT assigned to products made by compounders
How often should environmental wipe sampling should be completed?
At baseline Every 6 months
How often should an isolator be cleaned?
At each time it is opened Once it is closed after each time it is opened After each cycle cleaning if cleaning occurs without opening
When performing sterility testing for CSP's, the sample should be incubated for not less than:
At least 14 days
How long should all compounding records be kept for?
At least 3 years
According to USP 797, how long should hands and forearms should be washed with bactericidal soap and warm water for?
At least 30 seconds
How long should hands be washed before garbing?
At least 30 seconds
How often should C-PEC be decontaminated?
At least daily After any spill Between compounding different types of HD's Before and after certification Voluntary interruption occurs Ventilation tool is moved Effectiveness is assessed by performing surface wipe sampling
How often should a C-PEC be cleaned?
At least monthly
How often should surface sampling be done?
At least monthly Done with TSA with lecithin and polysorbate 80 Areas to test: -- Multiple locations within each ISO-classified area -- Interior of the PEC and equipment contained in it -- Staging or work areas near the PEC --Frequently touched surfaces -- Pass-through chambers
When must the entity's list of HD's be reviewed?
At least once yearly + whenever there's a new HD on NIOSH list
Proper HD storage
Avoid spillage/breakage (account for events of natural disasters) NOT on the floor — store at/below eye level
According to USP 797, if the hood is turned off, it must be operated for at least how long before compounding sterile products? A. immediately B. 30 minutes C. 60 minutes D. 12 hours
B. 30 minutes
Hazardous CSPs are prepared in which of the following? A. compounding aseptic isolator B. biological safety cabinet C. laminar airflow workbench
B. biological safety cabinet BSC Class II, specifically
When can closed system vial-transfer devices (e.g. PhaSeal) can be used for low volume facilities?
BSC or CACI Not for replacing an ISO 5 environment Can NOT use in a LAFW
How often should the PEC be cleaned?
Before + after each shift Before each batch After 30 minutes of continuous compounding After spills When surface contamination (e.g. splashes) is known or suspected
How often should a CAI/CACI/BSC be cleaned?
Before + after each shift Between batches Every 30 mins After spills When surface contamination (e.g. splashes) is known or suspected
How often should a LAFW be cleaned?
Before + after each shift Between batches Every 30 mins After spills When surface contamination (e.g. splashes) is known or suspected
Compounding non-sterile HD's
C-PEC can be either: BSC Class I BSC Class II CVE CACI non-sterile may be vented to the outside (preferred) or through redundant HEPA filters in series vs sterile ONLY may be vented to the outside
Compounding sterile HD's
C-PEC can be either: BSC Class II BSC Class III CACI Must be dedicated to compounding HD's only Externally vented ISO 5 or better C-SEC: Has ISO 7 w/ 30 ACPH (can be 12 ACPH but must assign shorter BUD) Water supplies 1 meter from C-PEC
Compounding non-sterile HD's
C-PEC must be externally vented C-SEC must be 12 ACPH (ISO 7 and 8 need 30 ACPH)
According to USP 797, an appropriate sanitizing agent is: A. 100% ethanol B. 70% methanol C. 70% isopropyl alcohol D. 100% acetone
C. 70% isopropyl alcohol
Which of the following clean environments maintains a superior level of operator safety? A. a horizontal laminar flow hood B. a vertical laminar flow hood C. a barrier isolator ("glove box")
C. a barrier isolator ("glove box")
Which C-PEC can be used for non-sterile compounding?
CVE Class I BSC Class II BSC (only if dedicated only for non-sterile) CACI (only if dedicated only for non-sterile) *DO NOT USE LAHW OR CAI FOR HD's!*
Terminal Sterilization
Can be done to seal containers to preserve sterility Must be pre-filtered with at least a 1.2 micron filter E.g. dry heat, steam, or irradiation
What is required by personnels compounding any type of preparation (non-sterile, sterile)?
Cannot work in compounding area until conditions resolve: • Rashes • Sunburn • Oozing tattoos or sores • Conjunctivitis • Respiratory infection or other active communicable disease Must remove items: • Remove personal outer garments • All cosmetics because they shed flakes and particles • All hand, wrist, and other exposed jewelry or piercings • Ear buds, headphones, and cell phones • Keep natural nails clean and neatly trimmed. • No nail polish, artificial nails, and extenders
Media Fill Test
Checks aseptic technique of compounding personnel + processes Checks that the processes used are able to produce CSP's w/o microbial contamination
BSC Class II
Class II A1: Has *positive* pressure Has contaminated air that is not surrounded by negative pressure and could re-enter the room Used to compound non-sterile non-HD's Class II A2: Has *negative* pressure space that prevents contaminated air from re-entering the room Used to compound sterile + non-sterile HD's Preferred for compounding sterile HD's Class II B1: All contaminated air is under negative pressure of surrounded by negative pressure Exhaust must be external 70% air exhausted and 30% air re-circulated Some contaminated air may be re-circulated into the air Used to compound sterile + non-sterile HD's Can be used with *trace amounts* of volatile toxic chemicals and radionuclides Class II B2: All contaminated air is under negative pressure of surrounded by negative pressure Exhaust must be external 100% air exhausted *No contaminated air may be recirculated* into the hood Used to compound sterile + non-sterile HD's Preferred for compounding volatile sterile HD's and radionuclides
Which C-PEC can be used for sterile compounding?
Class II BSC CACI *DO NOT USE LAHW OR CAI FOR HD's!*
Low risk compounding
Classified as aseptic compounding involving simple aseptic transfers between closed systems Uses ≤ 3 manufactured sterile products
gelling (thickening) agent, stabilizers - increases viscosity of substances and stabilizes the mixture
Common: gelatin, bentonite agar alginates guar gums acacia tragacanth carbomer cellulose starches
What are medical surveillance elements?
Completed after HD exposure during compounding Organized approach to identify workers who may be exposed to HDs Institution's employee health service should perform medical surveillance Initial baseline assessment (med history, physical exam, lab testing) Maintain medical records based on OSHA regulations Prospective monitoring or workers through periodic surveillance using elements of data collected at baseline Follow-up plans for workers who show a health change Exit examination
Isolator (glove box)
Completely enclosed PEC Able to put hands through the glove port in from of the isolator E.g. compounding aseptic isolator (CAI) compounding aseptic containment isolator (CACI)
What should I do if measurable contamination is found from environmental wipe sampling?
Compounding supervisor must identify, document, and contain the cause of contamination
ISO Class 5 Environment
Contains < 1,000 particles, 0.5 microns in diameter per cubic foot of air
ISO Class 7 Environment
Contains < 10,000 particles, 0.5 microns in diameter per cubic foot of air
ISO Class 8 Environment
Contains < 100,000 particles, 0.5 microns in diameter per cubic foot of air
High-efficiency particular air (HEPA) filter
Creates unidirectional air flow Filter removes particles from the compounding area (removes at least 99.97% of airborne particles as small as 0.3 microns)
How often should temperature + air pressure be monitored?
Daily
How often should work counters + floors be cleaned?
Daily After spills When surface contamination (e.g. splashes) is known or suspected
How can a person be exposed to HD's?
Dermal/mucosal absorption (most common) Inhalation Injection Ingestion
Each organization needs a _______ who is qualified and trained, responsible for regulations and enforcement, and continuous monitoring.
Designated person
Compounding Aseptic Isolator (CAI)
Designed to maintain a HEPA air filtered aseptic compounding environment Must be in ISO 7 environment For sterile compounding NOT for HD compounding
What are personnel compounding HD's responsible for?
Develop and implement procedure Oversee compliance Ensure competency of personnel Ensure environmental control Continuous monitoring Documenting Report
What is an automatic compounding device (ACD)?
Device used to make TPNs Must assess for accuracy daily Must review results for accuracy in measurements at least weekly to identify trends over time
What should be included in labeling information of a MFR?
Drug GN Quantity/concentration of each ingredient Assigned BUD Storage requirements Rx number
What must be worn when unpackaging HD's?
Elastomeric half-mas with multi-gas cartridge and P100-filter Keep wearing until packaging integrity is confirmed
What must be done to ensure worker safety during all aspects of handling HD's?
Establish a policy and procedure that defines... -- Plan on how to implement the standard -- All containers must be labeled with identity of material and appropriate hazard warnings -- Safety and Data Sheet (SDS) for each HD that are readily accessible to personnel during work -- Information and training provided to personnel who may be exposed prior to initial work assignment -- Personnel or reproductive capacity must confirm in writing that they understand the risks
How often should walls, ceilings, and storage shelving be cleaned?
Every 3 months After spills When surface contamination (e.g. splashes) is known or suspected
How often to change chemo gloves when compounding HD's?
Every 30 mins Immediately if spill occurs
How often is non-viable airborne monitoring performed?
Every 6 months
According to USP 797, when should the LAFW be tested?
Every 6 months Whenever the hood is moved Whenever filter damage is suspected
According to USP 797, how often should personnel responsible for low- and medium-risk sterile compounding undergo training on aseptic technique?
Every year
When should the competency of personnel compounding HD's be documented/demonstrated?
Every year When new HD is introduced When receiving new equipment Sig change in process
What PPE is required when *administrating a HD aerosol*?
Everything Gloves, gown, eye/face protection, resp. protection, ventilation
Critical Area
Exact area where compounding is done in a PEC Has ISO 5 environment ISO 5 >1 microbe contamination
Containment primary engineering control (C-PEC)
Externally vented through HEPA Physically separated from all other areas Has negative pressure (0.01-0.03 water column) Has sink for handwashing/emergency Must operate continuously if it supplies the negative pressure or if it is used for sterile compounding
T/F A pharmacist who draws sterile medication from a vial into a syringe for immediate use for a patient who is having a heart attack in a hospital is subject to the requirements included in USP 797
False
T/F According to USP 797, refrigerators may be placed in the clean room
False
T/F According to USP 797, the ante room for low- and medium-risk compounding of sterile products must be a separate room with a door between it and the compounding area
False
T/F According to USP 797, wedding rings may be worn when compounding sterile products
False
T/F The HEPA filter should be inspected by touching the filter to assure its integrity
False NEVER TOUCH THE HEPA FILTER
T/F According to USP 800, a low volume HD producing facility does not have to locate its BSC or CACI in a negative pressure room
False (was true under USP 797)
T/F Individual organizations are discouraged from making their own HD lists
False; they are encouraged!
CSP labeling requirements
For every CSP: 1. Date of preparation 2. Pt name and bed number 3. Each drug's name, strength, and amount 4. BUD 5. Name/initials of compounding RPh 6. Name/initials of dispensing RPh 7. Storage requirements 8. Special warnings For LTCF/hospice pt, label needs the above plus: 1. Rx number 2. Prescriber's full name 3. Pharmacy's name, address, phone number 4. Directions for use (infusion rate, date and time of administration)
Containment secondary engineering control (C-SEC)
For non-sterile compounding: -- Must be in a room that is physically separated from other compounding areas -- 12 ACPH -- Externally vented -- Negative pressure For sterile compounding in ISO 7 Buffer Room: -- 30 ACPH -- Externally vented -- Negative pressure For sterile compounding in C-SCA: -- 12 ACPH -- Externally vented -- Negative pressure
BSC Class III
Gas-tight enclosure accessed via glove ports HD's + supplies enter via pass-through box Provides maximum protection for environment and operator Designed for highly infectious microbial agents and other hazardous operation Used to compound both sterile + non-sterile HD's
What PPE is required when *cutting an intact tablet*?
Gloves, gown, and ventilation device Respiratory protection if not done in control device
What PPE is required for *compounding a solution (for inhalation)*?
Gloves, gown, ventilation (BSC or CACL) Eye/face protection Respiratory protection if not done in control device
What is the most common source of sterile product contamination?
Hands of personnel
Containment ventilated enclosure (CVE)
How it works: air is pulled in from the room toward HEPA filters in the back of the device, contaminated air is pulled back into the HEPA filters for filtration, clean air is recirculated back into the room Only used to compound non-sterile HD's
How much microbial air contamination is in each? ISO 5 ISO 7 ISO 8+ ISO 9
ISO 5 >1 ISO 7 >10 ISO 8+ >100 ISO 9 = normal air
What defines HD teratogenicity?
If animal dosing (at or below human doses) shows issues Any category D or X drug is listed (but is still reviewed for confirmation)
What defines HD organ toxicity?
If daily therapeutic dose < 10mg/day or 1 mg/kg If manufacturer lists safe-handling protocols that characterizes drug to be hazardous
What respiratory protection do I need when cleaning a spill?
If spill can be contained with a normal spill kit, normal respiratory protection is fine If larger spill, must use a full facepiece, chemical cartridge-type respirator
When can HD's be excluded from USP 800 containment guidelines?
If they do not require additional manipulation other than counting and repackaging Dispensing/counting work trays must be cleaned at least monthly
Where should sterility tests of sample sterile product be conducted?
In ISO 5 environment
NIOSH HD Group 1
Includes antineoplastic drugs Some may pose reproductive risk E.g. cisplastin, methotrexate, topotecan, trametinib
NIOSH HD Group 3
Includes drugs that primarily pose reproductive risk to men and women who are actively trying to conceive or women who are breastfeeding E.g. clonazepam, fluconazole, pamidronate, ribavirin, topiramate, voriconazole, warfarin
NIOSH HD Group 2
Includes non-antineoplastic drugs that meet one or more NIOSH criteria for HD Some may pose reproductive risk E.g. abacavir, cyclosporine, estrogen, phenytoin, spironolactone, zioduvine
Which areas should be tested for environmental wipe sampling?
Inside C-PEC Work areas near C-PEC Areas adjacent to C-PEC Pt administration areas
Multiple-Dose Container
Intended for parenteral administration for multiple uses Usually contains antimicrobial preservatives
Single-Dose Container
Intended for parenteral administration for single use only
Non-sterile compounding
Is for making... Solid oral preparations Liquid oral preparations Rectal preparations Vaginal preparations Topical preparations (e.g. creams, gels, irrigations for non-internal and non-surgical body cavities) Nasal and sinus preparations intended for local application Otic preparations
How often should PPE be re-certified?
Low + med risk: Every year High risk: 6 months HD: 6 months
According to USP 797, the ante room may be separated from the clean room by a strip curtain for:
Low and medium risk levels
When should personnel disinfect C-PEC?
Must be done for areas intended to be sterile REQUIRED step in sterile compounding At the beginning of the workday Between batches Beginning of each subsequent shift Routinely during compounding After anytime C-PEC is powered off
What is the process for dealing with new HD's?
NIOSH monitors HD for 2 years after FDA approval An expert panel is convened Outside input is sought through federal register
HD respiratory protection
NIOSH-certified N95 respirators -- No protection against gases and vapors -- Little protection against direct liquid splashes -- Protects against airborne particles Surgical masks -- Not protective -- N95 surgical masks + N95 respirators = extra splash protection Elastomeric half-mask with multi-gas cartridge and P100 filter -- Safest option for unpacking HD that are not contained in plastic Chemical cartridge type respirator -- Needed when attending to HD spills larger than what can be contained with a spill kit or suspected airborne exposure to powders or vapors
Who maintains the hazardous drug list?
National Institution for Occupational Safety and Health (NIOSH)
Negative pressure
Net airflow is flowing inward (into hood/room) in order to protect the staff from toxic drug fumes Air is vented outside Used for HD CSP's
Positive pressure
Net airflow is flowing outward to prevent contamination Used for non-HD CSP's
Can you clean C-PEC at any time?
No Not appropriate when compounding activities are occurring Must be done at least weekly
What cloths should be used for environmental wipe sampling? At what concentrations of contaminants are concerning?
No standards for: Wipes and how well they work What concentration of contaminants are concerning
Steam sterilization
Not an option if moisture, pressure, or temperatures would degrade the CSP
Dry heat sterilization
Not an option when heat liable
*NEW CATEGORY NAME: "Urgent use BUD"* Used to be called "Immediate-Use BUD"
Not required to label before administering RT: 1 hour Fridge: N/A Freezer: N/A
How many compounding preparations can be completed in one work space at a time?
Only one
What should be included in mixing instructions of a MFR?
Order of mixing Mixing temperatures (or other environmental controls) Duration of mixing Other factors relative to replicating final product
What is a 503B facility?
Outsourcing facilities: • Must comply with CGMP requirements • Will be inspected by FDA according to a risk-based schedule • Must meet certain other conditions, such as reporting adverse events and providing FDA with certain information about the products they compound
*NEW CATEGORY NAME: "Category II CSP's"* Used to be called... Low risk BUD Medium risk BUD High risk BUD
PEC needs ISO 5 environment SEC needs ISO 7 (buffer room + ante room) Need to perform sterility testing to determine BUD BUD > 12hr @RT, >24hr in fridge Used to be... Low risk BUD: RT: 48 hours Fridge: 14 days Freezer: 45 days Medium risk BUD: RT: 30 hours Fridge: 9 days Freezer: 45 days High risk BUD: RT: 24 hours Fridge: 3 days Freezer: 45 days
*NEW CATEGORY NAME" "Category I CSP's"* Used to be called... Low non-HD Low/med HD < 12-hr non-HD BUD
PEC needs ISO 5 environment or SCA No sterile testing required BUD ≤ 12hr @RT, ≤ 24hr in fridge Used to be... Low non-HD, low/med HD, < 12hr non-HD: RT: 12 hours Fridge: 12 hours Freezer: N/A
Laminar airflow workbench (LAFW) or laminar airflow hood
PEC used to prepare non-HD CSP's
hydrophilic solvent - liquid with high miscibility with water, used to dissolve solutes
PEG alcohols
According to USP 797, how must sterile compounding personnel demonstrate competence?
Pass a formal written exam Successfully complete a practical evaluation of aseptic technique using growth media
Sterilization by Filtration
Passage of a fluid/sol'n through a sterilizing grade membrane to produce a sterile effluent Not an option if compounding suspensions because it will affect the strength of the CSP Filter units used to sterilize CSP must be subjected to the manufacturer's recommended post-use integrity test (bubble point test) Requires a 0.2 or 0.22 nanometer filter Must occur in ISO 5 environment
Gowning/garbing procedure
Performed in ante room: 1. Shoe covers 2. Head cover 3. Facial hair cover 4. Handwashing technique 5. Lint-free disposable gown 6. Hand Sanitizer Performed in buffer room: 7. Powder-free sterile gloves 8. Sterile Isopropyl Alcohol If preparing HD's: 9. Another pair of shoe covers 10. Chemo gloves 11. Respiratory equipment 12. Eye/face protection
What happens if you're exposed to HD's while compounding?
Post-exposure physical contamination of employee involved Compare performance of controls with recommended standards Conduct environmental sampling Verify that controls are in proper operating condition and worker complied with exist policies Develop plan and action to prevent additional exposure Ensure confidential two way communication between the work and the employee health units Follow-up medical survey to demonstrate that the plan is implemented is effective Ensure employee is notified of any adverse health effect detected
What requirements must a compounding facility meet?
Potable water for washing Purified water for rinsing Separate areas for sterile compounding Adequate plumbing to prevent contamination Clean, orderly, and sanitary conditions Timely and adequate waste disposal Well lit Heating/air conditioning + ventilation -- Room temperature of 20⁰ or cooler -- Humidity less than 60% always -- Must have efficient heating, ventilation, and air conditioning system (HVAC)
Thermal sterilization
Preferred for aqueous preparations Before filling ampules and vials, solutions must pass through a filter having nominal pore size no bigger than 1.2 nanometer for removal of particulate matter
How should I transport HD's?
Preparations must be labeled as HD's at all times during transportation Do NOT transport HD liquids or antineoplastics with pneumatic tubes
Environmental sterility testing includes testing for:
Pressure differentials Temperature Humidity
IV bags containing HD's should be _______ in the C-PEC prior to administration to the patient.
Primed and spiked
Primary engineering control (PEC)
Provides ISO 5 environment Used for CSP's (797) Certified every 6 months
Compounding Aseptic Containment Isolator (CACI)
Provides personnel protection from exposure to undesirable levels of airborne drug -- Meet the requirements of both an aseptic isolator and a containment isolator -- May be placed in C-SCA physically separated from other compounding areas -- Does NOT have to be in ISO 7 or HEPA filtered air -- 12 ACPH -- Have negative pressure Used for sterile HD compounding -- Assign BUD based on 797
Sterile compounding
Purpose is to prevent harm to human/animal pts from... o Microbial contamination (non-sterility) o Excessive bacterial endotoxins o Variability from the intended strength of correct ingredients o Chemical and physical contaminants o Use of ingredients of inappropriate quality Includes... • Injections • Aqueous bronchial inhalations • Baths and soaks for live organs and tissues • Irrigations for internal body cavities (i.e. any space that does not freely communicate with the environment outside of the body) • Ophthalmic • Implants
How often should compounding personnel perform a media-fill test?
Quarterly
Air changes per hour (ACPH)
Rate which the air is vented to the outside ISO Class 7 buffer or ante-area supplied with HEPA-filtered air -- Requires ACPH no less than 30 Isolator w/ ISO Class 5 air quality -- Air exchange where the isolator is located can be reduced to 15 ACPH
Class I Recall
Reasonable probability that the use/exposure will cause serious adverse health consequences or death MUST notify public E.g. microbial growth observed in IT injection
What are requirements of ingredients for all compounded preparations?
Recommended sources: USP NF Food chemicals codex (FCC) substances API must be manufactured by FDA-registered facility When components of compendial quality are not obtainable, components of high quality such as chemically pure, analytical reagent grade, or American Chemical Society certified may be used Each component must be accompanied with a valid COA that meets the monograph Results of any in-house or third-party testing performed must be recorded
What must be performed after completing a compounded preparation?
Release Testing (physical inspection of finished product): -- Evidence of visible particulates -- Foreign matter -- Discoloration -- Container integrity (e.g. check leakage, cracks, improper seals) -- Check for precipitation, cloudiness, or leakage -- Against a lighted white background and a black background
Where should PPE be disposed of after completing HD compounding?
Remove chemo gloves when exiting the C-PEC and place into yellow chemo disposal bin if possible If not possible, place in a baggie to be disposed of prior to leaving the C-SEC Remove all other PPE before leaving C-SEC and place into yellow chemo disposal bin
Medium risk compounding
Requires ISO 5 environment ISO 5 PEC must be inside an ISO 7 buffer room CSPs prepared with complex aseptic manipulation using multiple ingredients such as TPNs Doses are pooled for multiple doses for pt(s) Includes complex manipulations or long mix time Uses > 3 manufactured sterile products EXAMPLES: • Filling reservoirs of infusion devices with sterile drug products (i.e. chemotherapy or pain management) • Compounding TPN's • Batch preparation of syringes
Where can Drug Toxicity Information be found?
SDS (MSDS) Product labeling International Agency for Research on Cancer (IARC) DrugBank DailyMed Special Health warnings from manufacturers or others Reports and Case Studies Evidence-based Recommendation
Line of demarcation
Separates ante area from buffer area if all in one room For the purpose of garbing Must have 40 ft/min air velocity in the direction of the ante area from the buffer area
Types of compounds:
Simple compound: Captopril oral sol'n Indomethacin topical gel Veterinary potassium bromide sol'n Medium compound: Morphine sulfate suppositories Diphenhydramine lozenges Difficult compound: Transdermal dosage forms A suppository for systemic effect
Assigning ITU's to finished sterile compounds
Single-dose vial: 6 hrs (if made in ISO 5) 1 hr (if made outside ISO 5) Multi-dose vial: 28 days Pharmacy bulk package: Only able to penetrate one time after constitution Ampules: one time only Proprietary bag/vial systems: depends on manufacturer
Surfaces of C-PEC
Smooth, seamless, and made of impervious surfaces To reduce difficulty of cleaning HD contamination from surfaces
Ante area (Ante room)
Space directly adjacent to the buffer area Where non-sterile activities related to sterile compounding occurs Faucets should be hands-free Must have air-hand dryers Must be at least ISO 8 if it opens to positive pressure cleanroom (non-HD) Must be at least ISO 7 if it opens to negative pressure cleanroom (HD)
Hazardous drug
Studies in animals or humans indicate that exposures to them have a potential for causing cancer, development or reproductive toxicity, or harm to organs. Any drug identified by at least one of the following six criteria: • Carcinogenicity • Teratogenicity or developmental toxicity • Reproductive toxicity in humans • Organ toxicity at low doses in humans or animals • Genotoxicity • New drugs that mimic existing hazardous drugs in structure or toxicity
What are the methods used for sterilization and depyrogenation of compounded CSP's?
Terminal sterilization Filtration Dry heat Steam sterilization Thermal sterilization
How often is viable airborne monitoring performed?
Testing of surfaces/airflow for microbial organisms Every month
What happens if a manufacturer does not provide an expiration date for a product/component used for compounding purposes?
The compounder must assign a "conservative" date, not to exceed 1 year after receipt
Beyond-Use Date (BUD)
The date/time after which a CSP shall not be used/administered/stored/transported When product has been added/mixed/removed Created by compounder NOT assigned to products made by manufacturer For sterile compounds
According to USP 797, the size of the ante room in a sterile compounding area within a hospital pharmacy is proportional to:
The number of sterile compounding personnel
What is the purpose of Standard Operating Procedures (SOP)?
To maintain proper packaging of HD's Includes... Hazard occupation programs Occupational safety programs Labeling of HD Procurement of HDs Use of proper environmental controls Use of PPE based on activity Decontamination/deactivation, cleaning, dissent. Transport Environmental monitoring Spill control Medical surveillance
What is a 503A facility?
Traditional compounding pharmacy that compounds patient-specific Rx's Required by state BOP to comply with USP and CGMP guidelines
T/F According to USP 797, makeup is not permitted while compounding sterile products
True
T/F Cleaning a spill is considered compounding
True
T/F All drugs listed Pregnancy Category X are on the NIOSH list
True For reproductive and developmental toxicity Categories C+D are also likely to be on list
How often should personnel responsible for high-risk sterile compounding undergo training on aseptic technique?
Twice a year
How should HD's be unpackaged upon receipt?
Unpackaged in neutral pressure or negative pressure Room should have *12 ACPH* Spill kit must be accessible within room Wear appropriate PPE DO NOT UNPACK IN POSITIVE PRESSURE ROOM DO NOT UNPACK IN STERILE COMPOUNDING AREA
Are there special requirements for compounding HD's (not PPE)?
Use disposable, plastic mat that must be discarded when spilled upon or at end of the day Use dedicated mortars, pestles, spatulas APIs should be avoided, liquid agents better than solid agents for compounding
Class II Recall
Use/exposure can cause temporary or reversible adverse health consequences or where the probability of harm is remote E.g. ketorolac inj recalled d/t to possibility of particles in the vials
Class III Recall
Use/exposure is not likely to cause adverse health consequences E.g. coloring on tabs may have been applied inconsistently
Immediate/urgent use compounding
Used in emergency situations (codes) Can NOT be medium/high risk OR HD products Drug is made/exposured in non-ISO 5 environment Must be administered within 1 hour from start of compounding
High risk compounding
Uses non-sterile drugs/equipment Sol'ns must pass through 1.2 micron filter Sterilization by filtration with 0.22 micron filter in ISO 5 environment
Bubble point test
Uses pressure to force liquid to "bubble" out of the filter to *test the filter integrity*
Biological safety cabinet (BSC)
Ventilated cabinet with... Inward airflow for personnel protection Downward HEPA-filtered air for product protection HEPA-filtered exhausted air for environmental protection Air entering cabinet working environment is NOT sterile Clean air is filtered outside Has negative pressure Used to prepare non-sterile + sterile HD's
Proper handwashing technique
Wash hands up to elbows with soap + water for ≥ 30 sec Dry hands with disposable towels/wipes
When is endotoxin testing required?
When compounding Category 2 CSP's made with one or more non-sterile ingredients (except for inhalation or topical ophthalmic administration)
Direct Compounding Area (DCA)
Where critical sites are exposed to unidirectional HEPA-filtered air (AKA first air) Inside PEC w/ ISO 5 environment
Buffer area (buffer room/cleanroom/IV room)
Where the PEC is physically located Has at least ISO 7 air Must be as far away from the main entrance as possible Should not contain refrigerators or freezers Activities that occur in this area: Preparation + staging of components and supplies used when compounding CSP's
Can you compound non-sterile HD's in the same area as where you compound sterile HD's?
Yes As long as everything is made in a BSC Class II or CACI Must be disinfected + cleaned before compounding different HD's
Can you prepare non-HD's in a C-PEC that's designated for compounding HD's?
Yes, If the non-HD preparation is placed into a protective outer wrapper during removal from the C-PEC Preparation must be labeled to require PPE handling precautions
Does the SOP ever need to be reviewed once implemented?
Yes, at least annually Personnel must document their review
Can HD's be stored in a negative pressure buffer room?
Yes, if they are sterile HD's As long as the buffer room is 12 ACPH
Can HD's be stored with non-HD drugs in the pharmacy?
Yes, if they are... Non-antineoplastics Have reproductive risk only In its final dosage form
Unclassified air
air without ISO classification (ie. room air)
disintegrant - oral products have to dissolve in order to be absorbed
alginic acid polacrilin potassium (ie. Amberlite) cellulose products starches compressible sugars (ie. Nu-Tab)
secondary engineering control (SEC)
ante area and buffer area Used for CSP's (797)
antioxidants - prevents oxidation
ascorbic acid
Air sampling should be done how often?
at least every 6 months Done with either Trypticase soy agar (TSA) or soybean-casein digest medium
enteric-coating
celulose acetate phthalate shellac
preservatives
chlorhexidine ophthalmics: EDTA, sodium benzoate, benzoic acid, benzalkonium chloride, thimerosal
suppository base
cocoa butter (theobroma oil) hydrogenated vegetable oils PEG polymers glycerinated gelatin
gliding - improves flow of properties of the powder mixture in tab or cap formulations by reducing inter particle friction
colloidal silica magnesium stearate
precipitation/sedimentation
dispersed phase settles (clumps) together; can settle at the bottom
diluents (fillers)
dry products (tabs, caps): starches, calcium salts, lactose, mannitol, sorbitol, cellulose
tituration
grinding power into smaller, finer particles
ISO classification
how clean the air is depending on the number of particles present per volume of air - The smaller ISO #, the "cleaner" it is (less particles per volume of air)
glass mortar and pestle
liquids (suspension, solutions) oily or can stain
adsorbants - keep powders dry
magnesium oxide/carbonate kaolin
lubricant, anti-adherent - help keep ingredients from sticking to each other and equipment
magnesium stearate
levigating (wetting) agent - help w/ the grinding process
mineral oil glycerin PEG propylene glycol
HLB < 10
more oil-soluble Used for water-in-oil emulsions (w/o)
HLB > 10
more water soluble Used for oil-in-water emulsions (o/w)
hydrophobic solvent - liquid w/ low or no miscibility w/ water, used to dissolve solutes
oils: borage, canola, coconut fats: omega-3, omega-6
Buffers - maintain formulation w/in acceptable pH range
potassium phosphate metaphosphate sodium acetate/citrate
comminution
reducing solids from avg. particle size to smaller avg. particle size process: grinding, crushing common ways: tituration or levigation
wedgwood mortar and pestle
rougher surface preferred for grinding dry crystals and hard powders
levigation
same as tituration, BUT a liquid is added (wetting agent or levigating agent) help w/ grinding process
coatings (regular) - prevent degradation due to oxygen, light, moisture, mask unpalatable taste
shellac gelatin gluten
anti-foaming agent
simethicone dimethicone
geometric dilution
smooth and uniform mixture small amp of drug powder mixed into equal amt of the other other ingredient
porcelain mortar and pestle
smoother surface preferred for blending powders pulverizing gummy
flavoring agent, sweetener
sugar-free artificial: aspartame, saccharin glycerin dextrose lactose mannitol sorbitol phylalanine stevia xylitol
emulsifier
type of surfactant that's used to reduce the surface tension b/t oil and water allowing two phases to come closer together; chosen by HLB#
Which agencies are involved in maintaining HD Rules & Regulations?
• OSHA • State Board of Pharmacy • NIOSH • Environmental Protection Agency (EPA)