Introduction and Scope of this Document
This document is a “rough draft” of notes from the CE presented at the 2022 ALSHP Annual Meeting concerning sterile compounding for hospital pharmacies on selected changes from the 2022 USP <797>, release on November 1, 2022. Note: The audience and scope for this CE was hospital compounding and is not intended to be all inclusive. Since this document is intended as a guide for health-system pharmacies, it does not focus on standards for compounders using terminal sterilization and/or sterility testing of the final CSP. Chapter USP <797> version 2022 must be read in its entirety for full concept and compliance.
Most changes found in the recently released 2022 USP <797> can be implemented now as pharmacies prepare for the official enforceable deadline of November 1, 2023. However, it is important to understand that State Boards of Pharmacy and other regulatory agencies need time to evaluate, adopt and give direction. This document contains selected changes in the 2022 USP <797> publication. Timing of implementation is the opinion of the author. Each facility should drive implementation based on their independent knowledge of priorities for governing bodies.
Categories and BUD
This is by far the major change for the chapter. We move away from risk levels (high, medium, low) associated with the number of products and the number on manipulations with the theory that with increased manipulations came increased potential for contamination. This move away from risk levels was considered necessary since ALL compounding holds risk. Therefore, we are now introduced to compounding Categories (1, 2, and 3) that are defined by the environment and conditions that a CSP is compounded.
Category 1: These are compounded in a segregated compounding area (SCA), outside of a cleanroom suite but inside an ISO 5 classified PEC. These compounds may be assigned a BUD of 12 hours at room temperature or 24 hours under refrigeration. [Category 1 compounding is done in a segregated compounding area].
Note: Immediate-Use is also compounded outside of a cleanroom suite and is still described in version 2022. Immediate-Use is a situation when a compound is required emergently and is done in room air with aseptic technique. In version 2008 immediate-use compounds had a BUD of 1 hour. Version 2022 allows for a BUD of 4 hours. The decision to increase the BUD for immediate-use compounding was based on expert collaboration and that bacteria proliferation takes between 4-6 hours. The standard was changed to give the compounder, who most likely isn’t used to compounding, more time to pay attention to detail while using aseptic technique and to ensure correct drug and quantities are used so that a quality product would be achieved.
Category 2: These are compounded in a full cleanroom suite and may get a variety of BUD (see chart below). This category is inclusive of non-sterile-to-sterile, sterile-to-sterile, terminal sterilization and/or sterility testing of the final CSP. BUD assignments are directly related to each of these criteria. Some of the BUD listed will be out of scope for hospital pharmacies since they require terminal sterilization and/or sterility testing of the final CSP. [Category 2 compounding is done inside a full compounding suite, consisting of an anteroom and a buffer room].
Category 3: This also includes criteria mentioned for Category 2 compounding however, it incorporates more cGMP-type regulations such as only sterile garb used, no exposed skin in the buffer room, increased viable surface and air testing, testing direct compounding areas (DCA) after every batch, and more frequent use of sporicidal agents when cleaning. Category 3 will unquestionably be out of scope for hospital pharmacies, not because of increased regulations approaching more cGMP quality but due to terminal sterilization and sterility testing of the final CSP.
Hospital pharmacies with full cleanroom suites will find themselves compounding under Category 2 as represented in the chart below.
The section highlighted in yellow deals with aseptically manipulated sterile-to-sterile compounding and is where most hospitals will land when assigning BUD for CSPs.
The orange deals with non-sterile-to-sterile or when dealing with a non-sterile component(s) but does not require terminal sterilization nor sterility testing of the final CSP. If there are hospitals that are compounding using non-sterile components, this orange area is where these hospitals will land. NOTE: We will need to hear what Boards of Pharmacy and other regulatory agencies have to say as it pertains to use of non-sterile components to compound sterile products. According to version 2022, there is no longer a term to identify nonsterile-to-sterile compounding. Additionally, no one should ever compound using non-sterile components intended to produce a sterile CSP without special knowledge and training.
The grayed-out areas, although still Category 2, will be out of scope for hospital pharmacies due to the need for terminal sterilization and/or sterility testing of the final CSP. These BUDs will not be obtainable for our purposes.
RABS (“Glove Boxes”)
USP <797> version 2022 is very clear that RABS “must” be located inside a full cleanroom suite, with a buffer room and an anteroom, in order the achieve BUD shown in these charts. If a RABS is in any other type of environment, then the compound would be considered Category 1 and would be assigned the potential BUD of 12 hours room temperature or 24 hours at refrigeration.
Assignment of Beyond Use Date (BUD)
This is not a change from version 2008 to version 2022 but worth mentioning. When assigning a BUD for any given CSP, it is important to remember that the BUD allowable by USP <797> be supported by literature showing stability and compatibility of the final preparation both physically and chemically with the fluid it is in, the container it is in and at the final CSP concentration and at the specific storage conditions that we will be storing the final CSP (i.e. room temperature, refrigeration, frozen, light, florescent light, etc.). Additionally, sorption and leaching need to be taken into consideration prior to assigning the BUD. If literature is unable to support the BUD allowable by USP <797> then the BUD found from the literature must be assigned instead.
Other Considerations for BUD
When it comes to opening a sterile container for manipulation, not much has changed from version 2008. The major change in version 2022 is that if a single-dose container is opened in and ISO 5 PEC can now be assigned a BUD of 12 hours (as opposed to 6 hours in version 2008).
Note the orange highlighted area, “bulk compounded solutions”. This is not a change from version 2008 to version 2022 but worth mentioning out of patient safety. Additionally, this is more prominent in version 2022 therefore increased focus from regulatory agencies can be expected.
A bulk compounded solution is a CSP that is made for future use as an ingredient in another CSP or a bulk medication from which individual doses will be repackaged for different patients. It is allowable to compound this in advance using USP <797> BUD but once altered it becomes a single-dose container and will be reassigned a BUD of 12 hours. Any unused portion must then be discarded.
Environmental Sampling
There are several changes for environmental sampling and incubation however one item to point out is that the 2022 chapter states that environmental sampling is done to see if “contamination is present at unacceptable levels”. This is important because it recognizes that we should expect to find growth in our environments. If fact if we never find growth in our environments, then the environmental sampling plan should be looked at closely to ensure that it is being done properly, testing the correct places and at the appropriate times.
Viable Surface Sampling: Reminder – Agar needs a neutralizing agent included so that it can neutralize any residues that are left behind from cleaning agents so that an accurate sample can be achieved.
Frequency of surface sampling is now increased to monthly for Category 1 and 2 compounding (weekly for Category 3). Samples must be taken inside the PEC, from equipment inside the PEC, areas around the PEC and pass-throughs. In addition to these areas, the designated person needs to sit back and watch workflow and note all the “high-touch” areas. Once all these areas are identified, all locations will be placed on a map showing the sampling locations (this map is a mandatory piece of documentation). Testing must be done at the busiest times, after compounding and prior to cleaning.
Viable Air Sampling: The frequency has not changed for this and remains every 6 months for Category 1 and 2 (monthly for Category 3). Samples must be taken inside the PEC. In addition, the designated person will sit back and observe workflow to identify all high traffic areas. Once identified, these areas and the PECs will be marked on a map (again, mandatory for your documentation). Testing will take place when the most people are in the room and under the most dynamic working conditions.
Most hospitals will not have the proper equipment for sampling air. If this is the case, hospitals will most likely rely on their certification company to do it for them. However, it is important for the Designated Person to take ownership of this sampling plan and dictate sample locations to the certification company.
Incubation of Surface and Air Samples
Incubation is changing quite a bit and will require 2 incubation intervals at 2 different temperatures to ensure that all potential microbes have opportunity to grow (some microbes grow better at different temperatures).
Initial incubation will be between 30-35°C for no LESS than 48 hours. Then the colony forming units (cfu) will be counted and recorded. Then the samples will be incubated at 20-25°C for no less than 5 days and again the cfu will be counted and recorded.
It must be understood that an incubator is required to incubate at 20-25°C and that the facility cannot simply place these samples in open air and monitor the room temperature. The chapter specifically states that a controlled incubation at 20-25°C must occur inside an incubator set at these temperatures.
Additionally, the chapter does give an alternative way to incubate using these 2 temperature intervals to decrease the incubation time by a couple of days. This can be found by referring to section 6, box 5 and 6 in the chapter. This process involves using 2 plates instead of one and incubating each plate at different temperatures.
A note worth mentioning. The chapter states to incubate for no less than 48 hours or for no less than 5 days. The idea is to incubate for these time frames stated to ensure growth. Incubation a bit over these time frames won’t harm the agar but incubation much longer will dry out the agar making if no longer viable for growth and/or destroying the microbes.
Identification of Colony Forming Units (cfu)
This is the most radical change for us and environmental sampling. In version 2008 we were required to identify any and all cfu to the genus level that was obtained on a sample. Now, in version 2022, this is no longer the case. The chapter no longer requires us to identify growth to the genus level UNLESS the action levels set by USP are exceeded. NOTE: This is something we will want to hold off on until we hear from State Boards of Pharmacy and other regulatory agencies. They may want to pass additional requirements for this identification process. Additionally, all the highly pathogenic organisms mentioned in version 2008 (gram negative rods, coagulase-positive staphococcus, yeast, mold, fungus) are no longer even mentioned in the chapter.
Through training, the expectation is to keep cfu growth down and keep it from spreading. This will be the goal going forward. It is a requirement to track and trend all cfu growth even if you do not exceed action levels but once action levels are exceeded, an attempt to identify all cfu to the genus level must be made. This will then drive your action plan that will identify the source of contamination, remediation of the issue and proof that remediation was effective.
Note: Now that the chapter only requires a trained professional to identify colony forming units (cfu) when limits are exceeded, we can have our own incubators on site and count and document cfu ourselves. However, be aware that these incubators will produce an undesirable smell and would be best placed in an area that is secluded from work environments or in your micro lab.
Action Levels for Air and Surface Samples
The action levels for ISO 5, 7 and 8 air don’t change in the new chapter. However, for ISO 8 surfaces, the action level is half of what it was in version 2008. Other action levels for surfaces remain the same.
Garbing
Garbing changes from a distinct order in version 2008 and allows the facility to dictate the garbing order based on the location of the sink (outside the anteroom, inside anteroom on the dirty-side or clean-side) if the order of garbing does not cross contaminate and is written in the facility’s SOPs. All employees must garb following the facility SOP. Additionally, version 2008 had us using alcohol-based had scrub and donning sterile gloves in the buffer room. Now, version 2022 states that gloves “must” be donned in a classified room (never a PEC) but “should” be done in the anteroom. This makes much more sense since exposed skin needs to be minimized in the buffer room.
Side Note: Sterile gloves need to have breakthrough times for isopropyl alcohol 70% (IPA 70%) on file. This information can be obtained from the manufacturer of the gloves.
Hand Hygiene
Scrub brushed and electric hand dryers are forbidden, and soap dispensers must be disposable.
Best Practice: Have a clock in view of the sink so that employees can time their 30-second hand washing.
Gloved Fingertip and Media Fill Testing
There is now a differentiation between those who compound and those who have oversight over compounding. There are different requirements for each of these individuals.
Initial fingertip testing: This remains the same and requires 3 successive glove/garb/hand hygiene tests with zero cfu growth. These must be successive (three in a row).
Ongoing fingertip testing frequency:
Compounder: Every 6 months for Category 1 and 2 (every 3 months for Category 3)
Oversight Person: Every 12 months (note that this is a requirement for those with oversight, but this person may NOT compound – if this person is needed for compounding, then this person must be on a 6-month testing interval)
NOTE: A documented observation of the garbing and hand hygiene process is now required. You will need some way to document that this observation took place. The employee being tested must not only pass the actual analytical fingertip test but also the observation of total process including garbing and hand hygiene.
Media Fill Testing Frequency:
Compounder: Every 6 months for Category 1 and 2 (every 3 months for Category 3)
Oversight Person: Every 12 months (note that this is a requirement for those with oversight, but this person may NOT compound – if this person is needed for compounding, then this person must be on a 6-month interval)
Fingertip samples will continue to be taken right after the media fill is complete.
An important addition to this process is the requirement to now take a sample of the direct compounding area (DCA) where the test took place.
NOTE: Each facility must have a certificate of analysis (COA) on file for each lot number of commercially purchased media fill and agar that shows proof that the media supports growth. This is obtained from the manufacturer.
Incubation of fingertip and media fill samples
This is very similar to the air and surface sample incubation with 2 incubation intervals at 2 different temperatures to ensure that all potential microbes have opportunity to grow (some grow better at different temperatures).
Fingertip Samples: First, these will be incubated between 30-35°C for no LESS than 48 hours. Then the colony forming units (cfu) will be counted and recorded. Then the samples will be incubated at 20-25°C for no less than 5 days and again the cfu will be counted and recorded.
Media Fill: These will be incubated somewhat differently by first incubating at the lower incubation temperature and for a duration of 7 days at both incubation temperatures. First, they will be incubated between 20-25°C for no LESS than 7 days. Then checked for turbidity and recorded. Then the samples will be incubated at 30-35°C for no less than 7 days and again checked for turbidity and recorded. However, there is provision in the chapter that allows the facility to document and change the order of incubation temperatures for media fills only (all other samples; air, surface, fingertips, must follow the order of incubation temperatures mentioned).
It must be understood that the chapter does state that an incubator is needed to incubate at 20-25°C and that the facility cannot simply place these samples in open air and monitor the room temperature. The chapter specifically states that a controlled incubation at 20-25°C must occur inside an incubator set at these temperatures.
Action Levels
Action levels for fingertips and media fills remain the same with the addition of required sampling of the DCA after media fill testing. The DCA action level is the same as described for ISO 5 surface sampling.
Compounding Documentation: Master Formulation Records and Compounding Records
Master Formulation Records (MFR) are used as the official and permanent source to document all information from how to compound any given CSP and supportive information for establishing BUD that are up to but not exceeding what is allowable by USP <797>. MFR were also required in the 2008 version but specific requirements for this document are now listed in section 11.1, Box 9 of the 2022 version. MFR are required when compounding for more than one patient or for when using non-sterile components.
Compounding Records (CR) are used to document the compounding process. CR were also required in the 2008 version but specific requirements for this document are listed in section 11.2, Box 10 of the 2022 version. CR are required for ALL compounded products, category 1, 2, and 3 without regard to the number of patients or sterility of the starting components. Only immediate-use compounding for only one patient does not require a CR. For clarification, all compounded CSPs require a CR, even if only one product is compounded for one patient.
The chapter does state that a prescription, medication order or label may be used as a CR but remember that there are specific requirements that must be included on the compounding record. The facility IT may need to get involved if the label is used for the CR to ensure all requirements are met (see section 11.2, Box 10).
Training and Evaluation
As mentioned earlier, this is key for ensuring the quality of our “environment and conditions under which we compound our CSP”. Section 2 of the chapter lists out the minimum requirements. Remember that compounders must be:
Trained – shown the process
Demonstrate knowledge of principles – show understanding through testing or verbalization
Show competency - by proof they can successfully complete a task
Facility Build
There are a couple new standards, but most are reminders to ensure a facility is ready. Again, this is not all inclusive and this section of the chapter must be reviewed by the facility.
Cleanroom Suite – Category 2 and 3 Compounding
HEPA filters: Must be in ceiling
Air Returns: Must be low on wall
There is a provision in the chapter that if the facility has a smoke study on file showing that there is not any stagnant air with air returns in other locations that they are ok to work as built
ISO 7 Buffer Room/Anteroom: Minimum 30 ACPH – stressing minimum, busy rooms will need higher ACHP
Buffer room requires at least 15 ACPH from HVAC
ISO 8 Anteroom: Minimum 20 ACPH – stressing minimum, busy anterooms will need higher ACHP
NOTE: Anterooms that are connected to a negative pressure buffer room MUST be ISO 7 (the same ISO classification of the buffer room as to lessen any contamination being pulled into the negative pressure buffer room)
Positive Pressure: Must be +0.20” WC or greater to the relative environment in a cascading fashion (buffer room more pressurized than anteroom, anteroom more pressurized to the general facility)
Line of Demarcation: Required - This was not required in a compounding suite in version 2008 but now it is required
Segregated Compounding Area (SCA) – Category 1 Compounding
This is an unclassified room or area with a visible perimeter that houses a PEC where compounding will take place.
Room or visible perimeter located away from other areas
Sink inside perimeter no less that 1 meter from the PEC
USP <800>: Hazardous Drugs - Handling in Healthcare Settings
USP <800> now becomes enforceable since the published 2022 USP <797> refers to USP <800>. It is important to note that USP <800> is not only about compounding sterile and non-sterile hazardous drugs but entails all handling of hazardous drugs. It follows the life of the hazardous drug in the facility from receipt, storage, compounding, delivery/transport, administration, and waste/disposal. It is important that teams are in place to ensure compliance with the USP <800> chapter.
Cleanroom Suite for Hazardous Drug Compounding – Category 2 and 3 Compounding
HEPA filters: Must be in ceiling
ISO 7 Negative Pressure Buffer Room/Anteroom: Minimum 30 ACPH – stressing minimum, busy rooms will need higher ACHP
Reminder: Anterooms that are connected to a negative pressure buffer room MUST be ISO 7 (the same ISO classification of the buffer room is required since negative pressure is pulling in air from the anteroom into the buffer room)
Negative Pressure: Must be between -0.01” to -0.3” WC
Positive Pressure Anteroom: Must be +0.2” WC or greater
Room and hood externally vented to the exterior of the building
Line of Demarcation: Required
Sink: Must be no less than 1 meter away from the entrance to the negative pressure buffer room to decrease water source contamination
Containment Segregated Compounding Area (C-SCA) for Hazardous Drugs – Category 1 Compounding
This is an unclassified room houses a C-PEC where compounding will take place.
Room made of fixed walls located away from other areas
Sink inside or outside of room (no less that 1 meter from the PEC)
Negative Pressure: Must be between -0.01” to -0.3” WC
Minimum ACHP of 12 (stressing that this is a minimum and busier rooms will require increased ACPH)
Room and hood externally vented to the exterior of the building
Other notable hazardous drug reminders for sterile compounding (not all inclusive):
Double Glove with ASTM-rated chemo gloves
Double shoe covers
CSTD recommended for compounding HDs/Required for administration
Note that this is strongly recommended because it does help decrease HD contamination but also required for nursing for administration. If pharmacy does not use CSTDs to compound, then this would require nurses to attach CSTD prior to administration outside of a protective C-PEC
Deactivation and decontamination introduced as a part of the cleaning process
Spill kits required in several areas but also required in buffer room
Chemo gowns (coated, seamless, closes in back)
Respiratory protection for spills and monthly cleaning under tray of C-PEC
Cleaning and Disinfection of Controlled Environments
When it comes to cleaning and disinfection of controlled environments, version 2008 didn’t go into specifics and left it up to the reader to understand how cleaning and disinfection was to be applied to the controlled environments. This wording used in 2008 is most likely the reason why many used IPA 70% as the end all, do all, be all cleaning agent in IV rooms for years. However, version 2022 does and exceptional job at explaining cleaning and disinfecting of controlled environments. Section 7 of 2022 USP <797> explains the cleaning and disinfection process and should be read closely. In this section, the minimum cleaning requirements are introduced as to ensure that proper cleaning and disinfection is in place for cleanroom environments.
Section 7 is titled “Cleaning, Disinfecting and Applying Sporicidal Disinfects and Sterile 70% IPA”. It should be noted that sterile IPA 70% is mentioned separately. This is because sterile IPA 70% is “downgraded” in the chapter. Sterile IPA 70% is a sanitizing agent and not a disinfectant. It does not kill all microbes and has a dwell time ranging from 10 seconds to one hour depending on the microbe, and sterile IPA 70% does nothing for spores, hence the reason it must be sterile (to ensure that no spores are in the IPA being used).
Sterile IPA 70% is now being looked to as a residue removal agent (for cleaning agents) and a sanitizer that is acceptable to use in cleanrooms to keep microbial growth down if other cleaning agents are in place and used appropriately. Note: Frequent use of sterile IPA 70% continues to play an important role in keeping microbial growth down when used on all surfaces throughout our controlled environments.
Special attention should be given to the chapter’s cleaning and disinfecting chart in section 7, table 10. This chart lists the different types on cleaning agents to use, how to use them and the minimum frequency of use. This table will be extremely helpful in aiding facilities to meet the minimum cleaning and disinfecting requirements of the chapter.
It should be noted that each element of cleaning and disinfecting is defined and unique. Although there is overlap between processes and products due to more advanced one-step cleaning agents, it is important to become familiar with these definitions.
Cleaning: Removal of residues (dirt, debris, microbes, residual drugs/chemicals) using an agent w/ surfactant or an enzymatic ingredient using manual or mechanical processes
Disinfection: Use of an EPA-registered germicidal to destroy microorganisms (bacteria, virus, fungi)
Sporicidal Activity: Use of an agent to destroy bacterial and fungal spores/spore-forming microbes
It should be noted that for cleaning includes the use of a surfactant or enzymatic agent in addition to manual or mechanical processes to remove contaminants. Surfactants were overlooked in previous years and the mechanical/manual removal of debris is of great importance. Applying product and allowing to dry is not regarded as cleaning without the manual/mechanical removal from wiping the area being cleaned.
Sterile IPA 70% continues to be used just prior to introducing components into the PEC with a manual/mechanical motion to wipe away residues left behind from cleaning agents and as a sanitizer to ensure the component is void of any microbial contaminant that may have been missed or introduced after it was initially clean and disinfected. Sterile IPA 70% continues to be used on critical sites for the same reason and again emphasizing the manual/mechanical motion to wipe away contaminants.
The use of cleaning agents and materials (i.e., wipers) inside the PEC “must” be sterile. However, there isn’t any need to open these sterile items inside the PEC or keep them in the PEC. This intent of this is not to keep the items sterile but instead to decrease the bioburden that could be introduced into the PEC from the manufacturer. Concerning cleaning agents and materials used in the rooms (SEC), these “should” be sterile according to 2022 USP <797>. Whether or not to use sterile items to clean classified rooms (SECs) will be up to the facility, keeping in mind that the intent is to decrease potential bioburden from being introduced into the area from the manufacturer.
When it comes to introducing items from uncontrolled environment to controlled rooms (SECs), the chapter does somewhat disappoint. The chapter does mention, to clean components prior to introducing them into controlled rooms (SECs) with a sporicidal agent, EPA-registered disinfectant, or sterile IPA 70%. However, when writing SOPs, it must be remembered the true status of sterile IPA 70%. Anything and everything can live on a component prior to cleaning and disinfecting, including but not limited to gram negative rods, fugus and spores. Alcohol does nothing for spores and if only sterile IPA 70% is used to clean and item prior to introduction then the spores would simply be transferred into the controlled area and rapidly spread contamination. Remember that USP is setting minimum standards and we can put into place more strict processes. It would be recommended as best practice that all components being introduced into controlled rooms (SECs) from uncontrolled spaces be cleaned initially with a sporicidal agent and allowing for adequate dwell time. However, the chapter states that at a minimum that any of the mentioned cleaning agents can be used prior to introducing items into controlled rooms but considerations should be taken into mind when establishing SOPs.
Once again, this is written as an introduction to the major changes for hospital compounding pertaining to the 2022 version of USP <797> and is not intended to be all inclusive. Additionally, this document does not contain information needed for those attempting to compound with non-sterile components, terminal sterilize CSPs or doing sterility testing of the final CSP. All compounders must read the 2022 USP <797> in full to get all important changes and minimum standards for patient safety and compounding compliance.
References
USP <797> 2008
USP <797> 2021 proposed revision
USP <800> 2020
USP <797> November 1, 2022
Contact Information
Steve Milstead, PharmD, BCSCP
Phone: (205) 862-6957
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