USP General Chapter <797> Frequently Asked Questions
Responses have been provided for informational
purposes only, and should not be construed as an official interpretation
of USP text or relied on to demonstrate compliance with USP standards or
requirements. (This is a
standard disclaimer for legal reasons - in case your State Board of
Pharmacy adds additional requirements not delineated in the current
version of USP <797> but the engineering aspects would apply -
MAS)
1. We are a privately owned physician's office. We do not
have a pharmacy license or pharmacist. We have 2 RN's trained and
certified to mix and give chemo in our outpatient infusion center. We
follow the NIOSH guidelines. Do we have to follow the USP 797
guidelines?
The USP Chapter <797> standards are not limited in their
application to any specific profession or to any specific type(s) of
sterile compounding site. USP Chapter <797> standard applies to sterile
compounding without regard to the location or profession of the
compounding personnel. This is because no patient should have to give up
their right to an accurate, safe, sterile dose no matter where that dose
is prepared or who prepares it.
Microbial Contamination Risk Level Categories
2. What types of sterile compounds can nurses prepare on the floor? Can
they draw up IV push medications?
Only Immediate-Use CSPs (Compounded Sterile Preparations)
may be prepared in worse (dirtier) than ISO Class 5 environments, such
as in clinical patient care areas. Refer to the Immediate Use CSPs
section for the six specific criteria.
3. Nurses in our practice currently mix Infliximab in the
home just prior to infusion. If we receive an order for 600 mg in 6
vials of 100 mg each admixed in a 250 mL bag of Normal Saline, would
this fall outside the Immediate Use CSP as defined in <797>, assuming
the bag entry is limited to two?
The standards for Medium-Risk Level CSPs apply, because
more than three containers of sterile ingredients are used. When there
are more than two entries into one sterile container, this also
qualifies as Medium-Risk Level. Increasing quantities of sterile
ingredients and manipulations of them increase the risk of dosage and
ingredient errors, and microbial contamination.
4. Can nurses draw up IVP medications on the nursing unit?
Can they keep the left over drug in a syringe in the patient's
medication drawer for future dosing?
Intravenous medications prepared in worse (dirtier) than
ISO Class 5 environments are subject to the standards for Immediate-Use
CSPs. Immediate-Use CSPs cannot be stored.
5. Is there a limit of how many times a vial can be entered
by a nurse using a single dose vial on a nursing unit within 24 hours?
This practice qualifies as an Immediate-Use CSP. A maximum
of two stopper entries is permitted within one hour from when the
preparation began for administration to the same patient.
6. Continuous infusion pumps and other devices that are
filled with a single ingredient that may require multiple vials and
where a Luer lock extension tubing is used to fill the catheter, can
this medication be prepared in the operating room in the sterile field?
Also can this preparation be administered over several days?
The requirements for Immediate-Use CSPs apply to
medications prepared in worse (dirtier) than ISO Class 5 environments.
Chapter <797> does not apply to clinical administration practices and
conditions; however, the Immediate-Use CSPs section states a warning
regarding potential harm to patients from extended administration
durations of contaminated CSPs.
7. Can a product be considered immediate use risk level if
product/device is administered over multiple days (continuous infusion
pumps, insulin pumps, etc.)?
The Immediate-Use CSPs category does not limit the duration
of clinical administration of the CSP. Please refer to the answer to
question 5.
8. Which risk level would apply to vials with the stopper
removed to compound for patient who are allergic to latex? They might be
prepared in ISO Class 5 or outside ISO Class 5
The stopper must be removed by contacting only sterile
surfaces, e.g., sterile forceps. If stopper and content removal occur
within an ISO Class 5 environment, and if the vial is one of three or
fewer sterile ingredients, then this qualifies as either a Low-risk
Level CSP or a Low-Risk Level CSPs with 12-Hour or Less BUD, depending
on whether or not the primary engineering control, PEC or ISO Class 5
source is located in an ISO Class 7 buffer area. If the vial is one of
more than three sterile ingredients, then this requires compliance with
Medium-Risk Level CSPs standards. If the stopper is removed by
contacting only sterile surfaces in worse (dirtier) than an ISO Class 5
environment, then this qualifies as an Immediate-Use CSP.
9. Can you define the risk level for white blood cell
labeling?
The microbial contamination risk level of blood cell
labeling depends on whether or not the procedure is performed by a
properly prepared and attired person in an ISO Class 5 environment, on
how many sterile ingredients are used, and if any unsterile ingredients
or devices are used.
10. If you prepare a large batch of drug and submit a
portion of the batch for sterility testing, as dictated in Chapter <71>,
and the batch passes, does this validate the process for subsequent
batches allowing use of chemical stability BUD?
No. Sterility testing is required for each batch in order
to extend BUD to chemical stability.
11. When compounding a high risk CSP that is at a
concentration that may not remain in solution below body temperature,
i.e., intrathecal medications, be stored in an incubator at body
temperature ~37°C?
This is permissible when there is direct testing evidence
to verify sterility is maintained, and when there is either direct
testing or reliable literature evidence of chemical stability. Chemical
stability of drug products and preparations is generally defined as 90%
to 110% of initial strength of ingredients; however, some USP injections
limit the strength range to not less than 95% and not more than 105% of
labeled strength.
12. If compounding outside of the manufacturer's
instructions, it is understood that stability and purity must be
verified. Is this also the case for sterility and pyrogen testing if
beyond-use-date (BUD) is less than 48 hours?
The 48 hour BUD at controlled room temperature (see the
General Notices and Requirements) is required for Low-Risk Level CSPs in
the absence of sterility testing data. Testing for sterility and
pyrogens or bacterial endotoxins is required only for High-Risk Level
CSPs administered by specific routes, which are delineated in that
section.
13. In a code situation with the pharmacist preparing the
drugs, what kind of labeling will be necessary?
This will usually be an Immediate-Use CSP for which
labeling requirements are described in that section.
14. When risk levels are assigned, what is meant by "In
absence of passing sterility test?"
When there are no sterility testing results to establish a
statistical probability that each unit of CSP is sterile, i.e.,
sterility is assumed based on personnel practices and compliance with
standards for quality of air environments and surfaces.
15. Is there a standard for preparing intrathecal CSPs?
Standards for compounding intrathecal CSPs are according to
the particular microbial contamination risk level. The standards for
Low-Risk Level CSPs are, prudently, the least that should be applied to
intrathecal CSPs. While not expressly prohibited as Immediate-Use CSPs,
intrathecal injections pose the greatest risk of harm and death to
patients if contaminated with microorganism and bacterial endotoxins,
which is most likely to occur under Immediate-Use CSP conditions.
16. If you perform a large volume of medium risk
compounding is it necessary to perform low risk media fills?
No, because the Medium-Risk Level CSP medial fill testing
is more rigorous that that for Low-Risk Level CSPs.
17. If media fills are incubated for an extended period is
that sufficient to extend the BUD?
No. BUD applies to chemical and physical stability.
Extended incubation of media fill test specimens is irrelevant to
extending BUD and sterility storage times for a particular CSP microbial
contamination risk level. Extended BUDs require evidence from
stability-indicating chemical assays, and extended sterility storage
times require sterility testing evidence.
18. If single use containers can remain open in ISO Class 5
for 6 hours does this apply to solutions hanging on a TPN compounder
that are spiked (closed system)?
Yes, except for Pharmacy Bulk Packages, which bear a
manufacture's specific BUD, which is usually 4 hours after initial
puncture of the closure.
19. How would a bladder irrigation be categorized, such as
a product for immediate use that uses non-sterile ingredients (alum)?
If the product labeling indicates it is permitted to be
administered unsterile, then <797> does not apply. If it is supposed to
be sterile before administration, e.g., the <797> Introduction states
that irrigations for body cavities are required to be sterile, and then
this is a High-Risk Level CSP, which must be sterilized before
administration.
20. What is the reasoning behind not allowing a longer
beyond use date, especially when there is dependable literature which
shows a chemical/physical stability for perhaps several weeks or even
months? Does it make a difference if the final container is sealed?
The same data that confirm long term chemical and physical
stability give no assurance regarding sterility and lack or acceptable
level of bacterial endotoxins.
21. Immediate use CSPs must be administered within one hour
following preparation. Must administration be completed within that same
hour? With low-risk level CSPs with 12 hour BUD, must administration be
completed within those 12 hours?
Administration of Immediate-Use CSPs must begin within 1
hour from the start of their preparation; there is no requirement for
the duration of administration. For Low-Risk Level CSPs with 12-Hour or
Less BUD, there administration must begin within 12 hours from the start
of compounding, but there is no administration duration requirement.
22. If a pharmacy prepares an epidural bag of bupivacaine
in 100 mL normal saline, can an anesthesiologist add fentanyl to that
same bag on the floor? If so, what would the BUD be?
If fentanyl is added in worse (dirtier) than an ISO Class 5
environment, then this becomes an Immediate-Use CSP, for which there is
no administration duration requirement. The Immediate-Use CSPs section
states a warning regarding potential harm to patients from extended
administration durations of contaminated CSPs.
23. Does the 28 day expiration on multi-dose vials apply to
their use in additional compounding, or does it apply to only
administration of that preparation?
28 days is the USP chapter <51> testing requirement for
Multiple-Dose Containers to be used under any conditions. The BUD on
some products may be labeled more or less than 28 days, at the
discretion of the manufacturer.
24. The Chapter only mentions the expiration dates for
single-dose and multi-dose vials. What is the appropriate expiration
date for eye drops and for multi-dose vials of oral solutions if
commercially made?
For ophthalmics, the expiration date is labeled by the
manufacturer. Multi-dose vials of oral solutions are not required to be
sterile; thus, <797> does not apply thereto.
25. Nursing is known to mix IVPB way ahead of time for
administration. What is the BUD?
The BUD for intravenous piggyback (IVPB) infusions depends
on the conditions under which they were prepared. For example, when
prepared under conditions of Immediate-Use CSPs, infusion must start
within 1 hour of starting to prepare the CSP with no time limit to
finish the infusion; when prepared under conditions of Low-Risk Level
CSPs with 12-Hour or Less BUD, infusion must start within 12 hours of
preparing the CSP with no time limit to finish the infusion; when
prepared under conditions of Low-Risk Level CSPs, BUD is 48 hours at
controlled room temperature (see USP General Notices and Requirements),
14 days at cold temperature (see USP General Notices and Requirements),
and 45 days in solid frozen state between -25° and -10°, in the absence
of direct sterility testing evidence that supports longer BUDs.
26. Are there any criteria that specifies BUD if sterility
testing is done?
Sterility storage durations specified at the particular
temperature ranges for Low-Risk Level, Medium-Risk Level, and High-Risk
Level CSPs may be exceeded when evidence of sterility based on proper
testing can be documented. The particular BUD of longer sterility
storage times based on testing evidence shall be the judgment of
appropriate compounding personnel, and it shall assure chemical and
physical stability of the CSPs.
27. What type of expiration dating do you give to devices
such as continuous infusion pumps?
Refer to USP General Notices and Requirements to
differentiate expiration date from beyond-use date. The BUD of such
preparations in this question depends on the microbial contamination
risk level of the compounding process, i.e., whether for Immediate-Use
CSPs, Low-Risk Level CSPs with 12-Hour or Less BUD, Low-Risk Level CSPs,
or Medium-Risk Level CSPs.
28. What is the BUD for extemporaneously compounded eye
drops for both inpatient and outpatient use?
The BUD of ophthalmic CSPs depends on the microbial
contamination risk level of the compounding process, i.e., whether that
for Immediate-Use CSPs, Low-Risk Level CSPs with 12-Hour or Less BUD,
Low-Risk Level CSPs, Medium-Risk Level CSPs, or High-Risk Level CSPs.
29. If a commercially available IV fluid (i.e., Lactated
Ringers or Normal Saline) is spiked in anticipation of emergent
administration, for example in an ambulance, trauma emergency bay or a
trauma OR room, does the 1 hour expiration time apply to this situation?
No. Since the spiking of an IV bag is not considered
sterile compounding, the one hour time limit would not be applicable.
The individual performing this task should use appropriate technique and
should perform (if possible) a thorough hand sanitization.
Cleaning and Disinfecting the Compounding Area
30. Can vials be cleaned with alcohol swabs or 70% IPA
wetted gauze pads?
Alcohol swabs must be sterile. Sterile 70% IPA wetted gauze
pads or other particle generating material shall not be used to
disinfect the sterile entry points of packages and devices (see Cleaning
and Disinfecting the Compounding Area).
31. Can non-sterile 70% IPA be used to disinfect surfaces
other than those in the DCA of the primary engineering controls in the
ISO Class 5, 7, and 8 areas?
Yes. The chapter requires that surfaces be cleaned with
sterile water for irrigation or injection to remove any soluble residues
with low-shedding wipes. This is followed by wiping with a residue-free
disinfecting agent (such as sterile 70% IPA), which is allowed to dry
before compounding begins. However, the Chapter does not require that
the residue-free disinfecting agent be sterile.
32. Do supplies need to be decontaminated when they are put
on the shelf (taken out of shipping carton) if pharmacy is going to wipe
them before they are introduced into the buffer area?
If the supplies are going to be put on a shelf in a general
pharmacy area they do not need to be wiped until being introduced into
the buffer area.
33. How soon before going into the BSC do supplies need to
be sprayed with sterile IPA?
If supplies are sprayed immediately before being introduced
to the BSC the operator minimizes the risk of touch contamination that
may occur if supplies are sprayed in advance.
34. We currently store syringes and needles in bins in the
buffer area. Can we wipe every syringe down the day before and restock
bins to get ready for the next shift or do we need to remove them from
the buffer area? Do they need to be wiped immediately prior to use? Can
we re-spray with sterile IPA in the buffer area?
Removing supplies from the buffer area on a daily basis is
not required. If supplies are disinfected prior to use it minimizes the
risk of touch contamination. Re-spraying with sterile IPA in the buffer
area is acceptable.
35. Do you recommend spraying sterile IPA and wiping with
something dry (like Texwipe) or using a pre-moistened sterile wipe? Does
it matter?
Pre-moistened sterile IPA wipes are acceptable.
Water-soluble residues can be removed with sterile water and
low-shedding wipes. This is followed by wiping with a residue-free agent
such as sterile 70% IPA which is allowed to dry.
36. How does one clean the hood every 30 minutes during
continuous compounding if the compounding process takes more than 30
minutes?
Clean the hood after completing the compounding process
that takes more than 30 minutes.
37. Can bleach be used as appropriate cleaning agent and
can diluted bleach be used exclusively as a disinfectant?
Bleach can be effective as a disinfectant but is
inactivated by proteins. Bleach is not appropriate for disinfecting
critical sites. Bleach is appropriate if followed by sterile 70% IPA
wipe (see question #34) Consideration for the selection of cleaning
agents should be given to the effect on surfaces and potential
respiratory, skin, and eye irritation to the operator.
38. If practicing in a certified green building with limits
on the types of cleaners that can be used, are there any Green
alternatives for cleaning floors?
Vendors should be consulted for Green alternatives.
39. Are instant hand sanitizers adequate for use in the
cleanroom?
Products for use in the clean room must be classified as a
waterless, surgical hand antiseptic.
40. Individual alcohol wipes are used to swab the top of
vials which involves opening multiple individual swabs. Can you describe
a better process for this?
No
41. Are floor fatigue mats allowed and what is the cleaning
process for them?
Floor fatigue mats have the potential to collect grit and
grime. If fatigue mats are used they must be thoroughly cleaned on a
daily basis which means picking them up and cleaning all surfaces.
42. It has been stated that other procedures can be used if
proven better than <797> standards. Is this true for sterile IPA? If it
can be proved that the disinfectant we use is better than sterile IPA,
can we use our disinfectant?
Yes. However the operator needs to consider the effect on
surfaces, material compatibility, and the operator. The disinfectant
must not leave a residue.
43. Are we required to use sterile IPA for everything,
including cleaning carts before bringing them into the clean room or
just for the actual compounding activities?
Sterile 70% IPA is required for critical sites. Other
disinfectants may be appropriate for carts and other surfaces. Consider
the effect on surfaces, material compatibility and the operator.
44. We are seeing resistance to the use of sterile gloves
and sterile IPA. Can you direct us to scientific support for the
benefits of using sterile alcohol and sterile gloves over non-sterile?
Sterile gloves and alcohol have a lower bioburden.
45. In a facility that uses CACI/CAI would using sterile
gloves and sterile alcohol be needed outside the isolators?
Yes, unless documented by the equipment manufacturer that
this is not required.
46. May cleaning wipes be used for cleaning in the buffer
area as long as they are lint free?
Low-shedding wipes shall be used.
47. In autoclaving, in order to reach a temperature of 121°
C, should the pressure be raised higher than one atmosphere?
Steam sterilization is accomplished at 121°C at 1
atmosphere.
48. What concentration of sodium hydrochloric solution
should be used? Why are solutions of NaDCC not listed under chlorine
since they are more efficient, pH neutral, and more stable?
The chapter does not prohibit other agents. However, agents
that may be used need to be evaluated based on microbial inactivation as
well as chemical and physical properties.
49. When a secondary set and syringe/needle is attached to
a bulk bottle for withdrawal of drug, how long can the set be kept
before you need to change the set?
Pharmacy bulk packages are labeled as to the time period
they can be used after initial puncture.
Personnel Cleansing and Garbing
50. What garbing is appropriate for a pharmacist that is
checking but not manipulating CSPs in the buffer area? What if the
pharmacist is entering to check the pump setting and lyte pool and
calculation prior to mixing?
All individuals who enter the buffer area or clean room
shall be fully garbed with appropriate personal protective equipment.
51. Is nail polish allowed? The Chapter refers to natural
nails being kept short and neat but does not refer to polish. Is it
allowed under gloves?
No. Nail polish should be removed under all circumstances
as chipped nail polish has been shown to harbor microorganisms.
52. What garb is required for a CAI operator?
If the CAI is located in an ISO Class 7 environment,
typical clean room garb (i.e. shoe covers, gown, hair cover, and mask)
is required. If the CAI is not located in an ISO Class 7 environment,
and it meets the requirements as stated in the Chapter to allow such
placement, no additional garbing is required.
53. Are eye glasses required to be sterilized before
entering the clean room?
No.
54. Do healthcare practitioners preparing immediate use
parenteral products need to gown up, including gloves and mask?
No. Immediate use compounding is exempt from all
requirements of the Chapter. That does not preclude the process of
performing scrupulous hand hygiene and adhering to appropriate proper
aseptic compounding technique.
55. Is gowning required even in an isolator? Should the
isolator be located in a specific cleanroom?
See question 52. If the isolator does not meet the
requirements set forth in the Chapter for maintenance of ISO Class 5
conditions during dynamic use, then yes, it must be placed in an ISO
Class 7 environment (i.e. clean room) and gowning is required.
56. What do you consider sterile gloves? Do they have to be
individually wrapped or can they be those that come with multiple gloves
in a box?
As a rule, individually packaged gloves are considered
sterile, single use and labeled as such. Multiple gloves in a box are
generally not considered sterile once opened for use.
57. Are face covers required only for beards or do all
personnel male and female need to cover their mouth and nose?
Face masks (that adequately cover the mouth and nose) are
required for ALL compounding personnel.
58. If a glove is torn during compounding, do you have to
wash your hands again before re-gloving?
It is not necessary to do a hand cleansing with soap and
water within 30 seconds, but the hands should be re-sanitized using the
alcohol-based (waterless) surgical hand antiseptic agent.
59. Do we need to garb before cleaning the ante-area?
The need to garb before cleaning the ante-area is dependent
on the organization's policies and procedures. One should consider
requiring full garbing and gowning if the period of time spent in the
ante-area is of a longer duration (i.e. cleaning, stocking, etc.).
60. Can the gown be left in the ante area?
Yes.
61. Are we required to sterilize the lint free clothing?
No.
62. Are sterile chemotherapy gloves available?
None known at this time, but according to an authority at
NIOSH depending on the material used, double gloving with sterile gloves
made of nitrile or neoprene can be used in lieu of sterile chemo gloves.
63. If a vertical BSC (which is half-covered with glass in
the front) is used, do we have to use full mask and face shields?
The wearing of a face mask is required if the BSC is
located in one's clean room. A face shield is not required.
64. Must any headgear (including religious headgear) be
totally covered by a cap in the clean room?
Yes.
65. Are masks required in the ante-area? It was our
understanding that masks were only required in the clean room and buffer
area.
The need to wear masks in the ante-area is dependent on the
organization's policies and procedures. One should consider requiring
full garbing and gowning if the period of time spent in the ante-area is
of a longer duration (i.e. cleaning, stocking, etc.).
66. During cleaning of our biological safety cabinets our
operators wear N95 masks. Should other personnel in the clean room also
take exposure precautions?
Yes, if compounding is occurring during the cleaning of the
BSC. Optimally, cleaning of the BSC should occur when no other activity
is occurring in the clean room.
67. If humans are the greatest risk in the compounding of
IVs, why not consider secondary gowning requirements?
While the individual compounding is the greatest source of
contamination, the environment does contribute to a certain degree.
Appropriate use of PEC's along with the appropriate use of sterile
gloves, routine disinfection of those gloves and technique should result
or maintain a sterile CSP.
68. Please speak to the need for further
verification/validation of automated compounding devices when the
manufacturer states that calibration is the only necessary step?
Periodic additional verification/validation of the
automated compounding device ensures that the calibration and use
process result in the stated product (volume, contents, etc.) being
prepared.
69. If hazardous drugs are non-sterile does the requirement
to use an ISO Class 7 ante-area apply?
Hazardous non-sterile drugs used to compound non-sterile
dosage forms such as oral capsules or liquids and topical ointments
(among others) should also be handled in a manner to prevent
contamination of healthcare workers and others. Personnel protective
equipment (PPE) such as gloves should be worn when handling hazardous
drugs. Compounding hazardous drugs that are in powder form may require
the use of a device to control and contain powder that could become
airborne; a fume hood or similar device vented to the outside may be
satisfactory. An ISO Class 7 ante area is not required for preparing
non-sterile compounded preparations.
70. Can CACI that meets the negative pressure requirement
be used if it is placed in a regular room or does the negative pressure
CACI need to be placed in a separate negative pressure room?
The CACI shall be placed in a separate negative pressure
room. The ISO Class 5 (see Pharmacists' Pharmacopeia, Table 1, page 797)
BSC or CACI shall be placed in an ISO Class 7 (see Table 1 above) area
that is physically separated (i.e., a different area from other
preparation areas) and optimally has not less than 0.01- inch water
column negative pressure to adjacent positive pressure ISO Class 7 (see
Table 1 above) or better ante-areas, thus providing inward airflow to
contain any airborne drug. However, in facilities that prepare a low
volume of hazardous drugs, the use of two tiers of containment (example:
closed-system vial-transfer device within a BSC or CACI that is located
in a non-negative pressure room) is acceptable.
71. Do hazardous drugs need to be stored in a separate room
to meet the air changes standard?
Hazardous drugs may be stored in the same negative pressure
room as the CACI or BSC.
72. Does the storage standard apply to all hazardous drugs
or just the chemo agents?
It applies to all hazardous drugs. If documented
information becomes available as to the safety of storage and handling
of specific drugs, it may be possible to store them in standard storage
areas.
73. Should the room be negative pressure if you have a room
with a horizontal flow hood and a vertical flow hood for hazardous
drugs?
As stated in chapter <797>, hazardous drugs shall be
prepared in a negative pressure room. All hoods and procedures used in
the room should be designed for proper operation in the negative
pressure environment unless the situation allows for the low volume
exception in the chapter. A second-tier of containment (e.g., CSTD)
would be required when a BSC is located in a positive-pressure ISO Class
7 buffer area.
74. In a satellite pharmacy that compounds hazardous
medications, is an ante-area necessary if compounding is done in a CACI
that is vented to the outside located in a negative pressure room?
Ideally, yes. The reasoning here is that under most cases
patients being treated with these hazardous drugs are immune-compromised
and the extra sterility precaution is needed for their protection.
However, in facilities that prepare a low volume of hazardous drugs, the
use of two tiers of containment (example: closed-system vial-transfer
device within a BSC or CACI that is located in a non-negative pressure
room) without the use of an ante-area or buffer room is also permitted
in Chapter <797>.
75. If the CACI does not exchange air with the room that it
is placed in, does it have to be vented?
The issue with a CACI that does not vent to the outside is
that volatile substances (hazardous drugs) can build up inside the CACI
and contaminate the outside of IV bags, etc. thus increasing the
potential to bring contamination outside the CACI. All BSC's and CACI's
should be vented.
76. Can you explain what a "closed-system vial transfer
device (CSTD)" is?
A Closed System Vial Transfer Device is a generic term used
to describe a device that does not allow any substance to escape outside
the vial or bag during the transfer process. This will include vapors,
liquids, powders, etc. The system should be totally closed. An air vent
is not considered a closed system even if the vent includes a 0.22
micron filter.
77. How do you certify staff compounding cytotoxic agents?
Are there any guidelines?
There are many commercial certification programs available,
but a self-designed program may also be sufficient as long as all
criteria are met and personnel are continually evaluated. There are test
kits available to verify technique using fluorescein as a marker which
may be a method of annual evaluation of personnel.
78. If a pharmacy does a very limited number of chemos
using CSTD, why do they have to store drugs in (-) pressure?
No matter how few the doses prepared, the drugs are still
hazardous and should be stored properly to protect personnel working in
the area. However, USP <797> states "Thus storage is preferably within a
containment area such as a negative pressure room".
79. Does USP 797 require that hospitals maintain separate
ante-area/clean room environments for chemotherapy preparations and
non-chemotherapy preparations? In other words, for a hospital that makes
both types of therapies, do they need to have two production
environments that are independently certified?
Hazardous drugs should be prepared in an ISO class 5 BSC or
CACI that is placed in an ISO class 7 area that is physically separated
(i.e., a different area from other preparation areas). Separate areas
are needed for non-hazardous compounding and hazardous compounding. The
exception being for facilities in which hazardous compounding is
low-volume.
80. If a nuclear medicine tech prepares a kit from a Tc99m
standard preparation sent from a radiopharmacy, would this be considered
Immediate Use if it is a single dose? If multiple doses is it considered
Low Risk? 12 hr. BUD?
The classification of a radiopharmaceutical kit prepared by
a technologist using Technetium 99m Sodium Pertechnetate sent from a
radiopharmacy depends upon the environment that is used for its
preparation. The kit can be prepared in worse than ISO Class 5
conditions if it is intended for a single dose use within one hour of
its preparation. In this case, the technologist must comply with the six
conditions specified in the Immediate-Use CSPs category. Also, the
prepared radiopharmaceutical kit should not be stored for any
anticipated needs.
The kit may be used for multiple doses if it is prepared as a Low-Risk
Level CSP with 12-Hour or Less BUD in a segregated compounding area or
better environment by a technologist that is properly prepped and
garbed.
81. For radiopharmaceuticals, should the bubble point test
be performed before and after filtration or just after?
The bubble point test should be performed after the
filtration of radiopharmaceuticals. Precautions to control radioactive
contamination and to maintain radiation exposures to As Low As
Reasonably Achievable (ALARA) must be in place.
82. Under what circumstances can radiopharmaceuticals be
used beyond 12 hours?
The determination of beyond-use times and beyond-use dates
(BUDs) for radiopharmaceuticals as CSPs are reviewed in USP 32 NF 27
General Chapter <797> under the heading Determining Beyond-Use-Dates. It
reads that "when CSPs deviate from conditions in the approved labeling
of manufactured products contained in CSPs, compounding personnel may
consult the manufacturer of particular products for advice on assigning
BUDs based on chemical and physical stability parameters." It continues
with "compounding personnel may refer to applicable publications to
obtain relevant stability, compatibility, and degradation information
regarding the drug or its congeners. When assigning a beyond-use-date,
compounding personnel should consult and apply drug specific and general
stability documentation and literature where available, and they should
consider the nature of the drug and its degradation mechanism, the
container in which it is packaged, the expected storage conditions and
the intended duration of therapy." This section also describes the
limitations of theoretical BUDs of CSPs based on predictions derived
from other evidence such as publications, charts and tables. The section
also explains that "truly valid evidence of stability for predicting
BUDs can be obtained only through product-specific experimental studies
... such as thin-layer chromatography."
The Determining Beyond-Use-Dates section also states that "the
compounding facility shall have written policies and procedures
governing the determination of the BUDs for all compounded products." It
requires that "The SOP manual of the compounding facility and each
specific CSP formula record shall describe the general basis used to
assign the BUD and storage conditions."
A BUD can be established by following the methods described in the
Determining Beyond-Use-Dates section of General Chapter <797>. An
experimental study method for establishing the stability of the
radiopharmaceutical would require the compounding facility to verify the
CSPs quality and purity under its preparation and storage conditions
that are routinely used. For Radiopharmaceuticals as CSPs, compounding
personnel must consider verifying at a minimum: the conditions of
preparation that go beyond approved labeling of the product, packaging
used, storage conditions, and that the CSP maintains sterility, the
appropriate limit for pyrogens for its route of administration, its
radiochemical purity, and its radionuclidic purity. (Refer to page 338
USP 32 NF 27 General Chapter <797>)
83. When using high risk non-nuclear components in
synthesis of PET preparations the components are prepared in a clean
room adjacent to the synthesis area. Does the chapter apply to the clean
room specifications and to the preparation of the non-nuclear component
preparations?
General Chapter <797> is superseded by USP 32 NF 27 General
Chapter Radiopharmaceuticals for Positron Emission Tomography –
Compounding <823>. The PET chapter contains a section titled - Control
of Components, Materials and Supplies, which indicates that "a
designated person shall be responsible for ensuring that activities are
carried out and completed properly." It further requires that such
person "determine that each batch of components, containers and
closures, materials, and supplies used for the compounding of PET
radiopharmaceuticals are in compliance with established written
specifications." If the written SOPs of the facility references General
Chapter <797>, it would apply. If a clean room is designated as the area
of preparation in the written SOPs of the facility it would have to meet
the definition of a Clean Room in General Chapter <797> and general
information chapter Microbiological Evaluation of Clean Rooms <1116>. In
any case, professional judgment for patient safety in regard to the
compounding environment for components used in a PET radiopharmaceutical
preparation must be used.
84. Are radiolabeled white blood cells medium or high risk?
It is difficult to categorize CSPs that are radiolabeled
blood components as medium or high risk-level CSPs. The blood component
could be considered a nonsterile ingredient. If considered so, the
labeling process would be a high-risk condition and guides for that
category would be used (e.g. OSHA regulation 29 CFR 1910.1030 Bloodborne
pathogens)
85. How long may sterile plastic caps, syringes, or devices
be stored in a class 5 environment after being opened?
These supplies and devices should only be opened just prior
to use. Any opened packages need to be protected from touch
contamination and must be stored in "first-air" and within the ISO Class
5 air at all times. The USP Chapter does not stipulate this time and it
is responsibility of the compounder to ensure the sterility of any
supply or device used when compounding CSPs.
86. How often does the endotoxin challenge test need to be
performed?
The effectiveness of EACH dry-heat depyrogenation cycle
needs to be verified with an endotoxin challenge test.
87. Can you incubate a plate too long?
Yes.
88. Are fingertip sampling and surface sampling required in
CAIs and CACIs?
Yes. Sampling should be incorporated into an overall
Quality Improvement Program that measures the competency of the worker
and the effectiveness of the cleaning and disinfection process.
89. For initial sampling, 3 samples with 0 CFU are required
but the table for Microbiological Action Levels sets the action level as
>3. Can you clarify the requirements for glove finger tip sampling?
The initial sampling is to demonstrate the training and
garbing competency of personnel training prior to compounding.
Compounding personnel must be able to don sterile gloves without
contaminating them. The action level of 3 is the maximum allowable CFUs
on gloves during actual compounding activities.
90. A pressure gauge is required to monitor the pressure
between the buffer area and the ante-area, and also between the
ante-area and the main pharmacy room. Does this mean that we need two
pressure gauges for the IV room?
Yes.
91. Is there a requirement to use a third party for
particle count sampling or can we do it ourselves?
The particle counting can be done by the pharmacy staff or
by someone brought in from the outside so long as they are deemed
competent to operate such equipment.
92. What additional filter integrity testing methods exist?
The appropriate HEPA filter integrity testing method is to
use an aerosol photometer with an appropriate oil-based challenge such
as PAO.
93. Are there USP Action Levels for non-viable counts?
See Pharmacists' Pharmacopeia Table 1, page 797.
94. Can we use the USP recommended action levels instead of
using historical data, if the USP levels are stricter?
If historical data are higher than USP levels, a qualified
microbiologist should be consulted to investigate the differential
between USP levels versus actual levels. Changes in cleaning agents or
frequency may be required to decrease the microbial bioburden in the
area being tested.
95. Are random glove finger tip cultures recommended or
mandatory? Could they be incorporated into the media fill procedures?
Glove finger tip cultures are required as a measurement of
operator competency, and incorporating them into the media fill
procedure would be an excellent aseptic technique proficiency test.
96. Are there specific recommendations for air samplers in
terms of sampler size, air volume, etc.?
Specific recommendations are not provided. The impaction
air sampler should be able to collect a sufficient volume (e.g., 1000
liters) within a reasonable amount of time.
97. Should all positive cultures be sent for microbial
identification?
Yes. The chapter states: "Regardless of the number of cfu
identified in the compounding facility, further corrective actions will
be dictated by the identification of microorganisms recovered (at least
the genus level) by an appropriate credentialed laboratory of any
microbial bioburden captured as a cfu using an impaction air sampler.
Highly pathogenic microorganisms (e.g., Gram-negative rods, coagulase
positive staphylococcus, molds and yeasts) can be potentially fatal to
patients receiving CSPs and shall be immediately remedied, regardless of
cfu count, with the assistance of a competent microbiologist, infection
control professional or industrial hygienist."
98. How do we demonstrate competency of personnel
performing environmental testing if we are performing our own
environmental testing using our own purchased equipment?
There are vendors who sell training programs and there are
commercial environmental microbiology labs that can be contacted for
assistance in validating the competency of personnel.
99. Our facility uses an automix compounder for macro
ingredients when compounding TPNs. This compounder is gravimetrically
based so it is only tested for weight accuracy daily. Do we need to test
it for volume accuracy?
You contact the manufacturer and ask them how to verify the
device's volume accuracy. USP Chapter <797> states: "The intermediate
precision of the ACD can be determined on the basis of the day-to-day
variations in performance of the accuracy measures. Thus, compounding
personnel shall keep a daily record of the above-described accuracy
assessments and review the results over time. This review shall occur at
least at weekly intervals to avoid potentially clinically significant
cumulative errors over time. This is especially true for additives with
a narrow therapeutic index, such as potassium chloride."
100. Is end product testing required for low and medium
risk preparations?
No.
101. If using manufactured single use filters for high risk
compounding do we need to test each filter before use? Do you test the
lot of filters purchased?
USP Chapter <797> states: "Filter units used to sterilize
CSPs shall also be subjected to manufacturers' recommended integrity
test, such as the bubble point test."
102. Should bubble-point testing be done for every high
risk CSP that is sterilized by filtration?
Yes, see the answer above for Question #103.
103. When monitoring temperatures and humidity in rooms,
what are the humidity ranges we need to be looking for?
Temperatures below 20°C (68° F). Specific guidance is not
provided in USP Chapter <797> for humidity but general practice is to
maintain the humidity between 35% and 60%.
104. If a hood certifying company would perform every six
month electronic air sampling, what would the facility need to do? Alert
the lab in advance to accept plates (if pharmacy doesn't have incubator)
or would company take plates to incubate?
This must be agreed upon between the certification company
and the pharmacy. It is the pharmacy's responsibility to assure a plan
is in place that properly accomplishes the required tasks.
105. Do positive and negative isolators need to be in
separate rooms and what defines separation?
Positive isolators are appropriate for non-hazardous
compounding and must be in a separate room from the negative pressure
isolator used for hazardous compounding unless the low-volume exception
applies. Separation is physical separation such as a separate room.
106. What do you do if action levels are exceeded in
environmental monitoring?
You use the data to assist in identification of the source
of contamination and then develop and execute a remediation plan.
107. What is the proper disposal of culture media after
exposure and incubation?
Culture media should be autoclaved or discarded as
hazardous medical waste after exposure and incubation.
108. In a low volume (5-6 products per day) operation we
want to use one biologics hood. Can we move from hazardous to
nonhazardous when compounding these preparations?
USP <797> does not require nor forbid such a practice. The
decision is left up to each compounding site. However, whatever
procedures and practices are used, they should be designed to keep
personnel safe from exposure to drug contamination and keep the dose
safe from inadvertent microbial contamination. In addition, care must be
taken to prevent cross contamination from hazardous to nonhazardous such
as thorough cleaning of the hood, etc. Documentation such as wipe
studies can be conducted to make sure the hazardous drugs are being
contained.
109. How do we read the temperature listed in USP 797?
All temperatures in the USP and NF that lack a temperature
system abbreviation are degrees Celsius or Centigrade. When Fahrenheit
temperatures are used, they are in parentheses after Celsius or
Centigrade temperatures, and include the F designation. For example,
from the General Notices and Requirements, Cold – between 2° and 8° (36°
and 46° F).
110. We have recently purchased barrier isolators. These
hoods have an ISO Class 100 environment. Per the newest revisions what
is the maximum sterility/stability time for chemotherapeutic agents
compounded in this way?
The sterility storage durations for all CSPs depends on the
conditions under which they were prepared. The answer to follow assumes
that chemotherapeutic agents mean Hazardous Drugs by NIOSH definition.
Hazardous Drugs as CSPs are not permitted under the conditions of
Immediate-Use CSPs and Low-Risk Level CSPs with 12-Hour or Less BUD. The
sterility storage durations for Hazardous Drug compounded according to
the conditions for Low-Risk Level CSPs are 48 hours at controlled room
temperature (see USP General Notices and Requirements), 14 days at cold
temperature (see USP General Notices and Requirements), and 45 days in
solid frozen state between -25° and -10° in the absence of direct
sterility testing evidence that supports longer BUDs.
111. We compound all 3 risk levels of products. If we
compound high-risk products, are we required to do viable air sampling
monthly using an impaction device? I was under the impression that 797
requires this sampling every 6 months.
USP requires minimum sampling every 6 months. You should
evaluate your facility and trend your data to assure every 6 months is
adequate.
112. What physical objects are allowed to be in the clean
room, such as floor mats, printers, pens, markers, shelving, etc.? Does
alcohol have to be 70% IPA to disinfect the technician's gloves?
There is no prohibition to particular objects, devices, and
materials in clean rooms or buffer areas. The presence of such items
must be verified according to the Environmental Testing and Surface
Sampling standards to maintain the air and surface quality required for
these compounding areas. All 70% IPA used to disinfect the gloves of
compounding personnel and critical sites, such as vial stoppers and
ampul necks, must be sterile.
113. Commercial sterile empty vials are used by compounders
to be the packaging for sterile products. The practice is to inject the
sterile drug into the empty sterile vials. This results in a vial with a
punctured stopper and is usually sealed with a foil seal and given a BUD
in accordance with the 4 limits of low, medium, or high risk
compounding. Once a commercial sterile vial is punctured is it
considered a single use vial or can the defaults for low, medium, and
high risk BUD be used in absence of stability and sterility data?
The general notices section of USP 32 defines a
multiple-dose container as "a multiple-unit container for articles
intended for parenteral administration only". According to the same
section, "a multiple-unit container is a container that permits
withdrawal of successive portions of the contents without changing the
strength, quality, or purity of the remaining portion." Since stability
and sterility data are not available, it should be considered a
single-dose container.
114. Are BSCs and CACIs that re-circulate air within a room
after filtering through HEPA filters (versus venting to the outside)
completely prohibited in the revised USP 797 standard?
When preparing hazardous drugs, the answer is yes. All
BSC's CACI's must be vented to the outside. Utilization of
re-circulating BSC's or CACI's for non-hazardous CSI preparation is
acceptable.
115. Is a written examination required for personnel
training or would a verbal exam be enough?
Yes, a written competence assessment is required. <797>
states "Compounding personnel shall complete didactic training, pass
written competence assessments, undergo skill assessment using
observational audit tools, and media-fill testing".
116. If dispensing to patients, who then have the CSP
administered by a visiting nurse, is the pharmacy required to provide
formal education to the nurse or to the patient?
The patient and the nurse must both be educated. A formal
training program is provided as a means to ensure understanding and
compliance with the many special and complex responsibilities placed on
the patient or caregiver for the storage, handling, and administration
of CSPs. There are 12 instructional objectives given in the chapter and
at the conclusion of the training the patient or caregiver should,
correctly and consistently be able to perform them all. The compounding
facility, in conjunction with nursing or medical personnel, is
responsible for ensuring initially and on an ongoing basis that the
patient or caregiver understands, has mastered, and is capable of and
willing to comply with all of these home care responsibilities.
117. What protocol is recommended for compounding during
room certification? Should the technicians be working on actual
preparations?
When room certification is going on you have extra
equipment in the room and extra people. It would not be appropriate to
work on actual preparations but instead you may use that time to perform
a media fill which would be the very worst case scenario, or work using
expired drugs which are then destroyed. As long as it is a dynamic
situation with your people in the room going about normal tasks it is
fine. |
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